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Sample records for monogenic autosomal recessive

  1. Andhidrotic ectodermal dysplasia-autosomal recessive form

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    Inamadar Arun

    1994-01-01

    Full Text Available Anhidrotic ectodermal dysplasia with classical features in 2 sisters is reported. The mode of inheritance in these seems to be autosomal recessive; which is a very rare occurrence.

  2. New autosomal recessive faciodigitogenital syndrome.

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    Teebi, A S; Naguib, K K; Al-Awadi, S; Al-Saleh, Q A

    1988-01-01

    Most pedigrees of Aarskog's faciodigitogenital syndrome have suggested X linked inheritance. However, sex influenced autosomal dominant inheritance is also a possibility in some families. We describe an Arab family of normal consanguineous parents with five children (three males and two females) with some features of Aarskog syndrome in addition to some unusual hair changes. The possibility that this family represents a distinct previously unrecognised faciodigitogenital syndrome with short s...

  3. Autosomal recessive Charcot-Marie-Tooth neuropathy.

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    Espinós, Carmen; Calpena, Eduardo; Martínez-Rubio, Dolores; Lupo, Vincenzo

    2012-01-01

    Charcot-Marie-Tooth (CMT) disease, a hereditary motor and sensory neuropathy that comprises a complex group of more than 50 diseases, is the most common inherited neuropathy. CMT is generally divided into demyelinating forms, axonal forms and intermediate forms. CMT is also characterized by a wide genetic heterogeneity with 29 genes and more than 30 loci involved. The most common pattern of inheritance is autosomal dominant (AD), although autosomal recessive (AR) forms are more frequent in Mediterranean countries. In this chapter we give an overview of the associated genes, mechanisms and epidemiology of AR-CMT forms and their associated phenotypes.

  4. Pregnancy in autosomal recessive polycystic kidney disease.

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    Banks, Nicole; Bryant, Joy; Fischer, Roxanne; Huizing, Marjan; Gahl, William A; Gunay-Aygun, Meral

    2015-03-01

    Autosomal recessive polycystic kidney disease (ARPKD) is the most common childhood-onset ciliopathy. As treatments improve, more women are reaching reproductive age, but little is known about ARPKD and pregnancy. In our ongoing study on ARPKD and other ciliopathies, 12 females over 18 years of age were identified and systematically evaluated. Six had children; four carried pregnancies and delivered, one used assisted reproductive technology and had a surrogate carry the pregnancy, and one adopted. We report the outcomes of four pregnancies with live birth deliveries and two women who chose alternate family building options. Patient one was diagnosed at 6 months, and at age 21 had a pregnancy complicated by transient worsening of renal function (creatinine increase from 1.15 to 1.78 mg/dL). Patient two was diagnosed with ARPKD at age seven and had an uncomplicated pregnancy at age 23. Patient three was diagnosed incidentally with ARPKD at age 23, 3 months after completion of an uncomplicated pregnancy. Patient four who had an uncomplicated pregnancy at age 33 was diagnosed with ARPKD at age 46. Women with ARPKD face reproductive decisions largely bereft of information about the pregnancies of other ARPKD patients. We report four cases of pregnancy and ARPKD to expand current knowledge and encourage further research.

  5. Genetics Home Reference: autosomal recessive congenital stationary night blindness

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    ... collapse boxes. Description Autosomal recessive congenital stationary night blindness is a disorder of the retina , which is the specialized tissue at the back of the eye that detects light and color. People with this condition typically have difficulty seeing ...

  6. SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis

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    Orlacchio, Antonio; Babalini, Carla; Borreca, Antonella; Patrono, Clarice; Massa, Roberto; Basaran, Sarenur; Munhoz, Renato P.; Rogaeva, Ekaterina A.; St George-Hyslop, Peter H.; Bernardi, Giorgio; Kawarai, Toshitaka

    2010-01-01

    The mutation of the spatacsin gene is the single most common cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum. Common clinical, pathological and genetic features between amyotrophic lateral sclerosis and hereditary spastic paraplegia motivated us to investigate 25 families with autosomal recessive juvenile amyotrophic lateral sclerosis and long-term survival for mutations in the spatascin gene. The inclusion criterion was a diagnosis of clinically definite ...

  7. Evidence for nonallelic genetic heterogeneity in autosomal recessive retinitis pigmentosa

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    Bleeker-Wagemakers, L. M.; Gal, A.; Kumar-Singh, R.; van den Born, L. I.; Li, Y.; Schwinger, E.; Sandkuijl, L. A.; Bergen, A. A.; Kenna, P.; Humphries, P.

    1992-01-01

    Recent evidence suggesting the involvement of mutant rhodopsin proteins in the pathogenesis of autosomal recessive retinitis pigmentosa has prompted us to investigate whether this form of the disease shows non-allelic genetic heterogeneity, as has previously been shown to be the case in autosomal

  8. Unilateral Autosomal Recessive Anophthalmia in a Patient with Cystic Craniopharyngioma

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    Kumar, Amandeep; Bansal, Ankit; Garg, Ajay; Sharma, Bhawani S.

    2014-01-01

    Abstract Anophthalmia is a rare ocular malformation. It is a genetically determined disorder and is typically associated with syndromes. However, sporadic nonsyndromic familial as well as non-familial cases of anophthalmia have also been reported. Non-syndromic familial cases are usually bilateral and have been attributed to autosomal recessive, autosomal dominant, and X-linked inheritance patterns. The authors hereby report a rare case of autosomal recessive unilateral anophthalmia in a patient with no other associated congenital anomaly. Patient was operated for craniopharyngioma. The clinical, radiological and intraoperative findings are discussed. PMID:27928292

  9. Autosomal recessive anhidrotic ectodermal dysplasia: A rare entity

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    Sangita Ghosh

    2014-01-01

    Full Text Available We describe a case of anhidrotic ectodermal dysplasia (AED with an autosomal recessive mode of inheritance, a very rare entity, in a 2-year-old female child of two asymptomatic, consanguineous parents. Their previous child also had a similar condition. Autosomal recessive AED (AR-AED can have its full expression both in males and females and it is clinically indistinguishable from the x-linked recessive AED (XL-AED, which is the most common type of ectodermal dysplasia. Unlike the partially symptomatic carriers of XL-AED, the heterozygotes of AR-AED are phenotypically asymptomatic.

  10. Autosomal Recessive Polycystic Kidney Disease: Antenatal Diagnosis and Histopathological Correlation

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    Dayananda Kumar Rajanna

    2013-01-01

    Full Text Available Autosomal recessive polycystic kidney disease (ARPKD is one of the most common inheritable disease manifesting in infancy and childhood with a frequency of 1:6,000 to 1:55,000 births. The patient in her second trimester presented with a history of amenorrhea. Ultrasound examination revealed bilateral, enlarged, hyperechogenic kidneys, placentomegaly, and severe oligohydramnios. The pregnancy was terminated. An autopsy was performed on the fetus. Both the kidneys were found to be enlarged and the cut surface showed numerous cysts. The liver sections showed changes due to fibrosis. The final diagnosis of autosomal recessive polycystic kidney disease was made based on these findings. In this article, we correlate the ante-natal ultrasound and histopathological findings in autosomal recessive polycystic kidney disease.

  11. Two novel mutations in ILDR1 gene cause autosomal recessive ...

    Indian Academy of Sciences (India)

    In a recent screening programme on hearing loss (HL), we examined 17 common autosomal recessive nonsyndromic hearing loss (ARNSHL) genes in every consanguineous Ira- nian family with ARNSHL that was referred to our centre. We first screened GJB2 mutations and then utilized a panel of three to four short ...

  12. SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis.

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    Orlacchio, Antonio; Babalini, Carla; Borreca, Antonella; Patrono, Clarice; Massa, Roberto; Basaran, Sarenur; Munhoz, Renato P; Rogaeva, Ekaterina A; St George-Hyslop, Peter H; Bernardi, Giorgio; Kawarai, Toshitaka

    2010-02-01

    The mutation of the spatacsin gene is the single most common cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum. Common clinical, pathological and genetic features between amyotrophic lateral sclerosis and hereditary spastic paraplegia motivated us to investigate 25 families with autosomal recessive juvenile amyotrophic lateral sclerosis and long-term survival for mutations in the spatascin gene. The inclusion criterion was a diagnosis of clinically definite amyotrophic lateral sclerosis according to the revised El Escorial criteria. The exclusion criterion was a diagnosis of hereditary spastic paraplegia with thin corpus callosum in line with an established protocol. Additional pathological and genetic evaluations were also performed. Surprisingly, 12 sequence alterations in the spatacsin gene (one of which is novel, IVS30 + 1 G > A) were identified in 10 unrelated pedigrees with autosomal recessive juvenile amyotrophic lateral sclerosis and long-term survival. The countries of origin of these families were Italy, Brazil, Canada, Japan and Turkey. The variants seemed to be pathogenic since they co-segregated with the disease in all pedigrees, were absent in controls and were associated with amyotrophic lateral sclerosis neuropathology in one member of one of these families for whom central nervous system tissue was available. Our study indicates that mutations in the spatascin gene could cause a much wider spectrum of clinical features than previously recognized, including autosomal recessive juvenile amyotrophic lateral sclerosis.

  13. Exome Sequencing and Directed Clinical Phenotyping Diagnose Cholesterol Ester Storage Disease Presenting as Autosomal Recessive Hypercholesterolemia

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    Stitziel, Nathan O.; Fouchier, Sigrid W.; Sjouke, Barbara; Peloso, Gina M.; Moscoso, Alessa M.; Auer, Paul L.; Goel, Anuj; Gigante, Bruna; Barnes, Timothy A.; Melander, Olle; Orho-Melander, Marju; Duga, Stefano; Sivapalaratnam, Suthesh; Nikpay, Majid; Martinelli, Nicola; Girelli, Domenico; Jackson, Rebecca D.; Kooperberg, Charles; Lange, Leslie A.; Ardissino, Diego; McPherson, Ruth; Farrall, Martin; Watkins, Hugh; Reilly, Muredach P.; Rader, Daniel J.; de Faire, Ulf; Schunkert, Heribert; Erdmann, Jeanette; Samani, Nilesh J.; Charnas, Lawrence; Altshuler, David; Gabriel, Stacey; Kastelein, John J. P.; Defesche, Joep C.; Nederveen, Aart J.; Kathiresan, Sekar; Hovingh, G. Kees

    2013-01-01

    Objective Autosomal recessive hypercholesterolemia is a rare inherited disorder, characterized by extremely high total and low-density lipoprotein cholesterol levels, that has been previously linked to mutations in LDLRAP1. We identified a family with autosomal recessive hypercholesterolemia not

  14. Autosomal recessive osteopetrosis with a unique imaging finding: multiple encephaloceles

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    Saglam, Dilek; Bilgici, Meltem Ceyhan; Bekci, Tuemay; Albayrak, Canan; Albayrak, Davut

    2017-01-01

    Osteopetrosis is a hereditary form of sclerosing bone dysplasia with various radiological and clinical presentations. The autosomal recessive type, also known as malignant osteopetrosis, is the most severe type, with the early onset of manifestations. A 5-month-old infant was admitted to our hospital with recurrent respiratory tract infections. Chest X-ray and skeletal survey revealed the classic findings of osteopetrosis, including diffuse osteosclerosis and bone within a bone appearance. At follow-up, the patient presented with, thickened calvarium, multiple prominent encephaloceles, and dural calcifications leading to the intracranial clinical manifestations with bilateral hearing and sight loss. Autosomal recessive osteopetrosis is one of the causes of encephaloceles and this finding may become dramatic if untreated. (orig.)

  15. Autosomal recessive osteopetrosis with a unique imaging finding: multiple encephaloceles

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    Saglam, Dilek; Bilgici, Meltem Ceyhan; Bekci, Tuemay [Ondokuz Mayis University, Department of Radiology, School of Medicine, Kurupelit, Samsun (Turkey); Albayrak, Canan; Albayrak, Davut [Ondokuz Mayis University, Department of Pediatrics, School of Medicine, Kurupelit, Samsun (Turkey)

    2017-05-15

    Osteopetrosis is a hereditary form of sclerosing bone dysplasia with various radiological and clinical presentations. The autosomal recessive type, also known as malignant osteopetrosis, is the most severe type, with the early onset of manifestations. A 5-month-old infant was admitted to our hospital with recurrent respiratory tract infections. Chest X-ray and skeletal survey revealed the classic findings of osteopetrosis, including diffuse osteosclerosis and bone within a bone appearance. At follow-up, the patient presented with, thickened calvarium, multiple prominent encephaloceles, and dural calcifications leading to the intracranial clinical manifestations with bilateral hearing and sight loss. Autosomal recessive osteopetrosis is one of the causes of encephaloceles and this finding may become dramatic if untreated. (orig.)

  16. Autosomal recessive progressive myoclonus epilepsy due to impaired ceramide synthesis.

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    Ferlazzo, Edoardo; Striano, Pasquale; Italiano, Domenico; Calarese, Tiziana; Gasparini, Sara; Vanni, Nicola; Fruscione, Floriana; Genton, Pierre; Zara, Federico

    2016-09-01

    Autosomal recessive progressive myoclonus epilepsy due to impaired ceramide synthesis is an extremely rare condition, so far reported in a single family of Algerian origin presenting an unusual, severe form of progressive myoclonus epilepsy characterized by myoclonus, generalized tonic-clonic seizures and moderate to severe cognitive impairment, with probable autosomal recessive inheritance. Disease onset was between 6 and 16 years of age. Genetic study allowed to identify a homozygous nonsynonymous mutation in CERS1, the gene encoding ceramide synthase 1, a transmembrane protein of the endoplasmic reticulum (ER), catalyzes the biosynthesis of C18-ceramides. The mutation decreased C18-ceramide levels. In addition, downregulation of CerS1 in neuroblastoma cell line showed activation of ER stress response and induction of proapoptotic pathways. This observation demonstrates that impairment of ceramide biosynthesis underlies neurodegeneration in humans.

  17. Arrestin gene mutations in autosomal recessive retinitis pigmentosa.

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    Nakazawa, M; Wada, Y; Tamai, M

    1998-04-01

    To assess the clinical and molecular genetic studies of patients with autosomal recessive retinitis pigmentosa associated with a mutation in the arrestin gene. Results of molecular genetic screening and case reports with DNA analysis and clinical features. University medical center. One hundred twenty anamnestically unrelated patients with autosomal recessive retinitis pigmentosa. DNA analysis was performed by single strand conformation polymorphism followed by nucleotide sequencing to search for a mutation in exon 11 of the arrestin gene. Clinical features were characterized by visual acuity slitlamp biomicroscopy, fundus examinations, fluorescein angiography, kinetic visual field testing, and electroretinography. We identified 3 unrelated patients with retinitis pigmentosa associated with a homozygous 1-base-pair deletion mutation in codon 309 of the arrestin gene designated as 1147delA. All 3 patients showed pigmentary retinal degeneration in the midperipheral area with or without macular involvement. Patient 1 had a sibling with Oguchi disease associated with the same mutation. Patient 2 demonstrated pigmentary retinal degeneration associated with a golden-yellow reflex in the peripheral fundus. Patients 1 and 3 showed features of retinitis pigmentosa without the golden-yellow fundus reflex. Although the arrestin 1147delA has been known as a frequent cause of Oguchi disease, this mutation also may be related to the pathogenesis of autosomal recessive retinitis pigmentosa. This phenomenon may provide evidence of variable expressivity of the mutation in the arrestin gene.

  18. Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.

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    Johnston, Jennifer J; van der Smagt, Jasper J; Rosenfeld, Jill A; Pagnamenta, Alistair T; Alswaid, Abdulrahman; Baker, Eva H; Blair, Edward; Borck, Guntram; Brinkmann, Julia; Craigen, William; Dung, Vu Chi; Emrick, Lisa; Everman, David B; van Gassen, Koen L; Gulsuner, Suleyman; Harr, Margaret H; Jain, Mahim; Kuechler, Alma; Leppig, Kathleen A; McDonald-McGinn, Donna M; Can, Ngoc Thi Bich; Peleg, Amir; Roeder, Elizabeth R; Rogers, R Curtis; Sagi-Dain, Lena; Sapp, Julie C; Schäffer, Alejandro A; Schanze, Denny; Stewart, Helen; Taylor, Jenny C; Verbeek, Nienke E; Walkiewicz, Magdalena A; Zackai, Elaine H; Zweier, Christiane; Zenker, Martin; Lee, Brendan; Biesecker, Leslie G

    2018-02-22

    PurposeTo characterize the molecular genetics of autosomal recessive Noonan syndrome.MethodsFamilies underwent phenotyping for features of Noonan syndrome in children and their parents. Two multiplex families underwent linkage analysis. Exome, genome, or multigene panel sequencing was used to identify variants. The molecular consequences of observed splice variants were evaluated by reverse-transcription polymerase chain reaction.ResultsTwelve families with a total of 23 affected children with features of Noonan syndrome were evaluated. The phenotypic range included mildly affected patients, but it was lethal in some, with cardiac disease and leukemia. All of the parents were unaffected. Linkage analysis using a recessive model supported a candidate region in chromosome 22q11, which includes LZTR1, previously shown to harbor mutations in patients with Noonan syndrome inherited in a dominant pattern. Sequencing analyses of 21 live-born patients and a stillbirth identified biallelic pathogenic variants in LZTR1, including putative loss-of-function, missense, and canonical and noncanonical splicing variants in the affected children, with heterozygous, clinically unaffected parents and heterozygous or normal genotypes in unaffected siblings.ConclusionThese clinical and genetic data confirm the existence of a form of Noonan syndrome that is inherited in an autosomal recessive pattern and identify biallelic mutations in LZTR1.Genet Med advance online publication, 22 February 2018; doi:10.1038/gim.2017.249.

  19. Evidence for autosomal recessive inheritance in cerebral gigantism

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    Nevo, S.; Zeltzer, M.; Benderly, A.; Levy, J.

    1974-01-01

    Three cases of cerebral gigantism, two sibs and their double first cousin, are described in a large inbred family from Israel. Two of the three were observed and diagnosed at birth and two were followed for two years. They all presented the signs and symptoms considered typical of this syndrome, as well as some of the less frequent findings. Generalized oedema and flexion contractures of the feet were observed in two of the three at birth. This has not hitherto been reported in cases of cerebral gigantism, of whom only a few have been observed and diagnosed at birth. Autosomal recessive inheritance is clearly implied in this family. Images PMID:4841084

  20. Microcephaly-chorioretinopathy syndrome, autosomal recessive form. A case report

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    Rafael Fabiano Machado Rosa

    Full Text Available CONTEXT: The autosomal recessive form of microcephaly-chorioretinopathy syndrome is a rare genetic condition that is considered to be an important differential diagnosis with congenital toxoplasmosis.CASE REPORT: Our patient was a seven-year-old white boy who was initially diagnosed with congenital toxoplasmosis. However, his serological tests for congenital infections, including toxoplasmosis, were negative. He was the first child of young, healthy and consanguineous parents (fourth-degree relatives. The parents had normal head circumferences and intelligence. The patient presented microcephaly and specific abnormalities of the retina, with multiple diffuse oval areas of pigmentation and patches of chorioretinal atrophy associated with diffuse pigmentation of the fundus. Ophthalmological evaluations on the parents were normal. A computed tomography scan of the child's head showed slight dilation of lateral ventricles and basal cisterns without evidence of calcifications. We did not find any lymphedema in his hands and feet. He had postnatal growth retardation, severe mental retardation and cerebral palsy.CONCLUSIONS: The finding of chorioretinal lesions in a child with microcephaly should raise suspicions of the autosomal recessive form of microcephaly-chorioretinopathy syndrome, especially in cases with an atypical pattern of eye fundus and consanguinity. A specific diagnosis is essential for an appropriate clinical evaluation and for genetic counseling for the patients and their families.

  1. NDST1 missense mutations in autosomal recessive intellectual disability.

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    Reuter, Miriam S; Musante, Luciana; Hu, Hao; Diederich, Stefan; Sticht, Heinrich; Ekici, Arif B; Uebe, Steffen; Wienker, Thomas F; Bartsch, Oliver; Zechner, Ulrich; Oppitz, Cornelia; Keleman, Krystyna; Jamra, Rami Abou; Najmabadi, Hossein; Schweiger, Susann; Reis, André; Kahrizi, Kimia

    2014-11-01

    NDST1 was recently proposed as a candidate gene for autosomal recessive intellectual disability in two families. It encodes a bifunctional GlcNAc N-deacetylase/N-sulfotransferase with important functions in heparan sulfate biosynthesis. In mice, Ndst1 is crucial for embryonic development and homozygous null mutations are perinatally lethal. We now report on two additional unrelated families with homozygous missense NDST1 mutations. All mutations described to date predict the substitution of conserved amino acids in the sulfotransferase domain, and mutation modeling predicts drastic alterations in the local protein conformation. Comparing the four families, we noticed significant overlap in the clinical features, including both demonstrated and apparent intellectual disability, muscular hypotonia, epilepsy, and postnatal growth deficiency. Furthermore, in Drosophila, knockdown of sulfateless, the NDST ortholog, impairs long-term memory, highlighting its function in cognition. Our data confirm NDST1 mutations as a cause of autosomal recessive intellectual disability with a distinctive phenotype, and support an important function of NDST1 in human development. © 2014 Wiley Periodicals, Inc.

  2. Autosomal recessive mode of inheritance of a Coffin-Siris like syndrome.

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    Bonioli, E; Palmieri, A; Bertola, A; Bellini, C

    1995-01-01

    Autosomal recessive mode of inheritance of a Coffin-Siris like syndrome: Coffin-Siris syndrome is a rare mental retardation/multiple congenital anomalies syndrome; so far its pattern of inheritance is under debate. We report a child affected by this syndrome, the pedigree of which is consistent with autosomal recessive inheritance.

  3. Spectrum of Autosomal Recessive Congenital Ichthyosis in Scandinavia

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    Hellström Pigg, Maritta; Bygum, Anette; Gånemo, Agneta

    2016-01-01

    Autosomal recessive congenital ichthyosis (ARCI) represents a heterogeneous group of rare disorders of cornification with 3 major subtypes: harlequin ichthyosis (HI), lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE). A 4th subtype has also been proposed: pleomorphic...... ichthyosis (PI), characterized by marked skin changes at birth and subsequently mild symptoms. In nationwide screenings of suspected cases of ARCI in Denmark and Sweden, we identified 132 patients (age range 0.1-86 years) classified as HI (n = 7), LI (n = 70), CIE (n = 17) and PI (n = 38). At birth......-100%). A scoring (0-4) of ichthyosis/ery-thema past infancy showed widely different mean values in the subgroups: HI (3.2/3.1), LI (2.4/0.6), CIE (1.8/1.6), PI (1.1/0.3). Novel or recurrent mutations were found in 113 patients: TGM1 (n = 56), NIPAL4 (n = 15), ALOX12B (n = 15), ABCA12 (n = 8), ALOXE3 (n = 9), SLC27...

  4. Otologic Manifestations of Autosomal Recessive Congenital Ichthyosis in Children.

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    Martín-Santiago, A; Rodríguez-Pascual, M; Knöpfel, N; Hernández-Martín, Á

    2015-11-01

    Few studies have investigated ear involvement in nonsyndromic autosomal recessive congenital ichthyosis (ARCI). To assess the type and frequency of otologic manifestations of ARCI in patients under follow-up at the pediatric dermatology department of our hospital. We prospectively studied the presence of ear pain, ear itching, tinnitus, otitis, cerumen impaction, accumulation of epithelial debris, and hearing loss. Daily hygiene measures, topical treatments, medical-surgical interventions, and frequency of visits to an ear, nose, and throat (ENT) specialist were noted in the patients' medical records. Ear examination and hearing tests were performed in all cases. Ten patients were studied: 2 had a self-healing collodion baby phenotype and 8 had ichthyosis. There was mention of otologic manifestations in the records of all 8 patients with ichthyosis (100%); 6 of these patients (75%) had abnormalities in the external auditory canal examination and 2 (25%) had conductive hearing loss. Our findings are limited by the small number of patients studied, all of whom were younger than 19 years. The involvement of both dermatologists and ENT specialists in the management of patients with ichthyosis is crucial to ensure the application of the best therapeutic and preventive measures. More studies are needed to assess the prevalence and impact on quality of life of ear involvement in patients with ichthyosis and to determine the optimal interval between ENT visits for these patients. Copyright © 2015 Elsevier España, S.L.U. and AEDV. All rights reserved.

  5. Novel FAM20A mutation causes autosomal recessive amelogenesis imperfecta.

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    Volodarsky, Michael; Zilberman, Uri; Birk, Ohad S

    2015-06-01

    To relate the peculiar phenotype of amelogenesis imperfecta in a large Bedouin family to the genotype determined by whole genome linkage analysis. Amelogenesis imperfecta (AI) is a broad group of inherited pathologies affecting enamel formation, characterized by variability in phenotypes, causing mutations and modes of inheritance. Autosomal recessive or compound heterozygous mutations in FAM20A, encoding sequence similarity 20, member A, have been shown to cause several AI phenotypes. Five members from a large consanguineous Bedouin family presented with hypoplastic amelogenesis imperfecta with unerupted and resorbed permanent molars. Following Soroka Medical Center IRB approval and informed consent, blood samples were obtained from six affected offspring, five obligatory carriers and two unaffected siblings. Whole genome linkage analysis was performed followed by Sanger sequencing of FAM20A. The sequencing unravelled a novel homozygous deletion mutation in exon 11 (c.1523delC), predicted to insert a premature stop codon (p.Thr508Lysfs*6). We provide an interesting case of novel mutation in this rare disorder, in which the affected kindred is unique in the large number of family members sharing a similar phenotype. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Mutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa.

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    Arno, Gavin; Agrawal, Smriti A; Eblimit, Aiden; Bellingham, James; Xu, Mingchu; Wang, Feng; Chakarova, Christina; Parfitt, David A; Lane, Amelia; Burgoyne, Thomas; Hull, Sarah; Carss, Keren J; Fiorentino, Alessia; Hayes, Matthew J; Munro, Peter M; Nicols, Ralph; Pontikos, Nikolas; Holder, Graham E; Asomugha, Chinwe; Raymond, F Lucy; Moore, Anthony T; Plagnol, Vincent; Michaelides, Michel; Hardcastle, Alison J; Li, Yumei; Cukras, Catherine; Webster, Andrew R; Cheetham, Michael E; Chen, Rui

    2016-12-01

    Retinitis pigmentosa (RP) is the most frequent form of inherited retinal dystrophy. RP is genetically heterogeneous and the genes identified to date encode proteins involved in a wide range of functional pathways, including photoreceptor development, phototransduction, the retinoid cycle, cilia, and outer segment development. Here we report the identification of biallelic mutations in Receptor Expression Enhancer Protein 6 (REEP6) in seven individuals with autosomal-recessive RP from five unrelated families. REEP6 is a member of the REEP/Yop1 family of proteins that influence the structure of the endoplasmic reticulum but is relatively unstudied. The six variants identified include three frameshift variants, two missense variants, and a genomic rearrangement that disrupts exon 1. Human 3D organoid optic cups were used to investigate REEP6 expression and confirmed the expression of a retina-specific isoform REEP6.1, which is specifically affected by one of the frameshift mutations. Expression of the two missense variants (c.383C>T [p.Pro128Leu] and c.404T>C [p.Leu135Pro]) and the REEP6.1 frameshift mutant in cultured cells suggest that these changes destabilize the protein. Furthermore, CRISPR-Cas9-mediated gene editing was used to produce Reep6 knock-in mice with the p.Leu135Pro RP-associated variant identified in one RP-affected individual. The homozygous knock-in mice mimic the clinical phenotypes of RP, including progressive photoreceptor degeneration and dysfunction of the rod photoreceptors. Therefore, our study implicates REEP6 in retinal homeostasis and highlights a pathway previously uncharacterized in retinal dystrophy. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  7. Autosomal recessive type II hereditary motor and sensory neuropathy with acrodystrophy.

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    Thomas, P K; Claus, D; King, R H

    1999-02-01

    A family is described with presumed autosomal recessive inheritance in which three siblings developed a progressive neuropathy that combined limb weakness and severe distal sensory loss leading to prominent mutilating changes. Electrophysiological and nerve biopsy findings indicated an axonopathy. The disorder is therefore classifiable as type II hereditary motor and sensory neuropathy (HMSN II). The clinical features differ from those reported in previously described cases of autosomal recessive HMSN II. This disorder may therefore represent a new variant.

  8. Autosomal recessive retinitis pigmentosa with RP1 mutations is associated with myopia

    NARCIS (Netherlands)

    Chassine, T.; Bocquet, B.; Daien, V.; Avila-Fernandez, A.; Ayuso, C.; Collin, R.W.J.; Corton, M.; Hejtmancik, J.F.; Born, L.I. van den; Klevering, B.J.; Riazuddin, S.A.; Sendon, N.; Lacroux, A.; Meunier, I.; Hamel, C.P.

    2015-01-01

    OBJECTIVE: To determine the refractive error in patients with autosomal recessive retinitis pigmentosa (arRP) caused by RP1 mutations and to compare it with that of other genetic subtypes of RP. METHODS: Twenty-six individuals had arRP with RP1 mutations, 25 had autosomal dominant RP (adRP) with RP1

  9. Progeria (Hutchison - Gilford syndrome in siblings: In an autosomal recessive pattern of inheritance

    Directory of Open Access Journals (Sweden)

    Raghu Tanjore

    2001-09-01

    Full Text Available Progeria is an autosomal dominant, premature aging syndrome. Six and three year old female siblings had sclcrodermatous changes over the extremities, alopecia, beaked nose, prominent veins and bird-like facies. Radiological features were consistent with features of progeria. The present case highlights rarity of progeria in siblings with a possible autosomal recessive pattern.

  10. Genetic Counselors' Experiences Regarding Communication of Reproductive Risks with Autosomal Recessive Conditions found on Cancer Panels.

    Science.gov (United States)

    Mets, Sarah; Tryon, Rebecca; Veach, Patricia McCarthy; Zierhut, Heather A

    2016-04-01

    The development of hereditary cancer genetic testing panels has altered genetic counseling practice. Mutations within certain genes on cancer panels pose not only a cancer risk, but also a reproductive risk for autosomal recessive conditions such as Fanconi anemia, constitutional mismatch repair deficiency syndrome, and ataxia telangiectasia. This study aimed to determine if genetic counselors discuss reproductive risks for autosomal recessive conditions associated with genes included on cancer panels, and if so, under what circumstances these risks are discussed. An on-line survey was emailed through the NSGC list-serv. The survey assessed 189 cancer genetic counselors' experiences discussing reproductive risks with patients at risk to carry a mutation or variant of uncertain significance (VUS) in a gene associated with both an autosomal dominant cancer risk and an autosomal recessive syndrome. Over half (n = 82, 55 %) reported having discussed reproductive risks; the remainder (n = 66, 45 %) had not. Genetic counselors who reported discussing reproductive risks primarily did so when patients had a positive result and were of reproductive age. Reasons for not discussing these risks included when a patient had completed childbearing or when a VUS was identified. Most counselors discussed reproductive risk after obtaining results and not during the informed consent process. There is inconsistency as to if and when the discussion of reproductive risks is taking place. The wide variation in responses suggests a need to develop professional guidelines for when and how discussions of reproductive risk for autosomal recessive conditions identified through cancer panels should occur with patients.

  11. A novel NR2E3 gene mutation in autosomal recessive retinitis pigmentosa with cystic maculopathy

    OpenAIRE

    Mahajan, D.; Votruba, Marcela

    2017-01-01

    NR2E3 is a gene that encodes for photoreceptor cell specific nuclear receptor, which is involved in cone proliferation. The splice site mutation 119-2A>C in NR2E3 (15q23) has been previously reported to underlie recessive enhanced cone S sensitivity syndrome, clumped pigmentary retinal degeneration, Goldman-Favre syndrome and also autosomal dominant and autosomal recessive retinitis pigmentosa (RP). However, the mutation c 571 + 2 T > C in NR2E3 has not been previously reported with retinal d...

  12. Phenotypic spectrum of autosomal recessive cone-rod dystrophies caused by mutations in the ABCA4 (ABCR) gene.

    NARCIS (Netherlands)

    Klevering, B.J.; Blankenagel, A.; Maugeri, A.; Cremers, F.P.M.; Hoyng, C.B.; Rohrschneider, K.

    2002-01-01

    PURPOSE: To describe the phenotype of 12 patients with autosomal recessive or isolated cone-rod types of progressive retinal degeneration (CRD) caused by mutations in the ABCA4 gene. METHODS: The charts of patients who had originally received a diagnosis of isolated or autosomal recessive CRD were

  13. A Dutch family with autosomal recessively inherited lower motor neuron predominant motor neuron disease due to optineurin mutations

    NARCIS (Netherlands)

    Beeldman, Emma; van der Kooi, Anneke J.; de Visser, Marianne; van Maarle, Merel C.; van Ruissen, Fred; Baas, Frank

    2015-01-01

    Approximately 10% of motor neuron disease (MND) patients report a familial predisposition for MND. Autosomal recessively inherited MND is less common and is most often caused by mutations in the superoxide dismutase 1 (SOD1) gene. In 2010, autosomal recessively inherited mutations in the optineurin

  14. Congenital myotonic myopathy in the miniature schnauzer: an autosomal recessive trait.

    Science.gov (United States)

    Vite, C H; Melniczek, J; Patterson, D; Giger, U

    1999-01-01

    Myotonia is a clinical sign characterized by a delay in skeletal muscle relaxation following electrical or mechanical stimulation. A series of related miniature schnauzer dogs with congenital myotonic myopathy were studied. A composite pedigree of six affected litters and the results of a planned breeding between two affected animals are consistent with an autosomal recessive mode of inheritance.

  15. Identification of Mutations in SDR9C7 in 6 Families with Autosomal Recessive Congenital Ichthyosis

    DEFF Research Database (Denmark)

    Hotz, A; Fagerberg, C; Vahlquist, A

    2018-01-01

    Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization. To date, ARCI has been associated with following genes: ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, TGM1, PNPLA1 and recently SDR9C7 and SULT2B1.(1-6) Furthermore, seven patients from...

  16. Autosomal recessive ichthyosis with hypotrichosis syndrome: further delineation of the phenotype

    NARCIS (Netherlands)

    Avrahami, L.; Maas, S.; Pasmanik-Chor, M.; Rainshtein, L.; Magal, N.; Smitt, J. H. S.; van Marle, J.; Shohat, M.; Basel-Vanagaite, L.

    2008-01-01

    Autosomal recessive ichthyosis with hypotrichosis (ARIH) syndrome, which is characterized by congenital ichthyosis, abnormal hair and corneal involvement, has recently been shown in one consanguineous Israeli Arab family to be caused by a mutation in the ST14 gene, which encodes serine protease

  17. New parkin mutations and atypical phenotypes in families with autosomal recessive parkinsonism.

    NARCIS (Netherlands)

    Rawal, N.; Periquet, M.; Lohmann, E.; Lucking, C.B.; Teive, H.; Ambrosio, G.; Raskin, S.; Lincoln, S.; Hattori, N.; Guimaraes, J.; Horstink, M.W.I.M.; Santos Bele, W. Dos; Brousolle, E.; Destee, A.; Mizuno, Y.; Farrer, M.; Deleuze, J.F.; Michele, G. de; Agid, Y.; Durr, A.; Brice, A.

    2003-01-01

    The frequency of parkin mutations was evaluated in 30 families of highly diverse geographic origin with early-onset autosomal recessive parkinsonism. Twelve different mutations, six of which were new, were found in 10 families from Europe and Brazil. Patients with parkin mutations had significantly

  18. X-Linked and Autosomal Recessive Alport Syndrome

    DEFF Research Database (Denmark)

    Savige, Judith; Storey, Helen; Il Cheong, Hae

    2016-01-01

    Alport syndrome results from mutations in the COL4A5 (X-linked) or COL4A3/COL4A4 (recessive) genes. This study examined 754 previously- unpublished variants in these genes from individuals referred for genetic testing in 12 accredited diagnostic laboratories worldwide, in addition to all published...... COL4A5, COL4A3 and COL4A4 variants in the LOVD databases. It also determined genotype-phenotype correlations for variants where clinical data were available. Individuals were referred for genetic testing where Alport syndrome was suspected clinically or on biopsy (renal failure, hearing loss...

  19. Infantile variant of Bartter syndrome and sensorineural deafness: A new autosomal recessive disorder

    Energy Technology Data Exchange (ETDEWEB)

    Landau, D.; Shalev, H.; Carmi, Rivka; Ohaly, M. [Univ. of the Negev, Ashkelon (Israel)

    1995-12-04

    The infantile variant of Bartter syndrome (IBS) is usually associated with maternal polyhydramnios, premature birth, postnatal polyuria and hypokalemic hypochloremic metabolic alkalosis and a typical appearance. IBS is thought to be an autosomal recessive trait. Several congenital tubular defects are associated with sensorineural deafness (SND). However, an association between the IBS and SND has not been reported so far. Here we describe 5 children of an extended consanguineous Bedouin family with IBS and SND. In 3 of the cases, the typical electrolyte imbalance and facial appearance were detected neonatally. SND was detected as early as age 1 month, suggesting either coincidental homozygotization of 2 recessive genes or a pleiotropic effect of one autosomal recessive gene. This association suggests that evaluation of SND is warranted in every case of IBS. 35 refs., 2 figs., 2 tabs.

  20. Preimplantation genetic diagnosis for a Chinese family with autosomal recessive Meckel-Gruber syndrome type 3 (MKS3.

    Directory of Open Access Journals (Sweden)

    Yanping Lu

    Full Text Available Meckel-Gruber syndrome type 3 is an autosomal recessive genetic defect caused by mutations in TMEM67 gene. In our previous study, we have identified a homozygous TMEM67 mutation in a Chinese family exhibiting clinical characteristics of MKS3, which provided a ground for further PGD procedure. Here we report the development and the first clinical application of the PGD for this MKS3 family. Molecular analysis protocol for clinical PGD procedure was established using 50 single cells in pre-clinical set-up. After whole genomic amplification by multiple displacement amplification with the DNA from single cells, three techniques were applied simultaneously to increase the accuracy and reliability of genetic diagnosis in single blastomere, including real-time PCR with Taq Man-MGB probe, haplotype analysis with polymorphic STR markers and Sanger sequencing. In the clinical PGD cycle, nine embryos at cleavage-stage were biopsied and subjected to genetic diagnosis. Two embryos diagnosed as free of TMEM67 mutation were transferred and one achieving normal pregnancy. Non-invasive prenatal assessment of trisomy 13, 18 and 21 by multiplex DNA sequencing at 18 weeks' gestation excluded the aneuploidy of the analyzed chromosomes. A healthy boy was delivered by cesarean section at 39 weeks' gestation. DNA sequencing from his cord blood confirmed the result of genetic analysis in the PGD cycle. The protocol developed in this study was proved to be rapid and safe for the detection of monogenic mutations in clinical PGD cycle.

  1. ALS5/SPG11/ KIAA1840 mutations cause autosomal recessive axonal Charcot–Marie–Tooth disease

    Science.gov (United States)

    Montecchiani, Celeste; Pedace, Lucia; Lo Giudice, Temistocle; Casella, Antonella; Mearini, Marzia; Gaudiello, Fabrizio; Pedroso, José L.; Terracciano, Chiara; Caltagirone, Carlo; Massa, Roberto; St George-Hyslop, Peter H.; Barsottini, Orlando G. P.; Kawarai, Toshitaka

    2016-01-01

    Abstract Charcot–Marie–Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained. Mutations in the ALS5/SPG11/ KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for ∼40% of autosomal recessive juvenile amyotrophic lateral sclerosis. The overlap of axonal Charcot–Marie–Tooth disease with both diseases, as well as the common autosomal recessive inheritance pattern of thin corpus callosum and axonal Charcot–Marie–Tooth disease in three related patients, prompted us to analyse the ALS5/SPG11/ KIAA1840 gene in affected individuals with autosomal recessive axonal Charcot–Marie–Tooth disease. We investigated 28 unrelated families with autosomal recessive axonal Charcot–Marie–Tooth disease defined by clinical, electrophysiological, as well as pathological evaluation. Besides, we screened for all the known genes related to axonal autosomal recessive Charcot–Marie-Tooth disease (CMT2A2/HMSN2A2/ MFN2 , CMT2B1/ LMNA , CMT2B2/ MED25 , CMT2B5/ NEFL , ARCMT2F/dHMN2B/ HSPB1 , CMT2K/ GDAP1 , CMT2P/ LRSAM1 , CMT2R/ TRIM2 , CMT2S/ IGHMBP2 , CMT2T/ HSJ1 , CMTRID/ COX6A1 , ARAN-NM/ HINT and GAN/ GAN ), for the genes related to autosomal recessive hereditary spastic paraplegia with thin corpus callosum and axonal peripheral neuropathy (SPG7/ PGN , SPG15/ ZFYVE26, SPG21/ ACP33 , SPG35/ FA2H , SPG46/ GBA2 , SPG55/ C12orf65 and SPG56/ CYP2U1 ), as well as for the causative gene of peripheral neuropathy with or without agenesis of the corpus callosum ( SLC12A6 ) . Mitochondrial disorders related to Charcot–Marie–Tooth disease type 2 were also excluded by sequencing POLG and

  2. ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease.

    Science.gov (United States)

    Montecchiani, Celeste; Pedace, Lucia; Lo Giudice, Temistocle; Casella, Antonella; Mearini, Marzia; Gaudiello, Fabrizio; Pedroso, José L; Terracciano, Chiara; Caltagirone, Carlo; Massa, Roberto; St George-Hyslop, Peter H; Barsottini, Orlando G P; Kawarai, Toshitaka; Orlacchio, Antonio

    2016-01-01

    Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained. Mutations in the ALS5/SPG11/KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for ∼ 40% of autosomal recessive juvenile amyotrophic lateral sclerosis. The overlap of axonal Charcot-Marie-Tooth disease with both diseases, as well as the common autosomal recessive inheritance pattern of thin corpus callosum and axonal Charcot-Marie-Tooth disease in three related patients, prompted us to analyse the ALS5/SPG11/KIAA1840 gene in affected individuals with autosomal recessive axonal Charcot-Marie-Tooth disease. We investigated 28 unrelated families with autosomal recessive axonal Charcot-Marie-Tooth disease defined by clinical, electrophysiological, as well as pathological evaluation. Besides, we screened for all the known genes related to axonal autosomal recessive Charcot-Marie-Tooth disease (CMT2A2/HMSN2A2/MFN2, CMT2B1/LMNA, CMT2B2/MED25, CMT2B5/NEFL, ARCMT2F/dHMN2B/HSPB1, CMT2K/GDAP1, CMT2P/LRSAM1, CMT2R/TRIM2, CMT2S/IGHMBP2, CMT2T/HSJ1, CMTRID/COX6A1, ARAN-NM/HINT and GAN/GAN), for the genes related to autosomal recessive hereditary spastic paraplegia with thin corpus callosum and axonal peripheral neuropathy (SPG7/PGN, SPG15/ZFYVE26, SPG21/ACP33, SPG35/FA2H, SPG46/GBA2, SPG55/C12orf65 and SPG56/CYP2U1), as well as for the causative gene of peripheral neuropathy with or without agenesis of the corpus callosum (SLC12A6). Mitochondrial disorders related to Charcot-Marie-Tooth disease type 2 were also excluded by sequencing POLG and TYMP genes. An additional locus for autosomal recessive Charcot

  3. Molecular and clinical study of a cohort of 110 Algerian patients with autosomal recessive ataxia.

    Science.gov (United States)

    Hamza, Wahiba; Ali Pacha, Lamia; Hamadouche, Tarik; Muller, Jean; Drouot, Nathalie; Ferrat, Farida; Makri, Samira; Chaouch, Malika; Tazir, Meriem; Koenig, Michel; Benhassine, Traki

    2015-06-12

    Autosomal recessive cerebellar ataxias (ARCA) are a complex group of neurodegenerative disorders with great genetic and phenotypic heterogeneity, over 30 genes/loci have been associated with more than 20 different clinical forms of ARCA. Genetic heterogeneity combined with highly variable clinical expression of the cerebellar symptoms and overlapping features complicate furthermore the etiological diagnosis of ARCA. The determination of the most frequent mutations and corresponding ataxias, as well as particular features specific to a population, are mandatory to facilitate and speed up the diagnosis process, especially when an appropriate treatment is available. We explored 166 patients (115 families) refered to the neurology units of Algiers central hospitals (Algeria) with a cerebellar ataxia phenotype segregating as an autosomal recessive pattern of inheritance. Genomic DNA was extracted from peripheral blood samples and mutational screening was performed by PCR and direct sequencing or by targeted genomic capture and massive parallel sequencing of 57 genes associated with inherited cerebellar ataxia phenotypes. In this work we report the clinical and molecular results obtained on a large cohort of Algerian patients (110 patients/76 families) with genetically determined autosomal recessive ataxia, representing 9 different types of ARCA and 23 different mutations, including 6 novel ones. The five most common ARCA in this cohort were Friedreich ataxia, ataxia with isolated vitamin E deficiency, ataxia with oculomotor apraxia type 2, autosomal recessive spastic ataxia of Charlevoix-Saguenay and ataxia with oculomotor apraxia type 1. We report here a large cohort of patients with genetically determined autosomal recessive ataxia and the first study of the genetic context of ARCA in Algeria. This study showed that in Algerian patients, the two most common types of ataxia (Friedreich ataxia and ataxia with isolated vitamin E deficiency) coexist with forms that may be

  4. Genotype-phenotype correlation in FMF patients: A "non classic" recessive autosomal or "atypical" dominant autosomal inheritance?

    Science.gov (United States)

    Procopio, V; Manti, S; Bianco, G; Conti, G; Romeo, A; Maimone, F; Arrigo, T; Cutrupi, M C; Salpietro, C; Cuppari, C

    2018-01-30

    Uncertainty remains on the pathogenetic mechanisms, model of inheritance as well as genotype-phenotype correlation of FMF disease. To investigate the impact of genetic factors on the FMF phenotype and the disease inheritance model. A total of 107 FMF patients were enrolled. Patients were diagnosed clinically. All patients underwent genetic analysis of the FMF locus on 16p13.3. 9 distinct mutations were detected. Specifically, the 85.98% of patients showed a heterozygous genotype. The most common genotypes were p.Met680Ile/wt and p.Met694Val/wt. The most frequent clinical findings were fever, abdominal pain, joint pain, thoracic pain, and erysipelas-like erythema. Analysis of clinical data did not detect any significant difference in clinical phenotype among heterozygous, homozygous as well as compound homozygous subjects, further supporting the evidence that, contrary to the recessive autosomal inheritance, heterozygous patients fulfilled the criteria of clinical FMF. Moreover, subjects with p.Met694Val/wt and p.Met680Ile/wt genotype reported the most severe clinical phenotype. p.Ala744Ser/wt, p.Glu148Gln/Met680Ile, p.Met680Ile/Met680Ile, p.Met680Ile/Met694Val, p.Pro369Ser/wt, p.Met694Ile/wt, p.Glu148Gln/Glu148Gln, p.Lys695Arg/wt resulted in 100% pathogenicity. The existence of a "non classic" autosomal recessive inheritance as well as of an "atypical" dominant autosomal inheritance with incomplete penetrance and variable expressivity cannot be excluded in FMF. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. [Genetic study of the autosomal recessive form of Charcot-Marie-Tooth in an Algerian family].

    Science.gov (United States)

    Hamadouche, T; Tazir-Melboucy, M; Benhassine, T

    1998-01-01

    Charcot-Marie-Tooth disease (CMT) is a hereditary neuropathy characterized by muscular atrophy and progressive sensitive alterations that affect limbs. The CMT is one of the most heterogenous diseases, clinically as well as genetically. At least twelve loci are responsible for the CMT phenotype, four of them for the autosomal recessive form. The aim of our work was to determinate the implication/exclusion of these four loci in an Algerian family by linkage analysis using microsatellites markers. We have tested the four loci on 8q13-21.1 (CMT4A), 11q23 (CMT4B), 5q23-33 (CMT4C) 8q24 (CMTAR). The haplotype reconstruction allowed us to exclude all the loci in this family, suggesting that the locus (gene) responsible for this form of CMT is localized elsewhere in the genome, thus providing an other observation of the great heterogeneity of the CMT, particularly autosomal recessive.

  6. [Autosomal-recessive renal cystic disease and congenital hepatic fibrosis: clinico-anatomic case].

    Science.gov (United States)

    Rostol'tsev, K V; Burenkov, R A; Kuz'micheva, I A

    2012-01-01

    Clinico-anatomic observation of autosomal-recessive renal cystic disease and congenital hepatic fibrosis at two fetuses from the same family was done. Mutation of His3124Tyr in 58 exon of PKHD1 gene in heterozygous state was found out. The same pathomorphological changes in the epithelium of cystic renal tubules and bile ducts of the liver were noted. We suggest that the autopsy research of fetuses with congenital abnormalities, detected after prenatal ultrasonic screening, has high diagnostic importance.

  7. Missense variants in AIMP1 gene are implicated in autosomal recessive intellectual disability without neurodegeneration

    OpenAIRE

    Iqbal, Zafar; P?ttmann, Lucia; Musante, Luciana; Razzaq, Attia; Zahoor, Muhammad Yasir; Hu, Hao; Wienker, Thomas F; Garshasbi, Masoud; Fattahi, Zohreh; Gilissen, Christian; Vissers, Lisenka ELM; de Brouwer, Arjan PM; Veltman, Joris A; Pfundt, Rolph; Najmabadi, Hossein

    2015-01-01

    AIMP1/p43 is a multifunctional non-catalytic component of the multisynthetase complex. The complex consists of nine catalytic and three non-catalytic proteins, which catalyze the ligation of amino acids to their cognate tRNA isoacceptors for use in protein translation. To date, two allelic variants in the AIMP1 gene have been reported as the underlying cause of autosomal recessive primary neurodegenerative disorder. Here, we present two consanguineous families from Pakistan and Iran, presenti...

  8. A defect in the CLIP1 gene (CLIP-170) can cause autosomal recessive intellectual disability

    OpenAIRE

    Larti, Farzaneh; Kahrizi, Kimia; Musante, Luciana; Hu, Hao; Papari, Elahe; Fattahi, Zohreh; Bazazzadegan, Niloofar; Liu, Zhe; Banan, Mehdi; Garshasbi, Masoud; Wienker, Thomas F; Hilger Ropers, H; Galjart, Niels; Najmabadi, Hossein

    2015-01-01

    In the context of a comprehensive research project, investigating novel autosomal recessive intellectual disability (ARID) genes, linkage analysis based on autozygosity mapping helped identify an intellectual disability locus on Chr.12q24, in an Iranian family (LOD score=3.7). Next-generation sequencing (NGS) following exon enrichment in this novel interval, detected a nonsense mutation (p.Q1010*) in the CLIP1 gene. CLIP1 encodes a member of microtubule (MT) plus-end tracking proteins, which ...

  9. A Novel Mutation in the Transglutaminase-1 Gene in an Autosomal Recessive Congenital Ichthyosis Patient

    Directory of Open Access Journals (Sweden)

    D. Vaigundan

    2014-01-01

    Full Text Available Structure-function implication on a novel homozygous Trp250/Gly mutation of transglutaminase-1 (TGM1 observed in a patient of autosomal recessive congenital ichthyosis is invoked from a bioinformatics analysis. Structural consequences of this mutation are hypothesized in comparison to homologous enzyme human factor XIIIA accepted as valid in similar structural analysis and are projected as guidelines for future studies at an experimental level on TGM1 thus mutated.

  10. Novel CLCN7 compound heterozygous mutations in intermediate autosomal recessive osteopetrosis.

    Science.gov (United States)

    Okamoto, Nana; Kohmoto, Tomohiro; Naruto, Takuya; Masuda, Kiyoshi; Komori, Takahide; Imoto, Issei

    2017-01-01

    Osteopetrosis is a heritable disorder of the skeleton that is characterized by increased bone density on radiographs caused by defects in osteoclast formation and function. Mutations in >10 genes are identified as causative for this clinically and genetically heterogeneous disease in humans. We report two novel missense variations in a compound heterozygous state in the CLCN7 gene, detected through targeted exome sequencing, in a 15-year-old Japanese female with intermediate autosomal recessive osteopetrosis.

  11. Macroepiphyseal dysplasia with symptomatic osteoporosis, wrinkled skin, and aged appearance: A presumed autosomal recessive condition

    Energy Technology Data Exchange (ETDEWEB)

    McAlister, W.H.; Coe, J.D.; Whyte, M.P.

    1986-01-01

    We report our detailed investigation of a 7-1/2-year-old girl with short stature, aged appearance, decreased subcutaneous fat and muscle mass, dry coarse hair, foot deformities, macroepiphyses with prominent but lax joints, and osteoporosis with recurrent fractures who is the offspring of first cousins. This constellation of abnormalities differs from previously reported cases where macroepiphyses were a prominent finding. Our patient appears, therefore, to have a new, autosomal recessively inherited, syndrome.

  12. Macroepiphyseal dysplasia with symptomatic osteoporosis, wrinkled skin, and aged appearance: A presumed autosomal recessive condition

    International Nuclear Information System (INIS)

    McAlister, W.H.; Coe, J.D.; Whyte, M.P.; Shriners Hospital for Crippled Children, St. Louis, MO

    1986-01-01

    We report our detailed investigation of a 7-1/2-year-old girl with short stature, aged appearance, decreased subcutaneous fat and muscle mass, dry coarse hair, foot deformities, macroepiphyses with prominent but lax joints, and osteoporosis with recurrent fractures who is the offspring of first cousins. This constellation of abnormalities differs from previously reported cases where macroepiphyses were a prominent finding. Our patient appears, therefore, to have a new, autosomal recessively inherited, syndrome. (orig.)

  13. Genetic Causes of Putative Autosomal Recessive Intellectual Disability Cases in Hamedan Province

    Directory of Open Access Journals (Sweden)

    Milad Bastami

    2012-04-01

    Full Text Available Objective: The aim of this study was to investigate the genetic causes of autosomal recessive intellectual disabilities (AR-ID in Hamadan province of Iran. Materials & Methods: In this descriptive-analytical cross-sectional study, 25 families with more than one affected with putative autosomal recessive intellectual disability were chosen with collaboration of Welfare Organization of Hamadan province. Families were included a total of 60 patients (39 male and 21 female whose intellectual disability had been confirmed by Raven IQ test. Each family was asked for clinical examination and getting consent form. Blood sample was collected from each family. One proband from each family was tested for CGG repeat expansion in FMR1 gene, chromosomal abnormalities and inborn errors of metabolism. We also performed homozygosity mapping based on STR markers for seven known MCPH loci in families with primary microcephaly and AR-ID. Results: Five families had full mutation of Fragile X syndrome. No chromosomal abnormalities were identified. Metabolic screening revealed one family with Medium Chain Acyl CoA Dehydrogenase deficiency. None of three families with primary microcephaly and AR-ID showed linkage to any of known seven MCPH loci. Conclusion: The main causes of ID in Hamadan province were Fragile X syndrome and Autosomal Recessive Primary Microcephaly with the frequencies of 20% and 12%, respectively.

  14. Improved Structure and Function in Autosomal Recessive Polycystic Rat Kidneys with Renal Tubular Cell Therapy.

    Science.gov (United States)

    Kelly, K J; Zhang, Jizhong; Han, Ling; Kamocka, Malgorzata; Miller, Caroline; Gattone, Vincent H; Dominguez, Jesus H

    2015-01-01

    Autosomal recessive polycystic kidney disease is a truly catastrophic monogenetic disease, causing death and end stage renal disease in neonates and children. Using PCK female rats, an orthologous model of autosomal recessive polycystic kidney disease harboring mutant Pkhd1, we tested the hypothesis that intravenous renal cell transplantation with normal Sprague Dawley male kidney cells would improve the polycystic kidney disease phenotype. Cytotherapy with renal cells expressing wild type Pkhd1 and tubulogenic serum amyloid A1 had powerful and sustained beneficial effects on renal function and structure in the polycystic kidney disease model. Donor cell engraftment and both mutant and wild type Pkhd1 were found in treated but not control PCK kidneys 15 weeks after the final cell infusion. To examine the mechanisms of global protection with a small number of transplanted cells, we tested the hypothesis that exosomes derived from normal Sprague Dawley cells can limit the cystic phenotype of PCK recipient cells. We found that renal exosomes originating from normal Sprague Dawley cells carried and transferred wild type Pkhd1 mRNA to PCK cells in vivo and in vitro and restricted cyst formation by cultured PCK cells. The results indicate that transplantation with renal cells containing wild type Pkhd1 improves renal structure and function in autosomal recessive polycystic kidney disease and may provide an intra-renal supply of normal Pkhd1 mRNA.

  15. Mutations in c10orf11, a melanocyte-differentiation gene, cause autosomal-recessive albinism.

    Science.gov (United States)

    Grønskov, Karen; Dooley, Christopher M; Østergaard, Elsebet; Kelsh, Robert N; Hansen, Lars; Levesque, Mitchell P; Vilhelmsen, Kaj; Møllgård, Kjeld; Stemple, Derek L; Rosenberg, Thomas

    2013-03-07

    Autosomal-recessive albinism is a hypopigmentation disorder with a broad phenotypic range. A substantial fraction of individuals with albinism remain genetically unresolved, and it has been hypothesized that more genes are to be identified. By using homozygosity mapping of an inbred Faroese family, we identified a 3.5 Mb homozygous region (10q22.2-q22.3) on chromosome 10. The region contains five protein-coding genes, and sequencing of one of these, C10orf11, revealed a nonsense mutation that segregated with the disease and showed a recessive inheritance pattern. Investigation of additional albinism-affected individuals from the Faroe Islands revealed that five out of eight unrelated affected persons had the nonsense mutation in C10orf11. Screening of a cohort of autosomal-recessive-albinism-affected individuals residing in Denmark showed a homozygous 1 bp duplication in C10orf11 in an individual originating from Lithuania. Immunohistochemistry showed localization of C10orf11 in melanoblasts and melanocytes in human fetal tissue, but no localization was seen in retinal pigment epithelial cells. Knockdown of the zebrafish (Danio rerio) homolog with the use of morpholinos resulted in substantially decreased pigmentation and a reduction of the apparent number of pigmented melanocytes. The morphant phenotype was rescued by wild-type C10orf11, but not by mutant C10orf11. In conclusion, we have identified a melanocyte-differentiation gene, C10orf11, which when mutated causes autosomal-recessive albinism in humans. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  16. Enfermedad poliquística autosómica recesiva Recessive autosomal polycystic disease

    Directory of Open Access Journals (Sweden)

    Sandalio Durán Álvarez

    2007-06-01

    Full Text Available Como enfermedades renales poliquísticas hereditarias se describen clásicamente la autosómica recesiva y la autosómica dominante, mal llamadas enfermedad poliquística de tipo infantily de;tipo adulto, respectivamente, pues ambas pueden verse tanto en una como en otra edad. Los conceptos cambiantes en cuanto a la enfermedad autosómica recesiva, dados por los progresos en el tratamiento de los recién nacidos con la enfermedad, y la localización del gen, que por su mutación la produce, nos motivan hacer esta breve revisión con la finalidad de contribuir a la comprensión de la enfermedad por los estudiantes de medicina y el médico general básico.Recessive autosomal and dominant autosomal polycystic kidney diseases are classically described as hereditary illnesses; they are also called polycystic disease of child type” and of adult typerespectively since both may be seen in any of these two life stages. The changing concepts of recessive autosomal disease, given the advances made in the treatment of newborns with this disease, and the location of the gen, the mutation of which causes it, encouraged us to make a brief literature review to help medical students and general practitioners to understand this disease.

  17. Proprotein Convertase Subtilisin Kexin Type 9 Inhibition for Autosomal Recessive Hypercholesterolemia-Brief Report.

    Science.gov (United States)

    Thedrez, Aurélie; Sjouke, Barbara; Passard, Maxime; Prampart-Fauvet, Simon; Guédon, Alexis; Croyal, Mikael; Dallinga-Thie, Geesje; Peter, Jorge; Blom, Dirk; Ciccarese, Milco; Cefalù, Angelo B; Pisciotta, Livia; Santos, Raul D; Averna, Maurizio; Raal, Frederick; Pintus, Paolo; Cossu, Maria; Hovingh, Kees; Lambert, Gilles

    2016-08-01

    Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors lower low-density lipoprotein (LDL) cholesterol in the vast majority of patients with autosomal dominant familial hypercholesterolemia. Will PCSK9 inhibition with monoclonal antibodies, in particular alirocumab, be of therapeutic value for patients with autosomal recessive hypercholesterolemia (ARH)? Primary lymphocytes were obtained from 28 genetically characterized ARH patients and 11 controls. ARH lymphocytes treated with mevastatin were incubated with increasing doses of recombinant PCSK9 with or without saturating concentrations of alirocumab. Cell surface LDL receptor expression measured by flow cytometry and confocal microscopy was higher in ARH than in control lymphocytes. PCSK9 significantly reduced LDL receptor expression in ARH lymphocytes albeit to a lower extent than in control lymphocytes (25% versus 76%, respectively), an effect reversed by alirocumab. Fluorescent LDL cellular uptake, also measured by flow cytometry, was reduced in ARH lymphocytes compared with control lymphocytes. PCSK9 significantly lowered LDL cellular uptake in ARH lymphocytes, on average by 18%, compared with a 46% reduction observed in control lymphocytes, an effect also reversed by alirocumab. Overall, the effects of recombinant PCSK9, and hence of alirocumab, on LDL receptor expression and function were significantly less pronounced in ARH than in control cells. PCSK9 inhibition with alirocumab on top of statin treatment has the potential to lower LDL cholesterol in some autosomal recessive hypercholesterolemia patients. © 2016 American Heart Association, Inc.

  18. Autosomal recessive hypophosphataemic rickets with hypercalciuria is not caused by mutations in the type II renal sodium/phosphate cotransporter gene.

    NARCIS (Netherlands)

    Heuvel, L.P.W.J. van den; Koul, K. Op de; Knots, E.; Knoers, N.V.A.M.; Monnens, L.A.H.

    2001-01-01

    BACKGROUND: At present the genetic defect for autosomal recessive and autosomal dominant hypophosphataemic rickets with hypercalciuria (HHRH) is unknown. Type II sodium/phosphate cotransporter (NPT2) gene is a serious candidate for being the causative gene in either or both autosomal recessive and

  19. Birth prevalence and mutation spectrum in danish patients with autosomal recessive albinism

    DEFF Research Database (Denmark)

    Grønskov, Karen; Ek, Jakob; Sand, Annie

    2009-01-01

    PURPOSE: The study was initiated to investigate the mutation spectrum of four OCA genes and to calculate the birth prevalence in patients with autosomal recessive albinism. METHODS: Mutation analysis using dHPLC or direct DNA sequencing of TYR, OCA2, TYRP1, and MATP was performed in 62 patients....... Two mutations in one OCA gene explained oculocutaneous albinism (OCA) in 44% of the patients. Mutations in TYR were found in 26% of patients, while OCA2 and MATP caused OCA in 15% and 3%, respectively. No mutations were found in TYRP1. Of the remaining 56% of patients, 29% were heterozygous...... for a mutation in either TYR or OCA2, and 27% were without mutations in any of the four genes. Exclusive expression of the mutant allele was found in four heterozygous patients. A minimum birth prevalence of 1 in 14,000 was calculated, based on register data on 218 patients. The proportion of OCA to autosomal...

  20. SACS gene-related autosomal recessive spastic ataxia of Charlevoix-Saguenay from South India

    Directory of Open Access Journals (Sweden)

    M Suraj Menon

    2016-01-01

    Full Text Available Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS is a neurodegenerative disorder characterized by late infantile onset spastic ataxia and other neurological features. Initially described in the Charlevoix-Saguenay region of Quebec, Canada, it is being increasingly reported from many other countries. Here, we present the case of a 20-year-old male from South India, who presented with progressive ataxia, spasticity, and peripheral neuropathy with imaging features and genetic testing suggestive of SACS gene-related ARSACS. The phenotypic variability from other cases and occurrence in a geographically distinct region is stressed upon to alert the clinicians to consider ARSACS in progressive ataxias.

  1. Clinical and genetic characteristics of autosomal recessive axonal neuropathy with neuromyotonia in Russian patients

    Directory of Open Access Journals (Sweden)

    E. L. Dadali

    2017-01-01

    Full Text Available Introduction. Hereditary motor and sensory neuropathies are genetically heterogeneous group of disorders characterized by a progressive muscle weakness, atrophy of hand and leg muscles often associated with deformations, and mild to moderate sensory loss. Axonal neuropathy with neuromyotonia (AR-ANM is one of the rarest autosomal recessive hereditary neuropathies. Materials and methods. Six (6 patients (4 men, 2 women aged 14–40 years from unrelated families with suspicion of HMSN were examined clinically, neurophysiologically and using DNA analysis. Results. Neurophysiological examination revealed motor and sensory neuropathy with neuromyotonia signs in all patients. In all cases homozygous variant of recessive mutations с.110G/C (р.Arg37Pro in the gene encoding the histidine triad nucleotide binding protein 1 (HINT1 has been revealed. Conclusion. There is the first description of the clinical and neurophysiological features of six patients with AR-ANM in Russia. 

  2. Hereditary motor and sensory neuropathy-russe: new autosomal recessive neuropathy in Balkan Gypsies.

    Science.gov (United States)

    Thomas, P K; Kalaydjieva, L; Youl, B; Rogers, T; Angelicheva, D; King, R H; Guergueltcheva, V; Colomer, J; Lupu, C; Corches, A; Popa, G; Merlini, L; Shmarov, A; Muddle, J R; Nourallah, M; Tournev, I

    2001-10-01

    A novel peripheral neuropathy of autosomal recessive inheritance has been identified in Balkan Gypsies and termed hereditary motor and sensory neuropathy-Russe (HMSN-R). We investigated 21 affected individuals from 10 families. Distal lower limb weakness began between the ages of 8 and 16 years, upper limb involvement beginning between 10 and 43 years, with an average of 22 years. This progressive disorder led to severe weakness of the lower limbs, generalized in the oldest subject (aged 57 years), and marked distal upper limb weakness. Prominent distal sensory loss involved all modalities, resulting in neuropathic joint degeneration in two instances. All patients showed foot deformity, and most showed hand deformity. Motor nerve conduction velocity was moderately reduced in the upper limbs but unobtainable in the legs. Sensory nerve action potentials were absent. There was loss of larger myelinated nerve fibers and profuse regenerative activity in the sural nerve. HMSN-R is a new form of autosomal recessive inherited HMSN caused by a single founder mutation in a 1 Mb interval on chromosome 10q.

  3. Autosomal recessive dilated cardiomyopathy due to DOLK mutations results from abnormal dystroglycan O-mannosylation.

    Directory of Open Access Journals (Sweden)

    Dirk J Lefeber

    2011-12-01

    Full Text Available Genetic causes for autosomal recessive forms of dilated cardiomyopathy (DCM are only rarely identified, although they are thought to contribute considerably to sudden cardiac death and heart failure, especially in young children. Here, we describe 11 young patients (5-13 years with a predominant presentation of dilated cardiomyopathy (DCM. Metabolic investigations showed deficient protein N-glycosylation, leading to a diagnosis of Congenital Disorders of Glycosylation (CDG. Homozygosity mapping in the consanguineous families showed a locus with two known genes in the N-glycosylation pathway. In all individuals, pathogenic mutations were identified in DOLK, encoding the dolichol kinase responsible for formation of dolichol-phosphate. Enzyme analysis in patients' fibroblasts confirmed a dolichol kinase deficiency in all families. In comparison with the generally multisystem presentation in CDG, the nonsyndromic DCM in several individuals was remarkable. Investigation of other dolichol-phosphate dependent glycosylation pathways in biopsied heart tissue indicated reduced O-mannosylation of alpha-dystroglycan with concomitant functional loss of its laminin-binding capacity, which has been linked to DCM. We thus identified a combined deficiency of protein N-glycosylation and alpha-dystroglycan O-mannosylation in patients with nonsyndromic DCM due to autosomal recessive DOLK mutations.

  4. A Defect in NIPAL4 Is Associated with Autosomal Recessive Congenital Ichthyosis in American Bulldogs.

    Directory of Open Access Journals (Sweden)

    Margret L Casal

    Full Text Available Autosomal recessive congenital ichthyosis in the American bulldog is characterized by generalized scaling and erythema with adherent scale on the glabrous skin. We had previously linked this disorder to NIPAL4, which encodes the protein ichthyin. Sequencing of NIPAL4 revealed a homozygous single base deletion (CanFam3.1 canine reference genome sequence NC_06586.3 g.52737379del, the 157th base (cytosine in exon 6 of NIPAL4 as the most likely causative variant in affected dogs. This frameshift deletion results in a premature stop codon producing a truncated and defective NIPAL4 (ichthyin protein of 248 amino acids instead of the wild-type length of 404. Obligate carriers were confirmed to be heterozygous for this variant, and 150 clinically non-affected dogs of other breeds were homozygous for the wild-type gene. Among 800 American bulldogs tested, 34% of clinically healthy dogs were discovered to be heterozygous for the defective allele. More importantly, the development of this canine model of autosomal recessive congenital ichthyosis will provide insight into the development of new treatments across species.

  5. The efficacy of microarray screening for autosomal recessive retinitis pigmentosa in routine clinical practice

    Science.gov (United States)

    van Huet, Ramon A. C.; Pierrache, Laurence H.M.; Meester-Smoor, Magda A.; Klaver, Caroline C.W.; van den Born, L. Ingeborgh; Hoyng, Carel B.; de Wijs, Ilse J.; Collin, Rob W. J.; Hoefsloot, Lies H.

    2015-01-01

    Purpose To determine the efficacy of multiple versions of a commercially available arrayed primer extension (APEX) microarray chip for autosomal recessive retinitis pigmentosa (arRP). Methods We included 250 probands suspected of arRP who were genetically analyzed with the APEX microarray between January 2008 and November 2013. The mode of inheritance had to be autosomal recessive according to the pedigree (including isolated cases). If the microarray identified a heterozygous mutation, we performed Sanger sequencing of exons and exon–intron boundaries of that specific gene. The efficacy of this microarray chip with the additional Sanger sequencing approach was determined by the percentage of patients that received a molecular diagnosis. We also collected data from genetic tests other than the APEX analysis for arRP to provide a detailed description of the molecular diagnoses in our study cohort. Results The APEX microarray chip for arRP identified the molecular diagnosis in 21 (8.5%) of the patients in our cohort. Additional Sanger sequencing yielded a second mutation in 17 patients (6.8%), thereby establishing the molecular diagnosis. In total, 38 patients (15.2%) received a molecular diagnosis after analysis using the microarray and additional Sanger sequencing approach. Further genetic analyses after a negative result of the arRP microarray (n = 107) resulted in a molecular diagnosis of arRP (n = 23), autosomal dominant RP (n = 5), X-linked RP (n = 2), and choroideremia (n = 1). Conclusions The efficacy of the commercially available APEX microarray chips for arRP appears to be low, most likely caused by the limitations of this technique and the genetic and allelic heterogeneity of RP. Diagnostic yields up to 40% have been reported for next-generation sequencing (NGS) techniques that, as expected, thereby outperform targeted APEX analysis. PMID:25999674

  6. Inhibitory action of chlorophyllin of autosome recessive lethals induced by irradiation

    International Nuclear Information System (INIS)

    Salceda, V.M.; Pimentel, P.A.E.; Cruces, M.P.

    2006-01-01

    The chlorophyllin is a sodium salt of the chlorophyll that has a strong protective action of the damage induced by different agents so much physical as chemical. In Drosophila there is reported this effect in somatic cells. In contrast, in germinal cells using tests with the sexual chromosomes has not been found such inhibitory action. For this reason, in this occasion we will refer to the effect of the lethality induced in autosome chromosomes, in particular to the chromosome II of this species. For such effect groups of males of the line Canton-S its were pre-treated for 24h with or without 69 mm of CCS and later on treaties with or without 40 Gy of gamma irradiation. The males were then subjected to the technical Cy L / Pm for the detection of recessive lethals. In the third generation the respective counts of the descendant of each one of them to determine the corresponding categories for each extracted chromosome were made. To be mendelian crosses it is expected for a normal chromosome a proportion 2:1 of individuals with genotype Cy L / +: +/+. The absence of individuals +/+ it is indicative of a lethal gene, until 10% of these individuals of each male's total descendant, it is considered that is carrying of a semi lethal gene. The sum of lethal and semi lethals constitutes the category detrimental. The obtained results indicated that the pre-treatment with CCS reduces in a significant way the frequency of induced lethals by 40 Gy of gamma rays. The fact that an effect inhibitor has not been observed in the test of recessive lethal bound to the sex obtained previously, it contrasts with the effect observed in the chromosome II, results of this study and with the one observed in the chromosome III in somatic cells. The above-mentioned shows a differential action of the CCS between sexual chromosomes and autosomal before the effect of the gamma radiation. At the moment we don't have an explanation to these evidences. To evaluate the action of the chlorophyllin

  7. Molecular diagnostic in two families affected with Autosomic Recessive Pigmentary Retinitis

    International Nuclear Information System (INIS)

    Leal Esquivel, A.

    1996-01-01

    This study included two Costa Rican families with members affected by Recessive Pigmentary Autosomic Retinitis (RPAR). The first family (C1) from the province of San Jose, has 10 alive affected members, and 14 obligatory carriers. They present an Early Appearance Degeneration, RPAR tipe1 (cane-cone). The author used polymorphic markers (STRPs) to discard some related regions, with the RP in the literature. He also used the Linkage program, for the analysis of ligaments. The second family (P1), proceeding from Acosta (situated in the province of Alajuela), has 13 alive affected members and 23 obligatory carriers and they present numerous consanguineous unions. This case is a RPAR with Early Appearance (Night Blindness, fat ERG), but with a shower degeneration. The author concludes that, with studies such as this one, there will be a capacity to offer RP molecular diagnostic, and also advance in its knowledge and treatment. (S. Grainger)

  8. Congenital non-syndromal autosomal recessive deafness in Bengkala, an isolated Balinese village.

    Science.gov (United States)

    Winata, S; Arhya, I N; Moeljopawiro, S; Hinnant, J T; Liang, Y; Friedman, T B; Asher, J H

    1995-01-01

    Bengkala is an Indonesian village located on the north shore of Bali that has existed for over 700 years. Currently, 2.2% of the 2185 people in this village have profound congenital deafness. In response to the high incidence of deafness, the people of Bengkala have developed a village specific sign language which is used by many of the hearing and deaf people. Deafness in Bengkala is congenital, sensorineural, non-syndromal, and caused by a fully penetrant autosomal recessive mutation at the DFNB3 locus. The frequency of the DFNB3 mutation is estimated to be 9.4% among hearing people who have a 17.2% chance of being heterozygous for DFNB3. PMID:7616538

  9. Novel compound heterozygous mutations in SERPINH1 cause rare autosomal recessive osteogenesis imperfecta type X.

    Science.gov (United States)

    Song, Y; Zhao, D; Xu, X; Lv, F; Li, L; Jiang, Y; Wang, O; Xia, W; Xing, X; Li, M

    2018-03-09

    We identified novel compound heterozygous mutations in SERPINH1 in a Chinese boy suffering from recurrent fractures, femoral deformities, and growth retardation, which resulted in extremely rare autosomal recessive OI type X. Long-term treatment of BPs was effective in increasing BMD Z-score, reducing fracture incidence and reshaping vertebrae compression. Osteogenesis imperfecta (OI) is a heritable bone disorder characterized by low bone mineral density, recurrent fractures, and progressive bone deformities. Mutation in serpin peptidase inhibitor clade H, member 1 (SERPINH1), which encodes heat shock protein 47 (HSP47), leads to rare autosomal recessive OI type X. We aimed to detect the phenotype and the pathogenic mutation of OI type X in a boy from a non-consanguineous Chinese family. We investigated the pathogenic mutations and analyzed their relationship with the phenotype in the patient using next-generation sequencing (NGS) and Sanger sequencing. Moreover, the efficacy of long-term bisphosphonate treatment in this patient was evaluated. The patient suffered from multiple fractures, low bone mass, and bone deformities in the femur, without dentinogenesis imperfecta or hearing loss. Compound heterozygous variants were found in SERPINH1 as follows: c.149 T>G in exon 2 and c.1214G>A in exon 5. His parents were heterozygous carriers of each of these mutations, respectively. Bisphosphonates could be helpful in increasing BMD Z-score, reducing bone fracture risk and reshaping the compressed vertebral bodies of this patient. We reported novel compound heterozygous mutations in SERPINH1 in a Chinese OI patient for the first time, which expanded the spectrum of phenotype and genotype of extremely rare OI type X.

  10. Autosomal recessive primary microcephaly (MCPH): clinical manifestations, genetic heterogeneity and mutation continuum

    Science.gov (United States)

    2011-01-01

    Autosomal Recessive Primary Microcephaly (MCPH) is a rare disorder of neurogenic mitosis characterized by reduced head circumference at birth with variable degree of mental retardation. In MCPH patients, brain size reduced to almost one-third of its original volume due to reduced number of generated cerebral cortical neurons during embryonic neurogensis. So far, seven genetic loci (MCPH1-7) for this condition have been mapped with seven corresponding genes (MCPH1, WDR62, CDK5RAP2, CEP152, ASPM, CENPJ, and STIL) identified from different world populations. Contribution of ASPM and WDR62 gene mutations in MCPH World wide is more than 50%. By and large, primary microcephaly patients are phenotypically indistinguishable, however, recent studies in patients with mutations in MCPH1, WDR62 and ASPM genes showed a broader clinical and/or cellular phenotype. It has been proposed that mutations in MCPH genes can cause the disease phenotype by disturbing: 1) orientation of mitotic spindles, 2) chromosome condensation mechanism during embryonic neurogenesis, 3) DNA damage-response signaling, 4) transcriptional regulations and microtubule dynamics, 5) certain unknown centrosomal mechanisms that control the number of neurons generated by neural precursor cells. Recent discoveries of mammalian models for MCPH have open up horizons for researchers to add more knowledge regarding the etiology and pathophysiology of MCPH. High incidence of MCPH in Pakistani population reflects the most probable involvement of consanguinity. Genetic counseling and clinical management through carrier detection/prenatal diagnosis in MCPH families can help reducing the incidence of this autosomal recessive disorder. PMID:21668957

  11. Molecular genetic analysis of consanguineous Pakistani families with autosomal recessive hypohidrotic ectodermal dysplasia.

    Science.gov (United States)

    Bibi, Nosheen; Ahmad, Saeed; Ahmad, Wasim; Naeem, Muhammad

    2011-02-01

    Hypohidrotic ectodermal dysplasia is an inherited disorder characterized by defective development of teeth, hairs and sweat glands. X-linked hypohidrotic ectodermal dysplasia is caused by mutations in the EDA gene, and autosomal forms of hypohidrotic ectodermal dysplasia are caused by mutations in either the EDAR or the EDARADD genes. To study the molecular genetic cause of autosomal recessive hypohidrotic ectodermal dysplasia in three consanguineous Pakistani families (A, B and C), genotyping of 13 individuals was carried out by using polymorphic microsatellite markers that are closely linked to the EDAR gene on chromosome 2q11-q13 and the EDARADD gene on chromosome 1q42.2-q43. The results revealed linkage in the three families to the EDAR locus. Sequence analysis of the coding exons and splice junctions of the EDAR gene revealed two mutations: a novel non-sense mutation (p.E124X) in the probands of families A and B and a missense mutation (p.G382S) in the proband of family C. In addition, two synonymous single-nucleotide polymorphisms were also identified. The finding of mutations in Pakistani families extends the body of evidence that supports the importance of EDAR for the development of hypohidrotic ectodermal dysplasia. © 2010 The Authors. Australasian Journal of Dermatology © 2010 The Australasian College of Dermatologists.

  12. Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy

    NARCIS (Netherlands)

    Lesage, S.; Drouet, V.; Majounie, E.; Deramecourt, V.; Jacoupy, M.; Nicolas, A.; Cormier-Dequaire, F.; Hassoun, S.M.; Pujol, C.; Ciura, S.; Erpapazoglou, Z.; Usenko, T.; Maurage, C.A.; Sahbatou, M.; Liebau, S.; Ding, J.; Bilgic, B.; Emre, M.; Erginel-Unaltuna, N.; Guven, G.; Tison, F.; Tranchant, C.; Vidailhet, M.; Corvol, J.C.; Krack, P.; Leutenegger, A.L.; Nalls, M.A.; Hernandez, D.G.; Heutink, P.; Gibbs, J.R.; Hardy, J.; Wood, N.W.; Gasser, T.; Durr, A.; Deleuze, J.F.; Tazir, M.; Destee, A.; Lohmann, E.; Kabashi, E.; Singleton, A.; Corti, O.; Brice, A.; Scheffer, H.; Bloem, B.R.; et al.,

    2016-01-01

    Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with

  13. A Challenging Case of Hepatoblastoma Concomitant with Autosomal Recessive Polycystic Kidney Disease and Caroli Syndrome—Review of the Literature

    Directory of Open Access Journals (Sweden)

    Nevil Kadakia

    2017-06-01

    Full Text Available We report a rare case of an 18-month-old female with autosomal recessive polycystic kidney disease, Caroli syndrome, and pure fetal type hepatoblastoma. The liver tumor was surgically resected with no chemotherapy given. Now 9 years post resection she demonstrates no local or distant recurrence and stable renal function.

  14. Molecular and phenotypic analysis of a family with autosomal recessive cone-rod dystrophy and Stargardt disease.

    NARCIS (Netherlands)

    Ijzer, Suzanne; Born, L.I. van den; Zonneveld, M.N.; Lopez, I.; Ayyagari, R.; Teye-Botchway, L.; Mota-Vieira, L.; Cremers, F.P.M.; Koenekoop, R.K.

    2007-01-01

    PURPOSE: To identify the causative gene mutations in three siblings with severe progressive autosomal recessive cone-rod dystrophy (arCRD) and their fifth paternal cousin with Stargardt disease (STGD1) and to specify the phenotypes. METHODS: We evaluated eight sibs of one family, three family

  15. Homozygous mutations in IHH cause acrocapitofemoral dysplasia, an autosomal recessive disorder with cone- shaped epiphyses in hands and hips

    NARCIS (Netherlands)

    Hellemans, J; Coucke, PJ; Giedion, A; De Paepe, A; Kramer, P; Beemer, F; Mortier, GR

    Acrocapitofemoral dysplasia is a recently delineated autosomal recessive skeletal dysplasia, characterized clinically by short stature with short limbs and radiographically by cone-shaped epiphyses, mainly in hands and hips. Genome-wide homozygosity mapping in two consanguineous families linked the

  16. Modeling autosomal recessive cutis laxa type 1C in mice reveals distinct functions for Ltbp-4 isoforms

    DEFF Research Database (Denmark)

    Bultmann-Mellin, Insa; Conradi, Anne; Maul, Alexandra C

    2015-01-01

    Recent studies have revealed an important role for LTBP-4 in elastogenesis. Its mutational inactivation in humans causes autosomal recessive cutis laxa type 1C (ARCL1C), which is a severe disorder caused by defects of the elastic fiber network. Although the human gene involved in ARCL1C has been ...

  17. Splicing defect in FKBP10 gene causes autosomal recessive osteogenesis imperfecta disease: a case report.

    Science.gov (United States)

    Maghami, Fatemeh; Tabei, Seyed Mohammad Bagher; Moravej, Hossein; Dastsooz, Hassan; Modarresi, Farzaneh; Silawi, Mohammad; Faghihi, Mohammad Ali

    2018-05-25

    Osteogenesis imperfecta (OI) is a group of connective tissue disorder caused by mutations of genes involved in the production of collagen and its supporting proteins. Although the majority of reported OI variants are in COL1A1 and COL1A2 genes, recent reports have shown problems in other non-collagenous genes involved in the post translational modifications, folding and transport, transcription and proliferation of osteoblasts, bone mineralization, and cell signaling. Up to now, 17 types of OI have been reported in which types I to IV are the most frequent cases with autosomal dominant pattern of inheritance. Here we report an 8- year- old boy with OI who has had multiple fractures since birth and now he is wheelchair-dependent. To identify genetic cause of OI in our patient, whole exome sequencing (WES) was carried out and it revealed a novel deleterious homozygote splice acceptor site mutation (c.1257-2A > G, IVS7-2A > G) in FKBP10 gene in the patient. Then, the identified mutation was confirmed using Sanger sequencing in the proband as homozygous and in his parents as heterozygous, indicating its autosomal recessive pattern of inheritance. In addition, we performed RT-PCR on RNA transcripts originated from skin fibroblast of the proband to analyze the functional effect of the mutation on splicing pattern of FKBP10 gene and it showed skipping of the exon 8 of this gene. Moreover, Real-Time PCR was carried out to quantify the expression level of FKBP10 in the proband and his family members in which it revealed nearly the full decrease in the level of FKBP10 expression in the proband and around 75% decrease in its level in the carriers of the mutation, strongly suggesting the pathogenicity of the mutation. Our study identified, for the first time, a private pathogenic splice site mutation in FKBP10 gene and further prove the involvement of this gene in the rare cases of autosomal recessive OI type XI with distinguished clinical manifestations.

  18. Autosomal recessive retinitis pigmentosa caused by mutations in the MAK gene.

    Science.gov (United States)

    Stone, Edwin M; Luo, Xunda; Héon, Elise; Lam, Byron L; Weleber, Richard G; Halder, Jennifer A; Affatigato, Louisa M; Goldberg, Jacqueline B; Sumaroka, Alexander; Schwartz, Sharon B; Cideciyan, Artur V; Jacobson, Samuel G

    2011-12-28

    To determine the disease expression in autosomal recessive (ar) retinitis pigmentosa (RP) caused by mutations in the MAK (male germ cell-associated kinase) gene. Patients with RP and MAK gene mutations (n = 24; age, 32-77 years at first visit) were studied by ocular examination, perimetry, and optical coherence tomography (OCT). All but one MAK patient were homozygous for an identical truncating mutation in exon 9 and had Ashkenazi Jewish heritage. The carrier frequency of this mutation among 1207 unrelated Ashkenazi control subjects was 1 in 55, making it the most common cause of heritable retinal disease in this population and MAK-associated RP the sixth most common Mendelian disease overall in this group. Visual acuities could be normal into the eighth decade of life. Kinetic fields showed early loss in the superior-temporal quadrant. With more advanced disease, superior and midperipheral function was lost, but the nasal field remained. Only a central island was present at late stages. Pigmentary retinopathy was less prominent in the superior nasal quadrant. Rod-mediated vision was abnormal but detectable in the residual field; all patients had rod>cone dysfunction. Photoreceptor layer thickness was normal centrally but decreased with eccentricity. At the stages studied, there was no evidence of photoreceptor ciliary elongation. The patterns of disease expression in the MAK form of arRP showed some resemblance to patterns described in autosomal dominant RP, especially the form caused by RP1 mutations. The similarity in phenotypes is of interest, considering that there is experimental evidence of interaction between Mak and RP1 in the photoreceptor cilium.

  19. Autosomal recessive retinitis pigmentosa with RP1 mutations is associated with myopia.

    Science.gov (United States)

    Chassine, Thomas; Bocquet, Béatrice; Daien, Vincent; Avila-Fernandez, Almudena; Ayuso, Carmen; Collin, Rob Wj; Corton, Marta; Hejtmancik, J Fielding; van den Born, L Ingeborgh; Klevering, B Jeroen; Riazuddin, S Amer; Sendon, Nathacha; Lacroux, Annie; Meunier, Isabelle; Hamel, Christian P

    2015-10-01

    To determine the refractive error in patients with autosomal recessive retinitis pigmentosa (arRP) caused by RP1 mutations and to compare it with that of other genetic subtypes of RP. Twenty-six individuals had arRP with RP1 mutations, 25 had autosomal dominant RP (adRP) with RP1 mutation, 8 and 33 had X-linked RP (xlRP) with RP2 and RPGR mutations, respectively, 198 and 93 had Usher syndrome and arRP without RP1 mutations, respectively. The median of the spherical equivalent (SE) and the IQR (Q25-Q75) was determined and multiple comparisons were performed. arRP patients with RP1 mutations had SE median at -4.0 dioptres (D) OD (Ocula Dextra); -3.88 D OS (Ocula Sinistra), whereas arRP patients without RP1 mutations (-0.50 D OD; -0.75 D OS) and Usher syndrome patients (-0.50 D OD; -0.38 D OS) were significantly less myopic (pUsher syndrome and adRP with RP1 mutation had a narrow IQR (-9.06 to -1.13 D), whereas arRP with RP1 mutations and xlRP with RP2 or RPGR mutations had a larger range (-9.06; -1.13 D). arRP patients with RP1 mutations have myopia not different from patients with xlRP with RP2 or RPGR mutations, while RP patients from other genetic subgroups were emmetropic or mildly myopic. We suggest that arRP patients with high myopic refractive error should be preferentially analysed for RP1 mutations. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  20. An intronic deletion in the PROM1 gene leads to autosomal recessive cone-rod dystrophy.

    Science.gov (United States)

    Eidinger, Osnat; Leibu, Rina; Newman, Hadas; Rizel, Leah; Perlman, Ido; Ben-Yosef, Tamar

    2015-01-01

    To investigate the genetic basis for autosomal recessive cone-rod dystrophy (CRD) in a consanguineous Israeli Jewish family. Patients underwent a detailed ophthalmic evaluation, including eye examination, visual field testing, optical coherence tomography (OCT), and electrophysiological tests, electroretinography (ERG) and visual evoked potential (VEP). Genome-wide homozygosity mapping using a single nucleotide polymorphism (SNP) array was performed to identify homozygous regions shared among two of the affected individuals. Mutation screening of the underlying gene was performed with direct sequencing. In silico and in vitro analyses were used to predict the effect of the identified mutation on splicing. The affected family members are three siblings who have various degrees of progressive visual deterioration, glare, color vision abnormalities, and night vision difficulties. Visual field tests revealed central scotomas of different extension. Cone and rod ERG responses were reduced, with cones more severely affected. Homozygosity mapping revealed several homozygous intervals shared among two of the affected individuals. One included the PROM1 gene. Sequence analysis of the 26 coding exons of PROM1 in one affected individual revealed no mutations in the coding sequence or in intronic splice sites. However, in intron 21, proximate to the intron-exon junction, we observed a homozygous 10 bp deletion between positions -26 and -17 (c.2281-26_-17del). The deletion was linked to a known SNP, c.2281-6C>G. The deletion cosegregated with the disease in the family, and was not detected in public databases or in 101 ethnically-matched control individuals. In silico analysis predicted that this deletion would lead to altered intron 21 splicing. Bioinformatic analysis predicted that a recognition site for the SRSF2 splicing factor is located within the deleted sequence. The in vitro splicing assay demonstrated that c.2281-26_-17del leads to complete exon 22 skipping. A novel

  1. Mutation in LIM2 Is Responsible for Autosomal Recessive Congenital Cataracts.

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    Bushra Irum

    Full Text Available To identify the molecular basis of non-syndromic autosomal recessive congenital cataracts (arCC in a consanguineous family.All family members participating in the study received a comprehensive ophthalmic examination to determine their ocular phenotype and contributed a blood sample, from which genomic DNA was extracted. Available medical records and interviews with the family were used to compile the medical history of the family. The symptomatic history of the individuals exhibiting cataracts was confirmed by slit-lamp biomicroscopy. A genome-wide linkage analysis was performed to localize the disease interval. The candidate gene, LIM2 (lens intrinsic membrane protein 2, was sequenced bi-directionally to identify the disease-causing mutation. The physical changes caused by the mutation were analyzed in silico through homology modeling, mutation and bioinformatic algorithms, and evolutionary conservation databases. The physiological importance of LIM2 to ocular development was assessed in vivo by real-time expression analysis of Lim2 in a mouse model.Ophthalmic examination confirmed the diagnosis of nuclear cataracts in the affected members of the family; the inheritance pattern and cataract development in early infancy indicated arCC. Genome-wide linkage analysis localized the critical interval to chromosome 19q with a two-point logarithm of odds (LOD score of 3.25. Bidirectional sequencing identified a novel missense mutation, c.233G>A (p.G78D in LIM2. This mutation segregated with the disease phenotype and was absent in 192 ethnically matched control chromosomes. In silico analysis predicted lower hydropathicity and hydrophobicity but higher polarity of the mutant LIM2-encoded protein (MP19 compared to the wild-type. Moreover, these analyses predicted that the mutation would disrupt the secondary structure of a transmembrane domain of MP19. The expression of Lim2, which was detected in the mouse lens as early as embryonic day 15 (E15

  2. Genetics of Autosomal Recessive Polycystic Kidney Disease and Its Differential Diagnoses

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    Carsten Bergmann

    2018-02-01

    Full Text Available Autosomal recessive polycystic kidney disease (ARPKD is a hepatorenal fibrocystic disorder that is characterized by enlarged kidneys with progressive loss of renal function and biliary duct dilatation and congenital hepatic fibrosis that leads to portal hypertension in some patients. Mutations in the PKHD1 gene are the primary cause of ARPKD; however, the disease is genetically not as homogeneous as long thought and mutations in several other cystogenes can phenocopy ARPKD. The family history usually is negative, both for recessive, but also often for dominant disease genes due to de novo arisen mutations or recessive inheritance of variants in genes that usually follow dominant patterns such as the main ADPKD genes PKD1 and PKD2. Considerable progress has been made in the understanding of polycystic kidney disease (PKD. A reduced dosage of disease proteins leads to the disruption of signaling pathways underlying key mechanisms involved in cellular homeostasis, which may help to explain the accelerated and severe clinical progression of disease course in some PKD patients. A comprehensive knowledge of disease-causing genes is essential for counseling and to avoid genetic misdiagnosis, which is particularly important in the prenatal setting (e.g., preimplantation genetic diagnosis/PGD. For ARPKD, there is a strong demand for early and reliable prenatal diagnosis, which is only feasible by molecular genetic analysis. A clear genetic diagnosis is helpful for many families and improves the clinical management of patients. Unnecessary and invasive measures can be avoided and renal and extrarenal comorbidities early be detected in the clinical course. The increasing number of genes that have to be considered benefit from the advances of next-generation sequencing (NGS which allows simultaneous analysis of a large group of genes in a single test at relatively low cost and has become the mainstay for genetic diagnosis. The broad phenotypic and genetic

  3. Homozygosity mapping in autosomal recessive retinitis pigmentosa families detects novel mutations

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    Marzouka, Nour al Dain; Hebrard, Maxime; Manes, Gaël; Sénéchal, Audrey; Meunier, Isabelle; Hamel, Christian P.

    2013-01-01

    Purpose Autosomal recessive retinitis pigmentosa (arRP) is a genetically heterogeneous disease resulting in progressive loss of photoreceptors that leads to blindness. To date, 36 genes are known to cause arRP, rendering the molecular diagnosis a challenge. The aim of this study was to use homozygosity mapping to identify the causative mutation in a series of inbred families with arRP. Methods arRP patients underwent standard ophthalmic examination, Goldman perimetry, fundus examination, retinal OCT, autofluorescence measurement, and full-field electroretinogram. Fifteen consanguineous families with arRP excluded for USH2A and EYS were genotyped on 250 K SNP arrays. Homozygous regions were listed, and known genes within these regions were PCR sequenced. Familial segregation and mutation analyzes were performed. Results We found ten mutations, seven of which were novel mutations in eight known genes, including RP1, IMPG2, NR2E3, PDE6A, PDE6B, RLBP1, CNGB1, and C2ORF71, in ten out of 15 families. The patients carrying RP1, C2ORF71, and IMPG2 mutations presented with severe RP, while those with PDE6A, PDE6B, and CNGB1 mutations were less severely affected. The five families without mutations in known genes could be a source of identification of novel genes. Conclusions Homozygosity mapping combined with systematic screening of known genes results in a positive molecular diagnosis in 66.7% of families. PMID:24339724

  4. Whole exome analysis identifies frequent CNGA1 mutations in Japanese population with autosomal recessive retinitis pigmentosa.

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    Satoshi Katagiri

    Full Text Available OBJECTIVE: The purpose of this study was to investigate frequent disease-causing gene mutations in autosomal recessive retinitis pigmentosa (arRP in the Japanese population. METHODS: In total, 99 Japanese patients with non-syndromic and unrelated arRP or sporadic RP (spRP were recruited in this study and ophthalmic examinations were conducted for the diagnosis of RP. Among these patients, whole exome sequencing analysis of 30 RP patients and direct sequencing screening of all CNGA1 exons of the other 69 RP patients were performed. RESULTS: Whole exome sequencing of 30 arRP/spRP patients identified disease-causing gene mutations of CNGA1 (four patients, EYS (three patients and SAG (one patient in eight patients and potential disease-causing gene variants of USH2A (two patients, EYS (one patient, TULP1 (one patient and C2orf71 (one patient in five patients. Screening of an additional 69 arRP/spRP patients for the CNGA1 gene mutation revealed one patient with a homozygous mutation. CONCLUSIONS: This is the first identification of CNGA1 mutations in arRP Japanese patients. The frequency of CNGA1 gene mutation was 5.1% (5/99 patients. CNGA1 mutations are one of the most frequent arRP-causing mutations in Japanese patients.

  5. Distribution of skeletal muscle involvement in autosomal recessive distal muscular dystrophy

    International Nuclear Information System (INIS)

    Mizusawa, Hidehiro; Nakanishi, Takao; Kobayashi, Fumie.

    1987-01-01

    Distribution of skeletal muscle involvement in 5 cases with autosomal recessive distal muscular dystrophy was studied clinically and by computed tomography (CT). Manual muscle test showed muscle involvement with a predilection for flexors in the lower leg and adductors in the thigh. Flexion and extension of the thigh and the lower leg was impaired to similar degree. In progressed cases, neck flexors and trunk muscles were also affected mildly. CT disclosed more clearly the preferential involvement of flexors in the lower leg, and involvement of both hamstrings · adductors group and extensors group of the thigh to similar degree. However, m. popliteus was curiously well preserved. In addition, there was a stage showing high density and hypertrophy of m. sartorius, m. gracilis, m. adductor, m. biceps femoris, m. semimenbranosus, m. semitendinosus or m. rectus femoris, which in thought to be compensatory hypertrophy. M. gluteus minimus in the pelvic girdle and m. dorsi proprii in the trunk were also liable to be affected. The CT findings are regarded as characteristic features noted clearly before muscle weakness and atrophy become apparent clinically. CT is very useful for distinguishing distal muscular dystrophy from rimmed vacuolar distal myopathy in which m. quadriceps femoris and flexors of the lower leg are usually well preserved without compensatory hypertrophy on CT. (author)

  6. Libyan Boy with Autosomal Recessive Trait (P22-phox Defect of Chronic Granulomatous Disease

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    Ilka Schulze

    2006-09-01

    Full Text Available Chronic granulomatous disease (CGD is a primary immune deficiency disorder of the phagocytes. In this disorder, phagocytic cells (polymorphonuclear leukocytes and monocytes cannot produce active oxygen metabolites, and therefore, cannot destroy the ingested intracellular bacteria. Clinically, patients with CGD usually have recurrent bacterial and fungal infections causing abscess and granuloma formation in the skin, lymph nodes and visceral organs.In this report, we present a boy from Libya with a rare autosomal recessive trait of CGD (defect of p22-phox who has chronic lung disease following multiple severe pneumonia attacks. The case we present suffered from bloody diarrhea since the third month of his life. He also had recurrent episodes of fever, and later, developed persistent cervical lymphadenitis and failure to gain weight. CGD is a very rare condition worldwide. It is also not recognized here in Libya, and usually not in the list of differential diagnosis for chronic pulmonary infections. We advise that pediatricians and general practitioners who treat chronic cases of lung diseases (with or without chronic diarrhea should consider primary immunodeficiency disorders in the hope that early diagnosis and treatment may prevent chronic complications especially of the respiratory tract. Furthermore, we state that, to the best of our knowledge, this is the first documented case of CGD from Libya.

  7. EYS Mutations Causing Autosomal Recessive Retinitis Pigmentosa: Changes of Retinal Structure and Function with Disease Progression

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    David B. McGuigan

    2017-07-01

    Full Text Available Mutations in the EYS (eyes shut homolog gene are a common cause of autosomal recessive (ar retinitis pigmentosa (RP. Without a mammalian model of human EYS disease, there is limited understanding of details of disease expression and rates of progression of the retinal degeneration. We studied clinically and with chromatic static perimetry, spectral-domain optical coherence tomography (OCT, and en face autofluoresence imaging, a cohort of 15 patients (ages 12–51 at first visit, some of whom had longitudinal data of function and structure. Rod sensitivity was able to be measured by chromatic perimetry in most patients at their earliest visits and some patients retained patchy rod function into the fifth decade of life. As expected from RP, cone sensitivity persisted after rod function was no longer measurable. The photoreceptor nuclear layer of the central retina was abnormal except at the fovea in most patients at first visit. Perifoveal disease measured over a period of years indicated that photoreceptor structural loss was followed by dysmorphology of the inner retina and loss of retinal pigment epithelial integrity. Although there could be variability in severity, preliminary analyses of the rates of vision loss suggested that EYS is a more rapidly progressive disease than other ciliopathies causing arRP, such as USH2A and MAK.

  8. Fetal brain disruption sequence versus fetal brain arrest: A distinct autosomal recessive developmental brain malformation phenotype.

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    Abdel-Salam, Ghada M H; Abdel-Hamid, Mohamed S; El-Khayat, Hamed A; Eid, Ola M; Saba, Soliman; Farag, Mona K; Saleem, Sahar N; Gaber, Khaled R

    2015-05-01

    The term fetal brain disruption sequence (FBDS) was coined to describe a number of sporadic conditions caused by numerous external disruptive events presenting with variable imaging findings. However, rare familial occurrences have been reported. We describe five patients (two sib pairs and one sporadic) with congenital severe microcephaly, seizures, and profound intellectual disability. Brain magnetic resonance imaging (MRI) revealed unique and uniform picture of underdeveloped cerebral hemispheres with increased extraxial CSF, abnormal gyral pattern (polymicrogyria-like lesions in two sibs and lissencephaly in the others), loss of white matter, dysplastic ventricles, hypogenesis of corpus callosum, and hypoplasia of the brainstem, but hypoplastic cerebellum in one. Fetal magnetic resonance imaging (FMRI) of two patients showed the same developmental brain malformations in utero. These imaging findings are in accordance with arrested brain development rather than disruption. Molecular analysis excluded mutations in potentially related genes such as NDE1, MKL2, OCLN, and JAM3. These unique clinical and imaging findings were described before among familial reports with FBDS. However, our patients represent a recognizable phenotype of developmental brain malformations, that is, apparently distinguishable from either familial microhydranencephaly or microlissencephaly that were collectively termed FBDS. Thus, the use of the umbrella term FBDS is no longer helpful. Accordingly, we propose the term fetal brain arrest to distinguish them from other familial patients diagnosed as FBDS. The presence of five affected patients from three unrelated consanguineous families suggests an autosomal-recessive mode of inheritance. The spectrum of fetal brain disruption sequence is reviewed. © 2015 Wiley Periodicals, Inc.

  9. Missense variants in AIMP1 gene are implicated in autosomal recessive intellectual disability without neurodegeneration.

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    Iqbal, Zafar; Püttmann, Lucia; Musante, Luciana; Razzaq, Attia; Zahoor, Muhammad Yasir; Hu, Hao; Wienker, Thomas F; Garshasbi, Masoud; Fattahi, Zohreh; Gilissen, Christian; Vissers, Lisenka E L M; de Brouwer, Arjan P M; Veltman, Joris A; Pfundt, Rolph; Najmabadi, Hossein; Ropers, Hans-Hilger; Riazuddin, Sheikh; Kahrizi, Kimia; van Bokhoven, Hans

    2016-03-01

    AIMP1/p43 is a multifunctional non-catalytic component of the multisynthetase complex. The complex consists of nine catalytic and three non-catalytic proteins, which catalyze the ligation of amino acids to their cognate tRNA isoacceptors for use in protein translation. To date, two allelic variants in the AIMP1 gene have been reported as the underlying cause of autosomal recessive primary neurodegenerative disorder. Here, we present two consanguineous families from Pakistan and Iran, presenting with moderate to severe intellectual disability, global developmental delay, and speech impairment without neurodegeneration. By the combination of homozygosity mapping and next generation sequencing, we identified two homozygous missense variants, p.(Gly299Arg) and p.(Val176Gly), in the gene AIMP1 that co-segregated with the phenotype in the respective families. Molecular modeling of the variants revealed deleterious effects on the protein structure that are predicted to result in reduced AIMP1 function. Our findings indicate that the clinical spectrum for AIMP1 defects is broader than witnessed so far.

  10. A defect in the CLIP1 gene (CLIP-170) can cause autosomal recessive intellectual disability.

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    Larti, Farzaneh; Kahrizi, Kimia; Musante, Luciana; Hu, Hao; Papari, Elahe; Fattahi, Zohreh; Bazazzadegan, Niloofar; Liu, Zhe; Banan, Mehdi; Garshasbi, Masoud; Wienker, Thomas F; Ropers, H Hilger; Galjart, Niels; Najmabadi, Hossein

    2015-03-01

    In the context of a comprehensive research project, investigating novel autosomal recessive intellectual disability (ARID) genes, linkage analysis based on autozygosity mapping helped identify an intellectual disability locus on Chr.12q24, in an Iranian family (LOD score = 3.7). Next-generation sequencing (NGS) following exon enrichment in this novel interval, detected a nonsense mutation (p.Q1010*) in the CLIP1 gene. CLIP1 encodes a member of microtubule (MT) plus-end tracking proteins, which specifically associates with the ends of growing MTs. These proteins regulate MT dynamic behavior and are important for MT-mediated transport over the length of axons and dendrites. As such, CLIP1 may have a role in neuronal development. We studied lymphoblastoid and skin fibroblast cell lines established from healthy and affected patients. RT-PCR and western blot analyses showed the absence of CLIP1 transcript and protein in lymphoblastoid cells derived from affected patients. Furthermore, immunofluorescence analyses showed MT plus-end staining only in fibroblasts containing the wild-type (and not the mutant) CLIP1 protein. Collectively, our data suggest that defects in CLIP1 may lead to ARID.

  11. Missense variants in AIMP1 gene are implicated in autosomal recessive intellectual disability without neurodegeneration

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    Iqbal, Zafar; Püttmann, Lucia; Musante, Luciana; Razzaq, Attia; Zahoor, Muhammad Yasir; Hu, Hao; Wienker, Thomas F; Garshasbi, Masoud; Fattahi, Zohreh; Gilissen, Christian; Vissers, Lisenka ELM; de Brouwer, Arjan PM; Veltman, Joris A; Pfundt, Rolph; Najmabadi, Hossein; Ropers, Hans-Hilger; Riazuddin, Sheikh; Kahrizi, Kimia; van Bokhoven, Hans

    2016-01-01

    AIMP1/p43 is a multifunctional non-catalytic component of the multisynthetase complex. The complex consists of nine catalytic and three non-catalytic proteins, which catalyze the ligation of amino acids to their cognate tRNA isoacceptors for use in protein translation. To date, two allelic variants in the AIMP1 gene have been reported as the underlying cause of autosomal recessive primary neurodegenerative disorder. Here, we present two consanguineous families from Pakistan and Iran, presenting with moderate to severe intellectual disability, global developmental delay, and speech impairment without neurodegeneration. By the combination of homozygosity mapping and next generation sequencing, we identified two homozygous missense variants, p.(Gly299Arg) and p.(Val176Gly), in the gene AIMP1 that co-segregated with the phenotype in the respective families. Molecular modeling of the variants revealed deleterious effects on the protein structure that are predicted to result in reduced AIMP1 function. Our findings indicate that the clinical spectrum for AIMP1 defects is broader than witnessed so far. PMID:26173967

  12. Genetic Defects Underlie the Non-syndromic Autosomal Recessive Intellectual Disability (NS-ARID

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    Saleha Shamim

    2017-05-01

    Full Text Available Intellectual disability (ID is a neurodevelopmental disorder which appears frequently as the result of genetic mutations and may be syndromic (S-ID or non-syndromic (NS-ID. ID causes an important economic burden, for patient's family, health systems, and society. Identifying genes that cause S-ID can easily be evaluated due to the clinical symptoms or physical anomalies. However, in the case of NS-ID due to the absence of co-morbid features, the latest molecular genetic techniques can be used to understand the genetic defects that underlie it. Recent studies have shown that non-syndromic autosomal recessive (NS-ARID is extremely heterogeneous and contributes much more than X-linked ID. However, very little is known about the genes and loci involved in NS-ARID relative to X-linked ID, and whose complete genetic etiology remains obscure. In this review article, the known genetic etiology of NS-ARID and possible relationships between genes and the associated molecular pathways of their encoded proteins has been reviewed which will enhance our understanding about the underlying genes and mechanisms in NS-ARID.

  13. Naturally- and experimentally-designed restorations of the Parkin gene deficit in autosomal recessive juvenile parkinsonism

    International Nuclear Information System (INIS)

    Asai, Hirohide; Hirano, Makito; Kiriyama, Takao; Ikeda, Masanori; Ueno, Satoshi

    2010-01-01

    Intranuclear events due to mutations in the Parkin gene remain elusive in autosomal recessive juvenile parkinsonism (ARJP). We identified a mutant PARKIN protein in fibroblast cultures from a pair of siblings with ARJP who were homozygous for the exon 4-deleted Parkin gene. Disease was mild in one patient and debilitating in the other. The detected mutant, encoded by a transcript lacking exon 3 as well as exon 4, is an in-frame deletion that removes 121 aa, resulting in a 344-aa protein (PaDel3,4). Cell culture and transfection studies revealed negative correlations between expression levels of PaDel3,4 and those of cell cycle proteins, including cyclin E, CDK2, ppRb, and E2F-1, and demonstrated that GFP-PaDel3,4 entered nucleus and ubiquitinated cyclin E as a part of SCF hSel-10 ligase complex in the patient cells. In addition, nuclear localization signal-tagged PaDel3,4 expressed in the transfected patient cells most effectively ubiquitinated cyclin E and reduced DNA damage, protecting cells from oxidative stress. Antisense-oligonucleotide treatment promoted skipping of exon 3 and thus generated PaDel3,4, increasing cell survival. Collectively, we propose that naturally- and experimentally-induced exon skipping at least partly restores the mutant Parkin gene deficit, providing a molecular basis for the development of therapeutic exon skipping.

  14. Novel mutations in the genes TGM1 and ALOXE3 underlying autosomal recessive congenital ichthyosis

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    Ullah, Rahim; Ansar, Muhammad; Durrani, Zaka Ullah; Lee, Kwanghyuk; Santos-Cortez, Regie Lyn P.; Muhammad, Dost; Ali, Mahboob; Zia, Muhammad; Ayub, Muhammad; Khan, Suliman; Smith, Josh D.; Nickerson, Deborah A.; Shendure, Jay; Bamshad, Michael; Leal, Suzanne M.; Ahmad, Wasim

    2016-01-01

    Background Ichthyoses are clinically characterized by scaling or hyperkeratosis of the skin or both. It can be an isolated condition limited to the skin or appear secondarily with involvement of other cutaneous or systemic abnormalities. Methods The present study investigated clinical and molecular characterization of three consanguineous families (A, B, C) segregating two different forms of autosomal recessive congenital ichthyosis (ARCI). Linkage in three consanguineous families (A, B, C) segregating two different forms of ARCI was searched by typing microsatellite and single nucleotide polymorphism marker analysis. Sequencing of the two genes TGM1 and ALOXE3 was performed by the dideoxy chain termination method. Results Genome-wide linkage analysis established linkage in family A to TGM1 gene on chromosome 14q11 and in families B and C to ALOXE3 gene on chromosome 17p13. Subsequently, sequencing of these genes using samples from affected family members led to the identification of three novel mutations: a missense variant p.Trp455Arg in TGM1 (family A); a nonsense variant p.Arg140* in ALOXE3 (family B); and a complex rearrangement in ALOXE3 (family C). Conclusion The present study further extends the spectrum of mutations in the two genes involved in causing ARCI. Characterizing the clinical spectrum resulting from mutations in the TGM1 and ALOXE3 genes will improve diagnosis and may direct clinical care of the family members. PMID:26578203

  15. Mutation analysis of 272 Spanish families affected by autosomal recessive retinitis pigmentosa using a genotyping microarray.

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    Ávila-Fernández, Almudena; Cantalapiedra, Diego; Aller, Elena; Vallespín, Elena; Aguirre-Lambán, Jana; Blanco-Kelly, Fiona; Corton, M; Riveiro-Álvarez, Rosa; Allikmets, Rando; Trujillo-Tiebas, María José; Millán, José M; Cremers, Frans P M; Ayuso, Carmen

    2010-12-03

    Retinitis pigmentosa (RP) is a genetically heterogeneous disorder characterized by progressive loss of vision. The aim of this study was to identify the causative mutations in 272 Spanish families using a genotyping microarray. 272 unrelated Spanish families, 107 with autosomal recessive RP (arRP) and 165 with sporadic RP (sRP), were studied using the APEX genotyping microarray. The families were also classified by clinical criteria: 86 juveniles and 186 typical RP families. Haplotype and sequence analysis were performed to identify the second mutated allele. At least one-gene variant was found in 14% and 16% of the juvenile and typical RP groups respectively. Further study identified four new mutations, providing both causative changes in 11% of the families. Retinol Dehydrogenase 12 (RDH12) was the most frequently mutated gene in the juvenile RP group, and Usher Syndrome 2A (USH2A) and Ceramide Kinase-Like (CERKL) were the most frequently mutated genes in the typical RP group. The only variant found in CERKL was p.Arg257Stop, the most frequent mutation. The genotyping microarray combined with segregation and sequence analysis allowed us to identify the causative mutations in 11% of the families. Due to the low number of characterized families, this approach should be used in tandem with other techniques.

  16. Novel compound heterozygous MYO7A mutations in Moroccan families with autosomal recessive non-syndromic hearing loss.

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    Amina Bakhchane

    Full Text Available The MYO7A gene encodes a protein belonging to the unconventional myosin super family. Mutations within MYO7A can lead to either non syndromic hearing loss or to the Usher syndrome type 1B (USH1B. Here, we report the results of genetic analyses performed on Moroccan families with autosomal recessive non syndromic hearing loss that identified two families with compound heterozygous MYO7A mutations. Five mutations (c.6025delG, c.6229T>A, c.3500T>A, c.5617C>T and c.4487C>A were identified in these families, the latter presenting two differently affected branches. Multiple bioinformatics programs and molecular modelling predicted the pathogenic effect of these mutations. In conclusion, the absence of vestibular and retinal symptom in the affected patients suggests that these families have the isolated non-syndromic hearing loss DFNB2 (nonsyndromic autosomal recessive hearing loss presentation, instead of USH1B.

  17. Genetic spectrum of autosomal recessive non-syndromic hearing loss in Pakistani families.

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    Sobia Shafique

    Full Text Available The frequency of inherited bilateral autosomal recessive non-syndromic hearing loss (ARNSHL in Pakistan is 1.6/1000 individuals. More than 50% of the families carry mutations in GJB2 while mutations in MYO15A account for about 5% of recessive deafness. In the present study a cohort of 30 ARNSHL families was initially screened for mutations in GJB2 and MYO15A. Homozygosity mapping was performed by employing whole genome single nucleotide polymorphism (SNP genotyping in the families that did not carry mutations in GJB2 or MYO15A. Mutation analysis was performed for the known ARNSHL genes present in the homozygous regions to determine the causative mutations. This allowed the identification of a causative mutation in all the 30 families including 9 novel mutations, which were identified in 9 different families (GJB2 (c.598G>A, p.Gly200Arg; MYO15A (c.9948G>A, p.Gln3316Gln; c.3866+1G>A; c.8767C>T, p.Arg2923* and c.8222T>C, p.Phe2741Ser, TMC1 (c.362+18A>G, BSND (c.97G>C, p.Val33Leu, TMPRSS3 (c.726C>G, p.Cys242Trp and MSRB3 (c.20T>G, p.Leu7Arg. Furthermore, 12 recurrent mutations were detected in 21 other families. The 21 identified mutations included 10 (48% missense changes, 4 (19% nonsense mutations, 3 (14% intronic mutations, 2 (9% splice site mutations and 2 (9% frameshift mutations. GJB2 accounted for 53% of the families, while mutations in MYO15A were the second most frequent (13% cause of ARNSHL in these 30 families. The identification of novel as well as recurrent mutations in the present study increases the spectrum of mutations in known deafness genes which could lead to the identification of novel founder mutations and population specific mutated deafness genes causative of ARNSHL. These results provide detailed genetic information that has potential diagnostic implication in the establishment of cost-efficient allele-specific analysis of frequently occurring variants in combination with other reported mutations in Pakistani populations.

  18. Deletion at the GCNT2 Locus Causes Autosomal Recessive Congenital Cataracts.

    Science.gov (United States)

    Irum, Bushra; Khan, Shahid Y; Ali, Muhammad; Daud, Muhammad; Kabir, Firoz; Rauf, Bushra; Fatima, Fareeha; Iqbal, Hira; Khan, Arif O; Al Obaisi, Saif; Naeem, Muhammad Asif; Nasir, Idrees A; Khan, Shaheen N; Husnain, Tayyab; Riazuddin, Sheikh; Akram, Javed; Eghrari, Allen O; Riazuddin, S Amer

    2016-01-01

    The aim of this study is to identify the molecular basis of autosomal recessive congenital cataracts (arCC) in a large consanguineous pedigree. All participating individuals underwent a detailed ophthalmic examination. Each patient's medical history, particularly of cataracts and other ocular abnormalities, was compiled from available medical records and interviews with family elders. Blood samples were donated by all participating family members and used to extract genomic DNA. Genetic analysis was performed to rule out linkage to known arCC loci and genes. Whole-exome sequencing libraries were prepared and paired-end sequenced. A large deletion was found that segregated with arCC in the family, and chromosome walking was conducted to estimate the proximal and distal boundaries of the deletion mutation. Exclusion and linkage analysis suggested linkage to a region of chromosome 6p24 harboring GCNT2 (glucosaminyl (N-acetyl) transferase 2) with a two-point logarithm of odds score of 5.78. PCR amplifications of the coding exons of GCNT2 failed in individuals with arCC, and whole-exome data analysis revealed a large deletion on chromosome 6p in the region harboring GCNT2. Chromosomal walking using multiple primer pairs delineated the extent of the deletion to approximately 190 kb. Interestingly, a failure to amplify a junctional fragment of the deletion break strongly suggests an insertion in addition to the large deletion. Here, we report a novel insertion/deletion mutation at the GCNT2 locus that is responsible for congenital cataracts in a large consanguineous family.

  19. Autosomal recessive atrial dilated cardiomyopathy with standstill evolution associated with mutation of Natriuretic Peptide Precursor A.

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    Disertori, Marcello; Quintarelli, Silvia; Grasso, Maurizia; Pilotto, Andrea; Narula, Nupoor; Favalli, Valentina; Canclini, Camilla; Diegoli, Marta; Mazzola, Silvia; Marini, Massimiliano; Del Greco, Maurizio; Bonmassari, Roberto; Masè, Michela; Ravelli, Flavia; Specchia, Claudia; Arbustini, Eloisa

    2013-02-01

    Atrial dilatation and atrial standstill are etiologically heterogeneous phenotypes with poorly defined nosology. In 1983, we described 8-years follow-up of atrial dilatation with standstill evolution in 8 patients from 3 families. We later identified 5 additional patients with identical phenotypes: 1 member of the largest original family and 4 unrelated to the 3 original families. All families are from the same geographic area in Northeast Italy. We followed up the 13 patients for up to 37 years, extended the clinical investigation and monitoring to living relatives, and investigated the genetic basis of the disease. The disease was characterized by: (1) clinical onset in adulthood; (2) biatrial dilatation up to giant size; (3) early supraventricular arrhythmias with progressive loss of atrial electric activity to atrial standstill; (4) thromboembolic complications; and (5) stable, normal left ventricular function and New York Heart Association functional class during the long-term course of the disease. By linkage analysis, we mapped a locus at 1p36.22 containing the Natriuretic Peptide Precursor A gene. By sequencing Natriuretic Peptide Precursor A, we identified a homozygous missense mutation (p.Arg150Gln) in all living affected individuals of the 6 families. All patients showed low serum levels of atrial natriuretic peptide. Heterozygous mutation carriers were healthy and demonstrated normal levels of atrial natriuretic peptide. Autosomal recessive atrial dilated cardiomyopathy is a rare disease associated with homozygous mutation of the Natriuretic Peptide Precursor A gene and characterized by extreme atrial dilatation with standstill evolution, thromboembolic risk, preserved left ventricular function, and severely decreased levels of atrial natriuretic peptide.

  20. A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects.

    Directory of Open Access Journals (Sweden)

    Jinglan Zhang

    2016-04-01

    Full Text Available Genetic leukoencephalopathies (gLEs are a group of heterogeneous disorders with white matter abnormalities affecting the central nervous system (CNS. The causative mutation in ~50% of gLEs is unknown. Using whole exome sequencing (WES, we identified homozygosity for a missense variant, VPS11: c.2536T>G (p.C846G, as the genetic cause of a leukoencephalopathy syndrome in five individuals from three unrelated Ashkenazi Jewish (AJ families. All five patients exhibited highly concordant disease progression characterized by infantile onset leukoencephalopathy with brain white matter abnormalities, severe motor impairment, cortical blindness, intellectual disability, and seizures. The carrier frequency of the VPS11: c.2536T>G variant is 1:250 in the AJ population (n = 2,026. VPS11 protein is a core component of HOPS (homotypic fusion and protein sorting and CORVET (class C core vacuole/endosome tethering protein complexes involved in membrane trafficking and fusion of the lysosomes and endosomes. The cysteine 846 resides in an evolutionarily conserved cysteine-rich RING-H2 domain in carboxyl terminal regions of VPS11 proteins. Our data shows that the C846G mutation causes aberrant ubiquitination and accelerated turnover of VPS11 protein as well as compromised VPS11-VPS18 complex assembly, suggesting a loss of function in the mutant protein. Reduced VPS11 expression leads to an impaired autophagic activity in human cells. Importantly, zebrafish harboring a vps11 mutation with truncated RING-H2 domain demonstrated a significant reduction in CNS myelination following extensive neuronal death in the hindbrain and midbrain. Thus, our study reveals a defect in VPS11 as the underlying etiology for an autosomal recessive leukoencephalopathy disorder associated with a dysfunctional autophagy-lysosome trafficking pathway.

  1. A defect in the TUSC3 gene is associated with autosomal recessive mental retardation.

    Science.gov (United States)

    Garshasbi, Masoud; Hadavi, Valeh; Habibi, Haleh; Kahrizi, Kimia; Kariminejad, Roxana; Behjati, Farkhondeh; Tzschach, Andreas; Najmabadi, Hossein; Ropers, Hans Hilger; Kuss, Andreas Walter

    2008-05-01

    Recent studies have shown that autosomal recessive mental retardation (ARMR) is extremely heterogeneous, and there is reason to believe that the number of underlying gene defects goes into the thousands. To date, however, only four genes have been implicated in nonsyndromic ARMR (NS-ARMR): PRSS12 (neurotrypsin), CRBN (cereblon), CC2D1A, and GRIK2. As part of an ongoing systematic study aiming to identify ARMR genes, we investigated a large consanguineous family comprising seven patients with nonsyndromic ARMR in four sibships. Genome-wide SNP typing enabled us to map the relevant genetic defect to a 4.6 Mbp interval on chromosome 8. Haplotype analyses and copy-number studies led to the identification of a homozygous deletion partly removing TUSC3 (N33) in all patients. All obligate carriers of this family were heterozygous, but none of 192 unrelated healthy individuals from the same population carried this deletion. We excluded other disease-causing mutations in the coding regions of all genes within the linkage interval by sequencing; moreover, we verified the complete absence of a functional TUSC3 transcript in all patients through RT-PCR. TUSC3 is thought to encode a subunit of the endoplasmic reticulum-bound oligosaccharyltransferase complex that catalyzes a pivotal step in the protein N-glycosylation process. Our data suggest that in contrast to other genetic defects of glycosylation, inactivation of TUSC3 causes nonsyndromic MR, a conclusion that is supported by a separate report in this issue of AJHG. TUSC3 is only the fifth gene implicated in NS-ARMR and the first for which mutations have been reported in more than one family.

  2. Disease course in patients with autosomal recessive retinitis pigmentosa due to the USH2A gene.

    Science.gov (United States)

    Sandberg, Michael A; Rosner, Bernard; Weigel-DiFranco, Carol; McGee, Terri L; Dryja, Thaddeus P; Berson, Eliot L

    2008-12-01

    To estimate the mean rates of ocular function loss in patients with autosomal recessive retinitis pigmentosa due to USH2A mutations. In 125 patients with USH2A mutations, longitudinal regression was used to estimate mean rates of change in Snellen visual acuity, Goldmann visual field area (V4e white test light), and 30-Hz (cone) full-field electroretinogram amplitude. These rates were compared with those of previously studied cohorts with dominant retinitis pigmentosa due to RHO mutations and with X-linked retinitis pigmentosa due to RPGR mutations. Rates of change in patients with the Cys759Phe mutation, the USH2A mutation associated with nonsyndromic disease, were compared with rates of change in patients with the Glu767fs mutation, the most common USH2A mutation associated with Usher syndrome type II (i.e., retinitis pigmentosa and hearing loss). Mean annual exponential rates of decline for the USH2A patients were 2.6% for visual acuity, 7.0% for visual field area, and 13.2% for electroretinogram amplitude. The rate of acuity loss fell between the corresponding rates for the RHO and RPGR patients, whereas the rates for field and ERG amplitude loss were faster than those for the RHO and RPGR patients. No significant differences were found for patients with the Cys759Phe mutation versus patients with the Glu767fs mutation. On average, USH2A patients lose visual acuity faster than RHO patients and slower than RPGR patients. USH2A patients lose visual field and cone electroretinogram amplitude faster than patients with RHO or RPGR mutations. Patients with a nonsyndromic USH2A mutation have the same retinal disease course as patients with syndromic USH2A disease.

  3. Monogenic Diabetes

    Science.gov (United States)

    ... but can return later in life How are MODY and neonatal diabetes diagnosed? Because monogenic diabetes is rare, this diagnosis ... type 1 or type 2 diabetes and identify MODY or neonatal diabetes. Blood tests Blood tests of glucose levels, and ...

  4. Localization of A Novel Autosomal Recessive Non-Syndromic Hearing Impairment Locus (DFNB38) to 6q26–q27 in a Consanguineous Kindred from Pakistan

    OpenAIRE

    Ansar, Muhammad; Ramzan, Mohammad; Pham, Thanh L.; Yan, Kai; Jamal, Syed Muhammad; Haque, Sayedul; Ahmad, Wasim; Leal, Suzanne M.

    2003-01-01

    For autosomal recessive nonsyndromic hearing impairment over 30 loci have been mapped and 19 genes have been identified. DFNB38, a novel locus for autosomal recessive nonsyndromic hearing impairment, was localized in a consanguineous Pakistani kindred to 6q26–q27. The affected family members present with profound prelingual sensorineural hearing impairment and use sign language for communications. Linkage was established to microsatellite markers located on chromosome 6q26–q27 (Multipoint lod...

  5. Computational analysis of TRAPPC9: candidate gene for autosomal recessive non-syndromic mental retardation.

    Science.gov (United States)

    Khattak, Naureen Aslam; Mir, Asif

    2014-01-01

    Mental retardation (MR)/ intellectual disability (ID) is a neuro-developmental disorder characterized by a low intellectual quotient (IQ) and deficits in adaptive behavior related to everyday life tasks such as delayed language acquisition, social skills or self-help skills with onset before age 18. To date, a few genes (PRSS12, CRBN, CC2D1A, GRIK2, TUSC3, TRAPPC9, TECR, ST3GAL3, MED23, MAN1B1, NSUN1) for autosomal-recessive forms of non syndromic MR (NS-ARMR) have been identified and established in various families with ID. The recently reported candidate gene TRAPPC9 was selected for computational analysis to explore its potentially important role in pathology as it is the only gene for ID reported in more than five different familial cases worldwide. YASARA (12.4.1) was utilized to generate three dimensional structures of the candidate gene TRAPPC9. Hybrid structure prediction was employed. Crystal Structure of a Conserved Metalloprotein From Bacillus Cereus (3D19-C) was selected as best suitable template using position-specific iteration-BLAST. Template (3D19-C) parameters were based on E-value, Z-score and resolution and quality score of 0.32, -1.152, 2.30°A and 0.684 respectively. Model reliability showed 93.1% residues placed in the most favored region with 96.684 quality factor, and overall 0.20 G-factor (dihedrals 0.06 and covalent 0.39 respectively). Protein-Protein docking analysis demonstrated that TRAPPC9 showed strong interactions of the amino acid residues S(253), S(251), Y(256), G(243), D(131) with R(105), Q(425), W(226), N(255), S(233), its functional partner 1KBKB. Protein-protein interacting residues could facilitate the exploration of structural and functional outcomes of wild type and mutated TRAPCC9 protein. Actively involved residues can be used to elucidate the binding properties of the protein, and to develop drug therapy for NS-ARMR patients.

  6. Calpain 12 Function Revealed through the Study of an Atypical Case of Autosomal Recessive Congenital Ichthyosis.

    Science.gov (United States)

    Bochner, Ron; Samuelov, Liat; Sarig, Ofer; Li, Qiaoli; Adase, Christopher A; Isakov, Ofer; Malchin, Natalia; Vodo, Dan; Shayevitch, Ronna; Peled, Alon; Yu, Benjamin D; Fainberg, Gilad; Warshauer, Emily; Adir, Noam; Erez, Noam; Gat, Andrea; Gottlieb, Yehonatan; Rogers, Tova; Pavlovsky, Mor; Goldberg, Ilan; Shomron, Noam; Sandilands, Aileen; Campbell, Linda E; MacCallum, Stephanie; McLean, W H Irwin; Ast, Gil; Gallo, Richard L; Uitto, Jouni; Sprecher, Eli

    2017-02-01

    Congenital erythroderma is a rare and often life-threatening condition, which has been shown to result from mutations in several genes encoding important components of the epidermal differentiation program. Using whole exome sequencing, we identified in a child with congenital exfoliative erythroderma, hypotrichosis, severe nail dystrophy and failure to thrive, two heterozygous mutations in ABCA12 (c.2956C>T, p.R986W; c.5778+2T>C, p. G1900Mfs*16), a gene known to be associated with two forms of ichthyosis, autosomal recessive congenital ichthyosis, and harlequin ichthyosis. Because the patient displayed an atypical phenotype, including severe hair and nail manifestations, we scrutinized the exome sequencing data for additional potentially deleterious genetic variations in genes of relevance to the cornification process. Two mutations were identified in CAPN12, encoding a member of the calpain proteases: a paternal missense mutation (c.1511C>A; p.P504Q) and a maternal deletion due to activation of a cryptic splice site in exon 9 of the gene (c.1090_1129del; p.Val364Lysfs*11). The calpain 12 protein was found to be expressed in both the epidermis and hair follicle of normal skin, but its expression was dramatically reduced in the patient's skin. The downregulation of capn12 expression in zebrafish was associated with abnormal epidermal morphogenesis. Small interfering RNA knockdown of CAPN12 in three-dimensional human skin models was associated with acanthosis, disorganized epidermal architecture, and downregulation of several differentiation markers, including filaggrin. Accordingly, filaggrin expression was almost absent in the patient skin. Using ex vivo live imaging, small interfering RNA knockdown of calpain 12 in skin from K14-H2B GFP mice led to significant hair follicle catagen transformation compared with controls. In summary, our results indicate that calpain 12 plays an essential role during epidermal ontogenesis and normal hair follicle cycling and that

  7. Novel compound heterozygous mutations in MYO7A gene associated with autosomal recessive sensorineural hearing loss in a Chinese family.

    Science.gov (United States)

    Ma, Yalin; Xiao, Yun; Zhang, Fengguo; Han, Yuechen; Li, Jianfeng; Xu, Lei; Bai, Xiaohui; Wang, Haibo

    2016-04-01

    Mutations in MYO7A gene have been reported to be associated with Usher Syndrome type 1B (USH1B) and nonsyndromic hearing loss (DFNB2, DFNA11). Most mutations in MYO7A gene caused USH1B, whereas only a few reported mutations led to DFNB2 and DFNA11. The current study was designed to investigate the mutations among a Chinese family with autosomal recessive hearing loss. In this study, we present the clinical, genetic and molecular characteristics of a Chinese family. Targeted capture of 127 known deafness genes and next-generation sequencing were employed to study the genetic causes of two siblings in the Chinese family. Sanger sequencing was employed to examine those variant mutations in the members of this family and other ethnicity-matched controls. We identified the novel compound heterozygous mutant alleles of MYO7A gene: a novel missense mutation c.3671C>A (p.A1224D) and a reported insert mutation c.390_391insC (p.P131PfsX9). Variants were further confirmed by Sanger sequencing. These two compound heterozygous variants were co-segregated with autosomal recessive hearing loss phenotype. The gene mutation analysis and protein sequence alignment further supported that the novel compound heterozygous mutations were pathogenic. The novel compound heterozygous mutations (c.3671C>A and c.390_391insC) in MYO7A gene identified in this study were responsible for the autosomal recessive sensorineural hearing loss of this Chinese family. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  8. Mutations in the ABCA4 (ABCR) Gene Are the Major Cause of Autosomal Recessive Cone-Rod Dystrophy

    OpenAIRE

    Maugeri, Alessandra; Klevering, B. Jeroen; Rohrschneider, Klaus; Blankenagel, Anita; Brunner, Han G.; Deutman, August F.; Hoyng, Carel B.; Cremers, Frans P. M.

    2000-01-01

    The photoreceptor cell–specific ATP-binding cassette transporter gene (ABCA4; previously denoted “ABCR”) is mutated in most patients with autosomal recessive (AR) Stargardt disease (STGD1) or fundus flavimaculatus (FFM). In addition, a few cases with AR retinitis pigmentosa (RP) and AR cone-rod dystrophy (CRD) have been found to have ABCA4 mutations. To evaluate the importance of the ABCA4 gene as a cause of AR CRD, we selected 5 patients with AR CRD and 15 patients with isolated CRD, all fro...

  9. A novel HSF4 gene mutation (p.R405X causing autosomal recessive congenital cataracts in a large consanguineous family from Pakistan

    Directory of Open Access Journals (Sweden)

    Cheema Abdul

    2008-11-01

    Full Text Available Abstract Background Hereditary cataracts are most frequently inherited as autosomal dominant traits, but can also be inherited in an autosomal recessive or X-linked fashion. To date, 12 loci for autosomal recessive cataracts have been mapped including a locus on chromosome 16q22 containing the disease-causing gene HSF4 (Genbank accession number NM_001040667. Here, we describe a family from Pakistan with the first nonsense mutation in HSF4 thus expanding the mutational spectrum of this heat shock transcription factor gene. Methods A large consanguineous Pakistani family with autosomal recessive cataracts was collected from Quetta. Genetic linkage analysis was performed for the common known autosomal recessive cataracts loci and linkage to a locus containing HSF4 (OMIM 602438 was found. All exons and adjacent splice sites of the heat shock transcription factor 4 gene (HSF4 were sequenced. A mutation-specific restriction enzyme digest (HphI was performed for all family members and unrelated controls. Results The disease phenotype perfectly co-segregated with markers flanking the known cataract gene HSF4, whereas other autosomal recessive loci were excluded. A maximum two-point LOD score with a Zmax = 5.6 at θ = 0 was obtained for D16S421. Direct sequencing of HSF4 revealed the nucleotide exchange c.1213C > T in this family predicting an arginine to stop codon exchange (p.R405X. Conclusion We identified the first nonsense mutation (p.R405X in exon 11 of HSF4 in a large consanguineous Pakistani family with autosomal recessive cataract.

  10. Phenotypic spectrum of autosomal recessive cone-rod dystrophies caused by mutations in the ABCA4 (ABCR) gene.

    Science.gov (United States)

    Klevering, B Jeroen; Blankenagel, Anita; Maugeri, Alessandra; Cremers, Frans P M; Hoyng, Carel B; Rohrschneider, Klaus

    2002-06-01

    To describe the phenotype of 12 patients with autosomal recessive or isolated cone-rod types of progressive retinal degeneration (CRD) caused by mutations in the ABCA4 gene. The charts of patients who had originally received a diagnosis of isolated or autosomal recessive CRD were reviewed after molecular analysis revealed mutations in the ABCA4 gene. In two of the patients both the photopic and scotopic electroretinogram were nonrecordable. In the remainder, the photopic cone b-wave amplitudes appeared to be more seriously affected than the scotopic rod b-wave amplitudes. Although the clinical presentation was heterogeneous, all patients experienced visual loss early in life, impaired color vision, and a central scotoma. Fundoscopy revealed evidence of early-onset maculopathy, sometimes accompanied by involvement of the retinal periphery in the later stages of the disease. Mutations in the ABCA4 gene are the pathologic cause of the CRD-like dystrophy in these patients, and the resultant clinical pictures are complex and heterogeneous. Given this wide clinical spectrum of CRD-like phenotypes associated with ABCA4 mutations, detailed clinical subclassifications are difficult and may not be very useful.

  11. Mutation analysis of 272 Spanish families affected by autosomal recessive retinitis pigmentosa using a genotyping microarray.

    NARCIS (Netherlands)

    Avila-Fernandez, A.; Cantalapiedra, D.; Aller, E.; Vallespin, E.; Aguirre-Lamban, J.; Blanco-Kelly, F.; Corton, M.; Riveiro-Alvarez, R.; Allikmets, R.; Trujillo-Tiebas, M.J.; Millan, J.M.; Cremers, F.P.M.; Ayuso, C.

    2010-01-01

    PURPOSE: Retinitis pigmentosa (RP) is a genetically heterogeneous disorder characterized by progressive loss of vision. The aim of this study was to identify the causative mutations in 272 Spanish families using a genotyping microarray. METHODS: 272 unrelated Spanish families, 107 with autosomal

  12. Autozygosity mapping of a large consanguineous Pakistani family reveals a novel non-syndromic autosomal recessive mental retardation locus on 11p15-tel

    DEFF Research Database (Denmark)

    Rehman, Shoaib ur; Baig, Shahid Mahmood; Eiberg, Hans

    2011-01-01

    done in all sampled individuals in the family. The nuclear central loop in the five generation family showed homozygosity for a 6-Mb telomeric region on 11p15, whereas all other linkage regions were excluded by calculation of logarithm of odds (LOD) for the SNP microarray data. A maximum LOD score of Z......Autosomal recessive inherited mental retardation is an extremely heterogeneous disease and accounts for approximately 25% of all non-syndromic mental retardation cases. Autozygosity mapping of a large consanguineous Pakistani family revealed a novel locus for non-syndromic autosomal recessive...

  13. Hypomorphic mutations in PGAP2, encoding a GPI-anchor-remodeling protein, cause autosomal-recessive intellectual disability

    DEFF Research Database (Denmark)

    Hansen, Lars; Tawamie, Hasan; Murakami, Yoshiko

    2013-01-01

    PGAP2 encodes a protein involved in remodeling the glycosylphosphatidylinositol (GPI) anchor in the Golgi apparatus. After synthesis in the endoplasmic reticulum (ER), GPI anchors are transferred to the proteins and are remodeled while transported through the Golgi to the cell membrane. Germline...... mutations in six genes (PIGA, PIGL, PIGM, PIGV, PIGN, and PIGO) in the ER-located part of the GPI-anchor-biosynthesis pathway have been reported, and all are associated with phenotypes extending from malformation and lethality to severe intellectual disability, epilepsy, minor dysmorphisms, and elevated...... alkaline phosphatase (ALP). We performed autozygosity mapping and ultra-deep sequencing followed by stringent filtering and identified two homozygous PGAP2 alterations, p.Tyr99Cys and p.Arg177Pro, in seven offspring with nonspecific autosomal-recessive intellectual disability from two consanguineous...

  14. A homozygous mutation in a consanguineous family consolidates the role of ALDH1A3 in autosomal recessive microphthalmia

    DEFF Research Database (Denmark)

    Roos, L; Fang, M; Dali, C

    2013-01-01

    to the identification of new genes. Very recently, homozygous variations within ALDH1A3 have been associated with autosomal recessive microphthalmia with or without cysts or coloboma, and with variable subphenotypes of developmental delay/autism spectrum disorder in eight families. In a consanguineous family where...... three of the five siblings were affected with microphthalmia/coloboma, we identified a novel homozygous missense mutation in ALDH1A3 using exome sequencing. Of the three affected siblings, one had intellectual disability and one had intellectual disability and autism, while the last one presented...... with normal development. This study contributes further to the description of the clinical spectrum associated with ALDH1A3 mutations, and illustrates the interfamilial clinical variation observed in individuals with ALDH1A3 mutations....

  15. A Novel Homozygous Missense Mutation in HOXC13 Leads to Autosomal Recessive Pure Hair and Nail Ectodermal Dysplasia.

    Science.gov (United States)

    Li, Xiaoxiao; Orseth, Meredith Lee; Smith, J Michael; Brehm, Mary Abigail; Agim, Nnenna Gebechi; Glass, Donald Alexander

    2017-03-01

    Pure hair and nail ectodermal dysplasia (PHNED) is a rare disorder that presents with hypotrichosis and nail dystrophy while sparing other ectodermal structures such as teeth and sweat glands. We describe a homozygous novel missense mutation in the HOXC13 gene that resulted in autosomal recessive PHNED in a Hispanic child. The mutation c.812A>G (p.Gln271Arg) is located within the DNA-binding domain of the HOXC13 gene, cosegregates within the family, and is predicted to be maximally damaging. This is the first reported case of a missense HOXC13 mutation resulting in PHNED and the first reported case of PHNED identified in a North American family. Our findings illustrate the critical role of HOXC13 in human hair and nail development. © 2017 Wiley Periodicals, Inc.

  16. The acrocallosal syndrome in first cousins: widening of the spectrum of clinical features and further support for autosomal recessive inheritance.

    Science.gov (United States)

    Schinzel, A

    1988-01-01

    First cousins, related through their mothers, showed a pattern of craniofacial, brain, and limb anomalies consistent with the acrocallosal syndrome. Both patients had a defect of the corpus callosum, macrocephaly with a protruding forehead and occiput, hypertelorism, non-horizontal palpebral fissures, a small nose, notched ear lobes, and postaxial polydactyly of the hands. The boy, in addition, had hypospadias, cryptorchidism, inguinal hernias, duplication with syndactyly of the phalanges of the big toe, and a bipartite right clavicle. The girl had an arachnoidal cyst, a calvarian defect, and digitalisation of the thumbs. Motor and mental development was retarded in both patients. This observation provides further evidence of probable autosomal recessive inheritance of the acrocallosal syndrome and widens the spectrum of clinical findings and the variability of features in this rare malformation syndrome. Images PMID:3385741

  17. Integration-free induced pluripotent stem cells derived from a patient with autosomal recessive Alport syndrome (ARAS).

    Science.gov (United States)

    Kuebler, Bernd; Aran, Begoña; Miquel-Serra, Laia; Muñoz, Yolanda; Ars, Elisabet; Bullich, Gemma; Furlano, Monica; Torra, Roser; Marti, Merce; Veiga, Anna; Raya, Angel

    2017-12-01

    A skin biopsy was obtained from a 25-year-old female patient with autosomal recessive Alport syndrome (ARAS) with the homozygous COL4A3 mutation c.345delG, p.(P166Lfs*37). Dermal fibroblasts were derived and reprogrammed by nucleofection with episomal plasmids carrying OCT3/4, SOX2, KLF4 LIN28, L-MYC and p53shRNA. The generated induced Pluripotent Stem Cell (iPSC) clone AS FiPS1 Ep6F-2 was free of genomically integrated reprogramming genes, had the specific homozygous mutation, a stable karyotype, expressed pluripotency markers and generated embryoid bodies which were differentiated towards the three germ layers in vitro. This iPSC line offers a useful resource to study Alport syndrome pathomechanisms and drug testing. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

  18. Mutations in DZIP1L, which encodes a ciliary transition zone protein, cause autosomal recessive polycystic kidney disease

    Science.gov (United States)

    Lu, Hao; Galeano, Maria C. Rondón; Ott, Elisabeth; Kaeslin, Geraldine; Kausalya, P. Jaya; Kramer, Carina; Ortiz-Brüchle, Nadina; Hilger, Nadescha; Metzis, Vicki; Hiersche, Milan; Tay, Shang Yew; Tunningley, Robert; Vij, Shubha; Courtney, Andrew D.; Whittle, Belinda; Wühl, Elke; Vester, Udo; Hartleben, Björn; Neuber, Steffen; Frank, Valeska; Little, Melissa H.; Epting, Daniel; Papathanasiou, Peter; Perkins, Andrew C.; Wright, Graham D.; Hunziker, Walter; Gee, Heon Yung; Otto, Edgar A.; Zerres, Klaus; Hildebrandt, Friedhelm; Roy, Sudipto; Wicking, Carol; Bergmann, Carsten

    2017-01-01

    Autosomal recessive polycystic kidney disease (ARPKD), usually considered to be a genetically homogeneous disease caused by mutations in PKHD1, has been associated with ciliary dysfunction. Here, we describe mutations in the DAZ interacting protein 1-like (DZIP1L) gene in patients with ARPKD, findings we have further validated by loss-of-function studies in mice and zebrafish. DZIP1L localizes to centrioles and at the distal end of basal bodies, and interacts with septin2, a protein implicated in maintenance of the periciliary diffusion barrier at the ciliary transition zone. Consistent with a defect in the diffusion barrier, we found that the ciliary membrane translocation of the PKD proteins, polycystin-1 and −2, is compromised in DZIP1L mutant cells. Together, these data provide the first conclusive evidence that ARPKD is not a homogeneous disorder, and establishes DZIP1L as a second gene involved in its pathogenesis. PMID:28530676

  19. Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease.

    Science.gov (United States)

    Lu, Hao; Galeano, Maria C Rondón; Ott, Elisabeth; Kaeslin, Geraldine; Kausalya, P Jaya; Kramer, Carina; Ortiz-Brüchle, Nadina; Hilger, Nadescha; Metzis, Vicki; Hiersche, Milan; Tay, Shang Yew; Tunningley, Robert; Vij, Shubha; Courtney, Andrew D; Whittle, Belinda; Wühl, Elke; Vester, Udo; Hartleben, Björn; Neuber, Steffen; Frank, Valeska; Little, Melissa H; Epting, Daniel; Papathanasiou, Peter; Perkins, Andrew C; Wright, Graham D; Hunziker, Walter; Gee, Heon Yung; Otto, Edgar A; Zerres, Klaus; Hildebrandt, Friedhelm; Roy, Sudipto; Wicking, Carol; Bergmann, Carsten

    2017-07-01

    Autosomal recessive polycystic kidney disease (ARPKD), usually considered to be a genetically homogeneous disease caused by mutations in PKHD1, has been associated with ciliary dysfunction. Here, we describe mutations in DZIP1L, which encodes DAZ interacting protein 1-like, in patients with ARPKD. We further validated these findings through loss-of-function studies in mice and zebrafish. DZIP1L localizes to centrioles and to the distal ends of basal bodies, and interacts with septin2, a protein implicated in maintenance of the periciliary diffusion barrier at the ciliary transition zone. In agreement with a defect in the diffusion barrier, we found that the ciliary-membrane translocation of the PKD proteins polycystin-1 and polycystin-2 is compromised in DZIP1L-mutant cells. Together, these data provide what is, to our knowledge, the first conclusive evidence that ARPKD is not a homogeneous disorder and further establish DZIP1L as a second gene involved in ARPKD pathogenesis.

  20. Birth of a healthy infant following preimplantation PKHD1 haplotyping for autosomal recessive polycystic kidney disease using multiple displacement amplification

    Science.gov (United States)

    Janson, Marleen M.; Roesler, Mark R.; Avner, Ellis D.; Strawn, Estil Y.; Bick, David P.

    2010-01-01

    Purpose To develop a reliable preimplantation genetic diagnosis protocol for couples who both carry a mutant PKHD1 gene wishing to conceive children unaffected with autosomal recessive polycystic kidney disease (ARPKD). Methods Development of a unique protocol for preimplantation genetic testing using whole genome amplification of single blastomeres by multiple displacement amplification (MDA), and haplotype analysis with novel short tandem repeat (STR) markers from the PKHD1 gene and flanking sequences, and a case report of successful utilization of the protocol followed by successful IVF resulting in the birth of an infant unaffected with ARPKD. Results We have developed 20 polymorphic STR markers suitable for linkage analysis of ARPKD. These linked STR markers have enabled unambiguous identification of the PKHD1 haplotypes of embryos produced by at-risk couples. Conclusions We have developed a reliable protocol for preimplantation genetic diagnosis of ARPKD using single-cell MDA products for PKHD1 haplotyping. PMID:20490649

  1. Decreased catalytic activity and altered activation properties of PDE6C mutants associated with autosomal recessive achromatopsia

    DEFF Research Database (Denmark)

    Grau, Tanja; Artemyev, Nikolai O; Rosenberg, Thomas

    2011-01-01

    study on PDE6C mutations including the mutation spectrum, its prevalence in a large cohort of ACHM/cone dysfunction patients, the clinical phenotype and the functional characterization of mutant PDE6C proteins. Twelve affected patients from seven independent families segregating PDE6C mutations were......Mutations in the gene encoding the catalytic subunit of the cone photoreceptor phosphodiesterase (PDE6C) have been recently reported in patients with autosomal recessive inherited achromatopsia (ACHM) and early-onset cone photoreceptor dysfunction. Here we present the results of a comprehensive...... identified in our total patient cohort of 492 independent families. Eleven different PDE6C mutations were found including two nonsense mutations, three mutations affecting transcript splicing as shown by minigene assays, one 1 bp-insertion and five missense mutations. We also performed a detailed functional...

  2. A case report of novel mutation in PRF1 gene, which causes familial autosomal recessive hemophagocytic lymphohistiocytosis.

    Science.gov (United States)

    Bordbar, Mohammad Reza; Modarresi, Farzaneh; Farazi Fard, Mohammad Ali; Dastsooz, Hassan; Shakib Azad, Nader; Faghihi, Mohammad Ali

    2017-05-03

    Hemophagocytic Lymphohistiocytosis (HLH) is a life-threatening immunodeficiency and multi-organ disease that affects people of all ages and ethnic groups. Common symptoms and signs of this disease are high fever, hepatosplenomegaly, and cytopenias. Familial form of HLH disease, which is an autosomal recessive hematological disorder is due to disease-causing mutations in several genes essential for NK and T-cell granule-mediated cytotoxic function. For an effective cytotoxic response from cytotoxic T lymphocyte or NK cell encountering an infected cell or tumor cell, different processes are required, including trafficking, docking, priming, membrane fusion, and entry of cytotoxic granules into the target cell leading to apoptosis. Therefore, genes involved in these steps play important roles in the pathogenesis of HLH disease which include PRF1, UNC13D (MUNC13-4), STX11, and STXBP2 (MUNC18-2). Here, we report a novel missense mutation in an 8-year-old boy suffered from hepatosplenomegaly, hepatitis, epilepsy and pancytopenia. The patient was born to a first-cousin parents with no previous documented disease in his parents. To identify mutated gene in the proband, Whole Exome Sequencing (WES) utilizing next generation sequencing was used on an Illumina HiSeq 2000 platform on DNA sample from the patient. Results showed a novel deleterious homozygous missense mutation in PRF1 gene (NM_001083116: exon3: c. 1120 T > G, p.W374G) in the patient and then using Sanger sequencing it was confirmed in the proband and his parents. Since his parents were heterozygous for the identified mutation, autosomal recessive pattern of inheritance was confirmed in the family. Our study identified a rare new pathogenic missense mutation in PRF1 gene in patient with HLH disease and it is the first report of mutation in PRF1 in Iranian patients with this disease.

  3. Genetic forms of nephrogenic diabetes insipidus (NDI): Vasopressin receptor defect (X-linked) and aquaporin defect (autosomal recessive and dominant).

    Science.gov (United States)

    Bichet, Daniel G; Bockenhauer, Detlef

    2016-03-01

    Nephrogenic diabetes insipidus (NDI), which can be inherited or acquired, is characterized by an inability to concentrate urine despite normal or elevated plasma concentrations of the antidiuretic hormone, arginine vasopressin (AVP). Polyuria with hyposthenuria and polydipsia are the cardinal clinical manifestations of the disease. About 90% of patients with congenital NDI are males with X-linked NDI who have mutations in the vasopressin V2 receptor (AVPR2) gene encoding the vasopressin V2 receptor. In less than 10% of the families studied, congenital NDI has an autosomal recessive or autosomal dominant mode of inheritance with mutations in the aquaporin-2 (AQP2) gene. When studied in vitro, most AVPR2 and AQP2 mutations lead to proteins trapped in the endoplasmic reticulum and are unable to reach the plasma membrane. Prior knowledge of AVPR2 or AQP2 mutations in NDI families and perinatal mutation testing is of direct clinical value and can avert the physical and mental retardation associated with repeated episodes of dehydration. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Malformations among 289,365 Births Attributed to Mutations with Autosomal Dominant and Recessive and X-Linked Inheritance.

    Science.gov (United States)

    Toufaily, M Hassan; Westgate, Marie-Noel; Nasri, Hanah; Holmes, Lewis B

    2018-01-01

    The number of malformations attributed to mutations with autosomal or X-linked patterns of inheritance has increased steadily since the cataloging began in the 1960s. These diagnoses have been based primarily on the pattern of phenotypic features among close relatives. A malformations surveillance program conducted in consecutive pregnancies can identify both known and "new" hereditary disorders. The Active Malformations Surveillance Program was carried out among 289,365 births over 41 years (1972-2012) at Brigham and Women's Hospital in Boston. The findings recorded by examining pediatricians and all consultants were reviewed by study clinicians to establish the most likely diagnoses. The findings in laboratory testing in the newborn period were reviewed, as well. One hundred ninety-six (0.06%) infants among 289,365 births had a malformation or malformation syndrome that was attributed to Mendelian inheritance. A total of 133 (68%) of the hereditary malformations were attributed to autosomal dominant inheritance, with 94 (71%) attributed to apparent spontaneous mutations. Forty-six (23%) were attributed to mutations with autosomal recessive inheritance, 17 associated with consanguinity. Seventeen (9%) were attributed to X-linked inheritance. Fifteen novel familial phenotypes were identified. The family histories showed that most (53 to 71%) of the affected infants were born, as a surprise, to healthy, unaffected parents. It is important for clinicians to discuss with surprised healthy parents how they can have an infant with an hereditary condition. Future studies, using DNA samples from consecutive populations of infants with malformations and whole genome sequencing, will identify many more mutations in loci associated with mendelizing phenotypes. Birth Defects Research 110:92-97, 2018.© 2018 Wiley Periodicals, Inc. © 2018 Wiley Periodicals, Inc.

  5. Novel mutation in TSPAN12 leads to autosomal recessive inheritance of congenital vitreoretinal disease with intra-familial phenotypic variability.

    Science.gov (United States)

    Gal, Moran; Levanon, Erez Y; Hujeirat, Yasir; Khayat, Morad; Pe'er, Jacob; Shalev, Stavit

    2014-12-01

    Developmental malformations of the vitreoretinal vasculature are a heterogeneous group of conditions with various modes of inheritance, and include familial exudative vitreoretinopathy (FEVR), persistent fetal vasculature (PFV), and Norrie disease. We investigated a large consanguineous kindred with multiple affected individuals exhibiting variable phenotypes of abnormal vitreoretinal vasculature, consistent with the three above-mentioned conditions and compatible with autosomal recessive inheritance. Exome sequencing identified a novel c.542G > T (p.C181F) apparently mutation in the TSPAN12 gene that segregated with the ocular disease in the family. The TSPAN12 gene was previously reported to cause dominant and recessive FEVR, but has not yet been associated with other vitreoretinal manifestations. The intra-familial clinical variability caused by a single mutation in the TSPAN12 gene underscores the complicated phenotype-genotype correlation of mutations in this gene, and suggests that there are additional genetic and environmental factors involved in the complex process of ocular vascularization during embryonic development. Our study supports considering PFV, FEVR, and Norrie disease a spectrum of disorders, with clinical and genetic overlap, caused by mutations in distinct genes acting in the Norrin/β-catenin signaling pathway. © 2014 Wiley Periodicals, Inc.

  6. Identification of FASTKD2 compound heterozygous mutations as the underlying cause of autosomal recessive MELAS-like syndrome.

    Science.gov (United States)

    Yoo, Da Hye; Choi, Young-Chul; Nam, Da Eun; Choi, Sun Seong; Kim, Ji Won; Choi, Byung-Ok; Chung, Ki Wha

    2017-07-01

    Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a condition that affects many parts of the body, particularly the brain and muscles. This study examined a Korean MELAS-like syndrome patient with seizure, stroke-like episode, and optic atrophy. Target sequencing of whole mtDNA and 73 nuclear genes identified compound heterozygous mutations p.R205X and p.L255P in the FASTKD2. Each of his unaffected parents has one of the two mutations, and both mutations were not found in 302 controls. FASTKD2 encodes a FAS-activated serine-threonine (FAST) kinase domain 2 which locates in the mitochondrial inner compartment. A FASTKD2 nonsense mutation was once reported as the cause of a recessive infantile mitochondrial encephalomyopathy. The present case showed relatively mild symptoms with a late onset age, compared to a previous patient with FASTKD2 mutation, implicating an inter-allelic clinical heterogeneity. Because this study is the second report of an autosomal recessive mitochondrial encephalomyopathy patient with a FASTKD2 mutation, it will extend the phenotypic spectrum of the FASTKD2 mutation. Copyright © 2017. Published by Elsevier B.V.

  7. Autosomal recessive Oliver-McFarlane syndrome: retinitis pigmentosa, short stature (GH deficiency), trichomegaly, and hair anomalies or CPD syndrome (chorioretinopathy-pituitary dysfunction).

    Science.gov (United States)

    Haimi, Motti; Gershoni-Baruch, Ruth

    2005-10-15

    We describe a brother and sister with retinitis pigmentosa (RP), growth failure, long eyelashes, and sparse hair. They were born to young healthy consanguineous parents and presented at birth with IUGR. Evolving pigmentary retinopathy was diagnosed at the age of 5 years. A similar condition (Oliver-McFarlane) syndrome was reported previously. Our two sibs confirm the existence of this autosomal recessive syndrome.

  8. A Nonsense Mutation in FAM161A Is a Recurrent Founder Allele in Dutch and Belgian Individuals With Autosomal Recessive Retinitis Pigmentosa

    NARCIS (Netherlands)

    Van Schil, Kristof; Klevering, B. Jeroen; Leroy, Bart P.; Pott, Jan Willem R.; Bandah-Rozenfeld, Dikla; Zonneveld-Vrieling, Marijke N.; Sharon, Dror; den Hollander, Anneke I.; Cremers, Frans P. M.; De Baere, Elfride; Collin, Rob W. J.; van den Born, L. Ingeborgh

    PURPOSE. To identify mutations in FAM161A underlying autosomal recessive retinitis pigmentosa (arRP) in the Dutch and Belgian populations and to investigate whether common FAM161A-associated phenotypic features could be identified. METHODS. Homozygosity mapping, amplification-refractory mutation

  9. Fine mapping of the autosomal recessive retinitis pigmentosa locus (RP12) on chromosome 1q; exclusion of the phosducin gene (PDC)

    NARCIS (Netherlands)

    van Soest, S.; te Nijenhuis, S.; van den Born, L. I.; Bleeker-Wagemakers, E. M.; Sharp, E.; Sandkuijl, L. A.; Westerveld, A.; Bergen, A. A.

    1996-01-01

    In a previous study on a large pedigree from a genetically isolated population in the Netherlands, we localized a gene for autosomal recessive retinitis pigmentosa with paraarteriolar preservation of the retinal pigment epithelium (PPRPE) on the long arm of chromosome 1. In this study, we present an

  10. Microarray-based mutation analysis of the ABCA4 (ABCR) gene in autosomal recessive cone-rod dystrophy and retinitis pigmentosa.

    NARCIS (Netherlands)

    Klevering, B.J.; Ijzer, S.; Rohrschneider, K.; Zonneveld-Vrieling, M.N.; Allikmets, R.; Born, L.I. van den; Maugeri, A.; Hoyng, C.B.; Cremers, F.P.M.

    2004-01-01

    Mutations in the ABCA4 gene have been associated with autosomal recessive Stargardt disease (STGD1), cone-rod dystrophy (CRD), and retinitis pigmentosa (RP). We employed a recently developed genotyping microarray, the ABCR400-chip, to search for known ABCA4 mutations in patients with isolated or

  11. Two Cases of Autosomal Recessive Congenital Ichthyosis due to CYP4F22 Mutations: Expanding the Genotype of Self-Healing Collodion Baby

    NARCIS (Netherlands)

    Noguera-Morel, L.; Feito-Rodriguez, M.; Maldonado-Cid, P.; Garcia-Minaur, S.; Kamsteeg, E.J.; Gonzalez-Sarmiento, R.; Lucas-Laguna, R. De; Hernandez-Martin, A.; Torrelo, A.

    2016-01-01

    Collodion babies are born with a tight, shiny cast that sheds in a few weeks. After shedding, most patients will display features of autosomal recessive congenital ichthyosis (ARCI) later in life but in up to 10% of cases, the skin eventually becomes normal or only minimally involved, a phenotype

  12. Autosomal-recessive and X-linked forms of hereditary motor and sensory neuropathy in childhood.

    Science.gov (United States)

    Ouvrier, Robert; Geevasingha, Nimeshan; Ryan, Monique M

    2007-08-01

    The hereditary motor and sensory neuropathies (HMSNs, Charcot-Marie-Tooth neuropathies) are the most common degenerative disorders of the peripheral nervous system. In recent years a dramatic expansion has occurred in our understanding of the molecular basis and cell biology of the recessively inherited demyelinating and axonal neuropathies, with delineation of a number of new neuropathies. Mutations in some genes cause a wide variety of clinical, neurophysiologic, and pathologic phenotypes, rendering diagnosis difficult. The X-linked forms of HMSN represent at least 10%-15% of all HMSNs and have an expanded disease spectrum including demyelinating, intermediate, and axonal neuropathies, transient central nervous system (CNS) dysfunction, mental retardation, and hearing loss. This review presents an overview of the recessive and X-linked forms of HMSN observed in childhood, with particular reference to disease phenotype and neurophysiologic and pathologic abnormalities suggestive of specific diagnoses. These findings can be used by the clinician to formulate a differential diagnosis and guide targeted genetic testing.

  13. The CC2D1A, a member of a new gene family with C2 domains, is involved in autosomal recessive non-syndromic mental retardation.

    Science.gov (United States)

    Basel-Vanagaite, L; Attia, R; Yahav, M; Ferland, R J; Anteki, L; Walsh, C A; Olender, T; Straussberg, R; Magal, N; Taub, E; Drasinover, V; Alkelai, A; Bercovich, D; Rechavi, G; Simon, A J; Shohat, M

    2006-03-01

    The molecular basis of autosomal recessive non-syndromic mental retardation (NSMR) is poorly understood, mostly owing to heterogeneity and absence of clinical criteria for grouping families for linkage analysis. Only two autosomal genes, the PRSS12 gene on chromosome 4q26 and the CRBN on chromosome 3p26, have been shown to cause autosomal recessive NSMR, each gene in only one family. To identify the gene causing autosomal recessive NSMR on chromosome 19p13.12. The candidate region established by homozygosity mapping was narrowed down from 2.4 Mb to 0.9 Mb on chromosome 19p13.12. A protein truncating mutation was identified in the gene CC2D1A in nine consanguineous families with severe autosomal recessive NSMR. The absence of the wild type protein in the lymphoblastoid cells of the patients was confirmed. CC2D1A is a member of a previously uncharacterised gene family that carries two conserved motifs, a C2 domain and a DM14 domain. The C2 domain is found in proteins which function in calcium dependent phospholipid binding; the DM14 domain is unique to the CC2D1A protein family and its role is unknown. CC2D1A is a putative signal transducer participating in positive regulation of I-kappaB kinase/NFkappaB cascade. Expression of CC2D1A mRNA was shown in the embryonic ventricular zone and developing cortical plate in staged mouse embryos, persisting into adulthood, with highest expression in the cerebral cortex and hippocampus. A previously unknown signal transduction pathway is important in human cognitive development.

  14. The CC2D1A, a member of a new gene family with C2 domains, is involved in autosomal recessive non‐syndromic mental retardation

    Science.gov (United States)

    Basel‐Vanagaite, L; Attia, R; Yahav, M; Ferland, R J; Anteki, L; Walsh, C A; Olender, T; Straussberg, R; Magal, N; Taub, E; Drasinover, V; Alkelai, A; Bercovich, D; Rechavi, G; Simon, A J; Shohat, M

    2006-01-01

    Background The molecular basis of autosomal recessive non‐syndromic mental retardation (NSMR) is poorly understood, mostly owing to heterogeneity and absence of clinical criteria for grouping families for linkage analysis. Only two autosomal genes, the PRSS12 gene on chromosome 4q26 and the CRBN on chromosome 3p26, have been shown to cause autosomal recessive NSMR, each gene in only one family. Objective To identify the gene causing autosomal recessive NSMR on chromosome 19p13.12. Results The candidate region established by homozygosity mapping was narrowed down from 2.4 Mb to 0.9 Mb on chromosome 19p13.12. A protein truncating mutation was identified in the gene CC2D1A in nine consanguineous families with severe autosomal recessive NSMR. The absence of the wild type protein in the lymphoblastoid cells of the patients was confirmed. CC2D1A is a member of a previously uncharacterised gene family that carries two conserved motifs, a C2 domain and a DM14 domain. The C2 domain is found in proteins which function in calcium dependent phospholipid binding; the DM14 domain is unique to the CC2D1A protein family and its role is unknown. CC2D1A is a putative signal transducer participating in positive regulation of I‐κB kinase/NFκB cascade. Expression of CC2D1A mRNA was shown in the embryonic ventricular zone and developing cortical plate in staged mouse embryos, persisting into adulthood, with highest expression in the cerebral cortex and hippocampus. Conclusions A previously unknown signal transduction pathway is important in human cognitive development. PMID:16033914

  15. Prevalence of GJB2 Mutations in Affected Individuals from United Arab Emirates with Autosomal Recessive Nonsyndromic Hearing Loss.

    Science.gov (United States)

    Tlili, Abdelaziz; Al Mutery, Abdullah; Kamal Eddine Ahmad Mohamed, Walaa; Mahfood, Mona; Hadj Kacem, Hassen

    2017-11-01

    Mutations in the gap junction protein beta 2 (GJB2) gene are responsible for more cases of nonsyndromic recessive hearing loss than any other gene. The purpose of our study was to evaluate the prevalence of GJB2 mutations among affected individuals from United Arab Emirates (UAE). There were 50 individuals diagnosed with hereditary hearing loss and 120 healthy individuals enrolled in the study. The Sanger sequencing method was used to screen the GJB2 coding region in all affected individuals. The c.-1G>A variant was determined by the polymerase chain reaction-restriction fragment length polymorphism method in normal individuals. Nine cases with bi-allelic mutations and three cases with mono-allelic mutations were detected in 12 out of 50 patients (24%). The homozygous mutation c.35delG was identified as the cause of hearing loss in six participants (12%). The mutation c.506G>A was identified in three affected individuals (6%). The allelic frequency (14%) and low percentage of individuals that were homozygous (2%) for the c.35delG mutation suggest that there are other genes responsible for nonsyndromic deafness in the UAE population. The results reported here are a preliminary step in collecting epidemiological data regarding autosomal recessive nonsyndromic hearing loss related to GJB2 gene mutations among the UAE population. The c.35delG mutation of the GJB2 gene is the most frequently seen causative mutation in the UAE and is followed by the p.Cys169Tyr mutation.

  16. Autosomal recessive spastic paraplegia (SPG30) with mild ataxia and sensory neuropathy maps to chromosome 2q37.3.

    Science.gov (United States)

    Klebe, Stephan; Azzedine, Hamid; Durr, Alexandra; Bastien, Patrick; Bouslam, Naima; Elleuch, Nizar; Forlani, Sylvie; Charon, Celine; Koenig, Michel; Melki, Judith; Brice, Alexis; Stevanin, Giovanni

    2006-06-01

    The hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases characterized by progressive spasticity in the lower limbs. Twenty-nine different loci (SPG) have been mapped so far, and 11 responsible genes have been identified. Clinically, one distinguishes between pure and complex HSP forms which are variably associated with numerous combinations of neurological and extra-neurological signs. Less is known about autosomal recessive forms (ARHSP) since the mapped loci have been identified often in single families and account for only a small percentage of patients. We report a new ARHSP locus (SPG30) on chromosome 2q37.3 in a consanguineous family with seven unaffected and four affected members of Algerian origin living in Eastern France with a significant multipoint lod score of 3.8. Ten other families from France (n = 4), Tunisia (n = 2), Algeria (n = 3) and the Czech Republic (n = 1) were not linked to the newly identified locus thus demonstrating further genetic heterogeneity. The phenotype of the linked family consists of spastic paraparesis and peripheral neuropathy associated with slight cerebellar signs confirmed by cerebellar atrophy on one CT scan.

  17. Mutation in WNT10A is associated with an autosomal recessive ectodermal dysplasia: the odonto-onycho-dermal dysplasia.

    Science.gov (United States)

    Adaimy, Lynn; Chouery, Eliane; Megarbane, Hala; Mroueh, Salman; Delague, Valerie; Nicolas, Elsa; Belguith, Hanen; de Mazancourt, Philippe; Megarbane, Andre

    2007-10-01

    Odonto-onycho-dermal dysplasia is a rare autosomal recessive syndrome in which the presenting phenotype is dry hair, severe hypodontia, smooth tongue with marked reduction of fungiform and filiform papillae, onychodysplasia, keratoderma and hyperhidrosis of palms and soles, and hyperkeratosis of the skin. We studied three consanguineous Lebanese Muslim Shiite families that included six individuals affected with odonto-onycho-dermal dysplasia. Using a homozygosity-mapping strategy, we assigned the disease locus to an ~9-cM region at chromosome 2q35-q36.2, located between markers rs16853834 and D2S353, with a maximum multipoint LOD score of 5.7. Screening of candidate genes in this region led us to identify the same c.697G-->T (p.Glu233X) homozygous nonsense mutation in exon 3 of the WNT10A gene in all patients. At the protein level, the mutation is predicted to result in a premature truncated protein of 232 aa instead of 417 aa. This is the first report to our knowledge of a human phenotype resulting from a mutation in WNT10A, and it is the first demonstration of an ectodermal dysplasia caused by an altered WNT signaling pathway, expanding the list of WNT-related diseases.

  18. Autosomal recessive posterior column ataxia with retinitis pigmentosa caused by novel mutations in the FLVCR1 gene.

    Science.gov (United States)

    Shaibani, Aziz; Wong, Lee-Jun; Wei Zhang, Victor; Lewis, Richard Alan; Shinawi, Marwan

    2015-01-01

    Posterior column ataxia with retinitis pigmentosa (PCARP) is an autosomal recessive disorder characterized by severe sensory ataxia, muscle weakness and atrophy, and progressive pigmentary retinopathy. Recently, mutations in the FLVCR1 gene were described in four families with this condition. We investigated the molecular basis and studied the phenotype of PCARP in a new family. The proband is a 33-year-old woman presented with sensory polyneuropathy and retinitis pigmentosa (RP). The constellation of clinical findings with normal metabolic and genetic evaluation, including mitochondrial DNA (mtDNA) analysis and normal levels of phytanic acid and vitamin E, prompted us to seek other causes of our patient's condition. Sequencing of FLVCR1 in the proband and targeted mutation testing in her two affected siblings revealed two novel variants, c.1547G > A (p.R516Q) and c.1593+5_+8delGTAA predicted, respectively, to be highly conserved throughout evolution and affecting the normal splicing, therefore, deleterious. This study supports the pathogenic role of FLVCR1 in PCARP and expands the molecular and clinical spectra of PCARP. We show for the first time that nontransmembrane domain (TMD) mutations in the FLVCR1 can cause PCARP, suggesting different mechanisms for pathogenicity. Our clinical data reveal that impaired sensation can be part of the phenotypic spectrum of PCARP. This study along with previously reported cases suggests that targeted sequencing of the FLVCR1 gene should be considered in patients with severe sensory ataxia, RP, and peripheral sensory neuropathy.

  19. Single Nucleotide Polymorphisms of the GJB2 and GJB6 Genes Are Associated with Autosomal Recessive Nonsyndromic Hearing Loss

    Directory of Open Access Journals (Sweden)

    Ana Paula Grillo

    2015-01-01

    Full Text Available Single nucleotide polymorphisms (SNPs are important markers in many studies that link DNA sequence variations to phenotypic changes; such studies are expected to advance the understanding of human physiology and elucidate the molecular basis of diseases. The DFNB1 locus, which contains the GJB2 and GJB6 genes, plays a key role in nonsyndromic hearing loss. Previous studies have identified important mutations in this locus, but the contribution of SNPs in the genes has not yet been much investigated. The aim of this study was to investigate the association of nine polymorphisms located within the DFNB1 locus with the occurrence of autosomal recessive nonsyndromic hearing loss (ARNSHL. The SNPs rs3751385 (C/T, rs7994748 (C/T, rs7329857 (C/T, rs7987302 (G/A, rs7322538 (G/A, rs9315400 (C/T, rs877098 (C/T, rs945369 (A/C, and rs7333214 (T/G were genotyped in 122 deaf patients and 132 healthy controls using allele-specific PCR. There were statistically significant differences between patients and controls, in terms of allelic frequencies in the SNPs rs3751385, rs7994748, rs7329857, rs7987302, rs945369, and rs7333214 (P<0.05. No significant differences between the two groups were observed for rs7322538, rs9315400, and rs877098. Our results suggest that SNPs present in the GJB2 and GJB6 genes may have an influence on ARNSHL in humans.

  20. Distribution of skeletal muscle involvement in autosomal recessive distal muscular dystrophy. A clinical and computed tomographic study

    Energy Technology Data Exchange (ETDEWEB)

    Mizusawa, Hidehiro; Nakanishi, Takao; Kobayashi, Fumie

    1987-02-01

    Distribution of skeletal muscle involvement in 5 cases with autosomal recessive distal muscular dystrophy was studied clinically and by computed tomography (CT). Manual muscle test showed muscle involvement with a predilection for flexors in the lower leg and adductors in the thigh. Flexion and extension of the thigh and the lower leg was impaired to similar degree. In progressed cases, neck flexors and trunk muscles were also affected mildly. CT disclosed more clearly the preferential involvement of flexors in the lower leg, and involvement of both hamstrings center dot adductors group and extensors group of the thigh to similar degree. However, m. popliteus was curiously well preserved. In addition, there was a stage showing high density and hypertrophy of m. sartorius, m. gracilis, m. adductor, m. biceps femoris, m. semimenbranosus, m. semitendinosus or m. rectus femoris, which in thought to be compensatory hypertrophy. M. gluteus minimus in the pelvic girdle and m. dorsi proprii in the trunk were also liable to be affected. The CT findings are regarded as characteristic features noted clearly before muscle weakness and atrophy become apparent clinically. CT is very useful for distinguishing distal muscular dystrophy from rimmed vacuolar distal myopathy in which m. quadriceps femoris and flexors of the lower leg are usually well preserved without compensatory hypertrophy on CT.

  1. Mutations in the ABCA4 (ABCR) gene are the major cause of autosomal recessive cone-rod dystrophy.

    Science.gov (United States)

    Maugeri, A; Klevering, B J; Rohrschneider, K; Blankenagel, A; Brunner, H G; Deutman, A F; Hoyng, C B; Cremers, F P

    2000-10-01

    The photoreceptor cell-specific ATP-binding cassette transporter gene (ABCA4; previously denoted "ABCR") is mutated, in most patients, with autosomal recessive (AR) Stargardt disease (STGD1) or fundus flavimaculatus (FFM). In addition, a few cases with AR retinitis pigmentosa (RP) and AR cone-rod dystrophy (CRD) have been found to have ABCA4 mutations. To evaluate the importance of the ABCA4 gene as a cause of AR CRD, we selected 5 patients with AR CRD and 15 patients from Germany and The Netherlands with isolated CRD. Single-strand conformation-polymorphism analysis and sequencing revealed 19 ABCA4 mutations in 13 (65%) of 20 patients. In six patients, mutations were identified in both ABCA4 alleles; in seven patients, mutations were detected in one allele. One complex ABCA4 allele (L541P;A1038V) was found exclusively in German patients with CRD; one patient carried this complex allele homozygously, and five others were compound heterozygous. These findings suggest that mutations in the ABCA4 gene are the major cause of AR CRD. A primary role of the ABCA4 gene in STGD1/FFM and AR CRD, together with the gene's involvement in an as-yet-unknown proportion of cases with AR RP, strengthens the idea that mutations in the ABCA4 gene could be the most frequent cause of inherited retinal dystrophy in humans.

  2. Mutations in the histamine N-methyltransferase gene, HNMT, are associated with nonsyndromic autosomal recessive intellectual disability.

    Science.gov (United States)

    Heidari, Abolfazl; Tongsook, Chanakan; Najafipour, Reza; Musante, Luciana; Vasli, Nasim; Garshasbi, Masoud; Hu, Hao; Mittal, Kirti; McNaughton, Amy J M; Sritharan, Kumudesh; Hudson, Melissa; Stehr, Henning; Talebi, Saeid; Moradi, Mohammad; Darvish, Hossein; Arshad Rafiq, Muhammad; Mozhdehipanah, Hossein; Rashidinejad, Ali; Samiei, Shahram; Ghadami, Mohsen; Windpassinger, Christian; Gillessen-Kaesbach, Gabriele; Tzschach, Andreas; Ahmed, Iltaf; Mikhailov, Anna; Stavropoulos, D James; Carter, Melissa T; Keshavarz, Soraya; Ayub, Muhammad; Najmabadi, Hossein; Liu, Xudong; Ropers, Hans Hilger; Macheroux, Peter; Vincent, John B

    2015-10-15

    Histamine (HA) acts as a neurotransmitter in the brain, which participates in the regulation of many biological processes including inflammation, gastric acid secretion and neuromodulation. The enzyme histamine N-methyltransferase (HNMT) inactivates HA by transferring a methyl group from S-adenosyl-l-methionine to HA, and is the only well-known pathway for termination of neurotransmission actions of HA in mammalian central nervous system. We performed autozygosity mapping followed by targeted exome sequencing and identified two homozygous HNMT alterations, p.Gly60Asp and p.Leu208Pro, in patients affected with nonsyndromic autosomal recessive intellectual disability from two unrelated consanguineous families of Turkish and Kurdish ancestry, respectively. We verified the complete absence of a functional HNMT in patients using in vitro toxicology assay. Using mutant and wild-type DNA constructs as well as in silico protein modeling, we confirmed that p.Gly60Asp disrupts the enzymatic activity of the protein, and that p.Leu208Pro results in reduced protein stability, resulting in decreased HA inactivation. Our results highlight the importance of inclusion of HNMT for genetic testing of individuals presenting with intellectual disability. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  3. Homozygous SLC6A17 Mutations Cause Autosomal-Recessive Intellectual Disability with Progressive Tremor, Speech Impairment, and Behavioral Problems

    Science.gov (United States)

    Iqbal, Zafar; Willemsen, Marjolein H.; Papon, Marie-Amélie; Musante, Luciana; Benevento, Marco; Hu, Hao; Venselaar, Hanka; Wissink-Lindhout, Willemijn M.; Vulto-van Silfhout, Anneke T.; Vissers, Lisenka E.L.M.; de Brouwer, Arjan P.M.; Marouillat, Sylviane; Wienker, Thomas F.; Ropers, Hans Hilger; Kahrizi, Kimia; Nadif Kasri, Nael; Najmabadi, Hossein; Laumonnier, Frédéric; Kleefstra, Tjitske; van Bokhoven, Hans

    2015-01-01

    We report on Dutch and Iranian families with affected individuals who present with moderate to severe intellectual disability and additional phenotypes including progressive tremor, speech impairment, and behavioral problems in certain individuals. A combination of exome sequencing and homozygosity mapping revealed homozygous mutations c.484G>A (p.Gly162Arg) and c.1898C>G (p.Pro633Arg) in SLC6A17. SLC6A17 is predominantly expressed in the brain, encodes a synaptic vesicular transporter of neutral amino acids and glutamate, and plays an important role in the regulation of glutamatergic synapses. Prediction programs and 3D modeling suggest that the identified mutations are deleterious to protein function. To directly test the functional consequences, we investigated the neuronal subcellular localization of overexpressed wild-type and mutant variants in mouse primary hippocampal neuronal cells. Wild-type protein was present in soma, axons, dendrites, and dendritic spines. p.Pro633Arg altered SLC6A17 was found in soma and proximal dendrites but did not reach spines. p.Gly162Arg altered SLC6A17 showed a normal subcellular distribution but was associated with an abnormal neuronal morphology mainly characterized by the loss of dendritic spines. In summary, our genetic findings implicate homozygous SLC6A17 mutations in autosomal-recessive intellectual disability, and their pathogenic role is strengthened by genetic evidence and in silico and in vitro functional analyses. PMID:25704603

  4. Mutations in the histamine N-methyltransferase gene, HNMT, are associated with nonsyndromic autosomal recessive intellectual disability

    Science.gov (United States)

    Heidari, Abolfazl; Tongsook, Chanakan; Najafipour, Reza; Musante, Luciana; Vasli, Nasim; Garshasbi, Masoud; Hu, Hao; Mittal, Kirti; McNaughton, Amy J. M.; Sritharan, Kumudesh; Hudson, Melissa; Stehr, Henning; Talebi, Saeid; Moradi, Mohammad; Darvish, Hossein; Arshad Rafiq, Muhammad; Mozhdehipanah, Hossein; Rashidinejad, Ali; Samiei, Shahram; Ghadami, Mohsen; Windpassinger, Christian; Gillessen-Kaesbach, Gabriele; Tzschach, Andreas; Ahmed, Iltaf; Mikhailov, Anna; Stavropoulos, D. James; Carter, Melissa T.; Keshavarz, Soraya; Ayub, Muhammad; Najmabadi, Hossein; Liu, Xudong; Ropers, Hans Hilger; Macheroux, Peter; Vincent, John B.

    2015-01-01

    Histamine (HA) acts as a neurotransmitter in the brain, which participates in the regulation of many biological processes including inflammation, gastric acid secretion and neuromodulation. The enzyme histamine N-methyltransferase (HNMT) inactivates HA by transferring a methyl group from S-adenosyl-l-methionine to HA, and is the only well-known pathway for termination of neurotransmission actions of HA in mammalian central nervous system. We performed autozygosity mapping followed by targeted exome sequencing and identified two homozygous HNMT alterations, p.Gly60Asp and p.Leu208Pro, in patients affected with nonsyndromic autosomal recessive intellectual disability from two unrelated consanguineous families of Turkish and Kurdish ancestry, respectively. We verified the complete absence of a functional HNMT in patients using in vitro toxicology assay. Using mutant and wild-type DNA constructs as well as in silico protein modeling, we confirmed that p.Gly60Asp disrupts the enzymatic activity of the protein, and that p.Leu208Pro results in reduced protein stability, resulting in decreased HA inactivation. Our results highlight the importance of inclusion of HNMT for genetic testing of individuals presenting with intellectual disability. PMID:26206890

  5. Genetic Linkage Analysis of the DFNB21 Locus in Autosomal Recessive Hearing Loss in Large Families from Khuzestan Province

    Directory of Open Access Journals (Sweden)

    Mahtab Khosrofar

    2017-06-01

    Full Text Available Abstract Background: Hearing loss (HL is the most common congenital defect in humans. One or two in thousand newborn babies have prelingual hearing loss. Autosomal recessive non-syndromic hearing loss (ARNSHL is the most common form of hereditary deafness. Hearing loss is more common in the developing countries which is due to genetic and environmental (cultural -health factors reasons. HL has a wide range of clinical demonstrations including: congenital or late onset, conductive or sensory-neural, syndromic or non-syndromic hearing loss. The goal of this project is to determine the portion of the DFNB21 (TECTA in ARNSHL in families with negative GJB2 gene in Khuzestan province. Materials and Methods: We studied 21 families with ARNSHL with at least 4 patients and negative for GJB2 mutations from Khuzestan province. Genetic linkage analysis was performed using STR markers linked to DFNB21 locus. Results: Following genetic linkage analysis and haplotyping, out of 21 families with ARNSHL, one family showed linkage to the DFNB21 (TECTA locus. Conclusion: The results of this project confirm other studies in Iran and give insight into the most common loci causing ARNSHL in Iran which could be helpful in research and clinic.

  6. Unraveling the genetic landscape of autosomal recessive Charcot-Marie-Tooth neuropathies using a homozygosity mapping approach

    Science.gov (United States)

    Zimoń, Magdalena; Battaloǧlu, Esra; Parman, Yesim; Erdem, Sevim; Baets, Jonathan; De Vriendt, Els; Atkinson, Derek; Almeida-Souza, Leonardo; Deconinck, Tine; Ozes, Burcak; Goossens, Dirk; Cirak, Sebahattin; Van Damme, Philip; Shboul, Mohammad; Voit, Thomas; Van Maldergem, Lionel; Dan, Bernard; El-Khateeb, Mohammed S.; Guergueltcheva, Velina; Lopez-Laso, Eduardo; Goemans, Nathalie; Masri, Amira; Züchner, Stephan; Timmerman, Vincent; Topaloǧlu, Haluk; De Jonghe, Peter

    2016-01-01

    Autosomal recessive forms of Charcot-Marie-Tooth disease (ARCMT) are rare but severe disorders of the peripheral nervous system. Their molecular basis is poorly understood due to the extensive genetic and clinical heterogeneity, posing considerable challenges for patients, physicians, and researchers. We report on the genetic findings from a systematic study of a large collection of 174 independent ARCMT families. Initial sequencing of the three most common ARCMT genes (ganglioside-induced differentiation protein 1—GDAP1, SH3 domain and tetratricopeptide repeats-containing protein 2—SH3TC2, histidine-triad nucleotide binding protein 1—HINT1) identified pathogenic mutations in 41 patients. Subsequently, 87 selected nuclear families underwent single nucleotide polymorphism (SNP) genotyping and homozygosity mapping, followed by targeted screening of known ARCMT genes. This strategy provided molecular diagnosis to 22 % of the families. Altogether, our unbiased genetic approach identified pathogenic mutations in ten ARCMT genes in a total of 41.3 % patients. Apart from a newly described founder mutation in GDAP1, the majority of variants constitute private molecular defects. Since the gene testing was independent of the clinical phenotype of the patients, we identified mutations in patients with unusual or additional clinical features, extending the phenotypic spectrum of the SH3TC2 gene. Our study provides an overview of the ARCMT genetic landscape and proposes guidelines for tackling the genetic heterogeneity of this group of hereditary neuropathies. PMID:25231362

  7. A Clinical and Molecular Genetic Study of 50 Families with Autosomal Recessive Parkinsonism Revealed Known and Novel Gene Mutations.

    Science.gov (United States)

    Taghavi, Shaghayegh; Chaouni, Rita; Tafakhori, Abbas; Azcona, Luis J; Firouzabadi, Saghar Ghasemi; Omrani, Mir Davood; Jamshidi, Javad; Emamalizadeh, Babak; Shahidi, Gholam Ali; Ahmadi, Mona; Habibi, Seyed Amir Hassan; Ahmadifard, Azadeh; Fazeli, Atena; Motallebi, Marzieh; Petramfar, Peyman; Askarpour, Saeed; Askarpour, Shiva; Shahmohammadibeni, Hossein Ali; Shahmohammadibeni, Neda; Eftekhari, Hajar; Shafiei Zarneh, Amir Ehtesham; Mohammadihosseinabad, Saeed; Khorrami, Mehdi; Najmi, Safa; Chitsaz, Ahmad; Shokraeian, Parasto; Ehsanbakhsh, Hossein; Rezaeidian, Jalal; Ebrahimi Rad, Reza; Madadi, Faranak; Andarva, Monavvar; Alehabib, Elham; Atakhorrami, Minoo; Mortazavi, Seyed Erfan; Azimzadeh, Zahra; Bayat, Mahdis; Besharati, Amir Mohammad; Harati-Ghavi, Mohammad Ali; Omidvari, Samareh; Dehghani-Tafti, Zahra; Mohammadi, Faraz; Mohammad Hossein Pour, Banafsheh; Noorollahi Moghaddam, Hamid; Esmaili Shandiz, Ehsan; Habibi, Arman; Taherian-Esfahani, Zahra; Darvish, Hossein; Paisán-Ruiz, Coro

    2018-04-01

    In this study, the role of known Parkinson's disease (PD) genes was examined in families with autosomal recessive (AR) parkinsonism to assist with the differential diagnosis of PD. Some families without mutations in known genes were also subject to whole genome sequencing with the objective to identify novel parkinsonism-related genes. Families were selected from 4000 clinical files of patients with PD or parkinsonism. AR inheritance pattern, consanguinity, and a minimum of two affected individuals per family were used as inclusion criteria. For disease gene/mutation identification, multiplex ligation-dependent probe amplification, quantitative PCR, linkage, and Sanger and whole genome sequencing assays were carried out. A total of 116 patients (50 families) were examined. Fifty-four patients (46.55%; 22 families) were found to carry pathogenic mutations in known genes while a novel gene, not previously associated with parkinsonism, was found mutated in a single family (2 patients). Pathogenic mutations, including missense, nonsense, frameshift, and exon rearrangements, were found in Parkin, PINK1, DJ-1, SYNJ1, and VAC14 genes. In conclusion, variable phenotypic expressivity was seen across all families.

  8. Localization of A Novel Autosomal Recessive Non-Syndromic Hearing Impairment Locus (DFNB38) to 6q26–q27 in a Consanguineous Kindred from Pakistan

    Science.gov (United States)

    Ansar, Muhammad; Ramzan, Mohammad; Pham, Thanh L.; Yan, Kai; Jamal, Syed Muhammad; Haque, Sayedul; Ahmad, Wasim; Leal, Suzanne M.

    2010-01-01

    For autosomal recessive nonsyndromic hearing impairment over 30 loci have been mapped and 19 genes have been identified. DFNB38, a novel locus for autosomal recessive nonsyndromic hearing impairment, was localized in a consanguineous Pakistani kindred to 6q26–q27. The affected family members present with profound prelingual sensorineural hearing impairment and use sign language for communications. Linkage was established to microsatellite markers located on chromosome 6q26–q27 (Multipoint lod score 3.6). The genetic region for DFNB38 spans 10.1 cM according to the Marshfield genetic map and is bounded by markers D6S980 and D6S1719. This genetic region corresponds to 3.4 MB on the sequence-based physical map. PMID:12890929

  9. Identification of a Novel Dentin Matrix Protein-1 (DMP-1) Mutation and Dental Anomalies in a Kindred with Autosomal Recessive Hypophosphatemia

    OpenAIRE

    Turan, Serap; Aydin, Cumhur; Bereket, Abdullah; Akcay, Teoman; Güran, Tülay; Yaralioglu, Betul Akmen; Bastepe, Murat; Jüppner, Harald

    2009-01-01

    An autosomal recessive form of hypophosphatemia (ARHP) was recently shown to be caused by homozygous mutations in DMP1, the gene encoding dentin matrix protein-1 (DMP-1), a non-collagenous bone matrix protein with an important role in the development and mineralization of bone and teeth. Here, we report a previously not reported consanguineous ARHP kindred in which the three affected individuals carry a novel homozygous DMP-1 mutation. The index case presented at the age of 3 years with bowin...

  10. An autosomal recessive leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa maps to chromosome 17q24.2-25.3

    OpenAIRE

    Bouhouche Ahmed; Benomar Ali; Errguig Leila; Lachhab Lamiae; Bouslam Naima; Aasfara Jehanne; Sefiani Sanaa; Chabraoui Layachi; El Fahime Elmostafa; El Quessar Abdeljalil; Jiddane Mohamed; Yahyaoui Mohamed

    2012-01-01

    Abstract Background Single-gene disorders related to ischemic stroke seem to be an important cause of stroke in young patients without known risk factors. To identify new genes responsible of such diseases, we studied a consanguineous Moroccan family with three affected individuals displaying hereditary leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa that appears to segregate in autosomal recessive pattern. Methods All family members underwent neurologic...

  11. AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE AND CONGENITAL HEPATIC FIBROSIS: SUMMARY STATEMENT OF A FIRST NATIONAL INSTITUTES OF HEALTH/OFFICE OF RARE DISEASES CONFERENCE

    Science.gov (United States)

    Gunay-Aygun, Meral; Avner, Ellis D.; Bacallo, Robert L.; Choyke, Peter L.; Flynn, Joseph T.; Germino, Gregory G.; Guay-Woodford, Lisa; Harris, Peter; Heller, Theo; Ingelfinger, Julie; Kaskel, Frederick; Kleta, Robert; LaRusso, Nicholas F.; Mohan, Parvathi; Pazour, Gregory J.; Shneider, Benjamin L.; Torres, Vicente E.; Wilson, Patricia; Zak, Colleen; Zhou, Jing; Gahl, William A.

    2010-01-01

    Researchers and clinicians with expertise in autosomal recessive polycystic kidney disease and congenital hepatic fibrosis (ARPKD/CHF) and related fields met on May 5-6, 2005, on the National Institutes of Health (NIH) campus for a 1.5-day symposium sponsored by the NIH Office of Rare Diseases, the National Human Genome Research Institute (NHGRI), and in part by the ARPKD/CHF Alliance. The meeting addressed the present status and the future of ARPKD/CHF research. PMID:16887426

  12. Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy.

    Science.gov (United States)

    Lesage, Suzanne; Drouet, Valérie; Majounie, Elisa; Deramecourt, Vincent; Jacoupy, Maxime; Nicolas, Aude; Cormier-Dequaire, Florence; Hassoun, Sidi Mohamed; Pujol, Claire; Ciura, Sorana; Erpapazoglou, Zoi; Usenko, Tatiana; Maurage, Claude-Alain; Sahbatou, Mourad; Liebau, Stefan; Ding, Jinhui; Bilgic, Basar; Emre, Murat; Erginel-Unaltuna, Nihan; Guven, Gamze; Tison, François; Tranchant, Christine; Vidailhet, Marie; Corvol, Jean-Christophe; Krack, Paul; Leutenegger, Anne-Louise; Nalls, Michael A; Hernandez, Dena G; Heutink, Peter; Gibbs, J Raphael; Hardy, John; Wood, Nicholas W; Gasser, Thomas; Durr, Alexandra; Deleuze, Jean-François; Tazir, Meriem; Destée, Alain; Lohmann, Ebba; Kabashi, Edor; Singleton, Andrew; Corti, Olga; Brice, Alexis

    2016-03-03

    Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression. Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  13. Possible influences on the expression of X chromosome-linked dystrophin abnormalities by heterozygosity for autosomal recessive Fukuyama congenital muscular dystrophy

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    Beggs, A.H.; Neumann, P.E.; Anderson, M.S.; Kunkel, L.M. (Harvard Medical School, Boston, MA (United States)); Arahata, Kiichi; Arikawa, Eri; Nonaka, Ikuya (National Inst. of Neuroscience, Tokyo (Japan))

    1992-01-15

    Abnormalities of dystrophin, a cytoskeletal protein of muscle and nerve, are generally considered specific for Duchenne and Becker muscular dystrophy. However, several patients have recently been identified with dystrophin deficiency who, before dystrophin testing, were considered to have Fukuyama congenital muscular dystrophy (FCMD) on the basis of clinical findings. Epidemiologic data suggest that only 1/3,500 males with autosomal recessive FCMD should have abnormal dystrophin. To explain the observation of 3/23 FCMD males with abnormal dystrophin, the authors propose that dystrophin and the FCMD gene product interact and that the earlier onset and greater severity of these patients' phenotype (relative to Duchenne muscular dystrophy) are due to their being heterozygous for the FCMD mutation in addition to being hemizygous for Duchenne muscular dystrophy, a genotype that is predicted to occur in 1/175,000 Japanese males. This model may help explain the genetic basis for some of the clinical and pathological variability seen among patients with FCMD, and it has potential implications for understanding the inheritance of other autosomal recessive disorders in general. For example, sex ratios for rare autosomal recessive disorders caused by mutations in proteins that interact with X chromosome-linked gene products may display predictable deviation from 1:1.

  14. Two novel mutations in the EYS gene are possible major causes of autosomal recessive retinitis pigmentosa in the Japanese population.

    Directory of Open Access Journals (Sweden)

    Katsuhiro Hosono

    Full Text Available Retinitis pigmentosa (RP is a highly heterogeneous genetic disease including autosomal recessive (ar, autosomal dominant (ad, and X-linked inheritance. Recently, arRP has been associated with mutations in EYS (Eyes shut homolog, which is a major causative gene for this disease. This study was conducted to determine the spectrum and frequency of EYS mutations in 100 Japanese arRP patients. To determine the prevalence of EYS mutations, all EYS exons were screened for mutations by polymerase chain reaction amplification, and sequence analysis was performed. We detected 67 sequence alterations in EYS, of which 21 were novel. Of these, 7 were very likely pathogenic mutations, 6 were possible pathogenic mutations, and 54 were predicted non-pathogenic sequence alterations. The minimum observed prevalence of distinct EYS mutations in our study was 18% (18/100, comprising 9 patients with 2 very likely pathogenic mutations and the remaining 9 with only one such mutation. Among these mutations, 2 novel truncating mutations, c.4957_4958insA (p.S1653KfsX2 and c.8868C>A (p.Y2956X, were identified in 16 patients and accounted for 57.1% (20/35 alleles of the mutated alleles. Although these 2 truncating mutations were not detected in Japanese patients with adRP or Leber's congenital amaurosis, we detected them in Korean arRP patients. Similar to Japanese arRP results, the c.4957_4958insA mutation was more frequently detected than the c.8868C>A mutation. The 18% estimated prevalence of very likely pathogenic mutations in our study suggests a major involvement of EYS in the pathogenesis of arRP in the Japanese population. Mutation spectrum of EYS in 100 Japanese patients, including 13 distinct very likely and possible pathogenic mutations, was largely different from the previously reported spectrum in patients from non-Asian populations. Screening for c.4957_4958insA and c.8868C>A mutations in the EYS gene may therefore be very effective for the genetic testing

  15. Disorders of fatty acid oxidation and autosomal recessive polycystic kidney disease-different clinical entities and comparable perinatal renal abnormalities.

    Science.gov (United States)

    Hackl, Agnes; Mehler, Katrin; Gottschalk, Ingo; Vierzig, Anne; Eydam, Marcus; Hauke, Jan; Beck, Bodo B; Liebau, Max C; Ensenauer, Regina; Weber, Lutz T; Habbig, Sandra

    2017-05-01

    Differential diagnosis of prenatally detected hyperechogenic and enlarged kidneys can be challenging as there is a broad phenotypic overlap between several rare genetic and non-genetic disorders. Metabolic diseases are among the rarest underlying disorders, but they demand particular attention as their prognosis and postnatal management differ from those of other diseases. We report two cases of cystic, hyperechogenic and enlarged kidneys detected on prenatal ultrasound images, resulting in the suspected diagnosis of autosomal recessive polycystic kidney disease (ARPKD). Postnatal clinical course and work-up, however, revealed early, neonatal forms of disorders of fatty acid oxidation (DFAO) in both cases, namely, glutaric acidemia type II, based on identification of the novel, homozygous splice-site mutation c.1117-2A > G in the ETFDH gene, in one case and carnitine palmitoyltransferase II deficiency in the other case. Review of pre- and postnatal sonographic findings resulted in the identification of some important differences that might help to differentiate DFAO from ARPKD. In DFAO, kidneys are enlarged to a milder degree than in ARPKD, and the cysts are located ubiquitously, including also in the cortex and the subcapsular area. Interestingly, recent studies have pointed to a switch in metabolic homeostasis, referred to as the Warburg effect (aerobic glycolysis), as one of the underlying mechanisms of cell proliferation and cyst formation in cystic kidney disease. DFAO are characterized by the inhibition of oxidative phosphorylation, resulting in aerobic glycolysis, and thus they do resemble the Warburg effect. We therefore speculate that this inhibition might be one of the pathomechanisms of renal hyperproliferation and cyst formation in DFAO analogous to the reported findings in ARPKD. Neonatal forms of DFAO can be differentially diagnosed in neonates with cystic or hyperechogenic kidneys and necessitate immediate biochemical work-up to provide early

  16. Canine disorder mirrors human disease: exonic deletion in HES7 causes autosomal recessive spondylocostal dysostosis in miniature Schnauzer dogs.

    Directory of Open Access Journals (Sweden)

    Cali E Willet

    Full Text Available Spondylocostal dysostosis is a congenital disorder of the axial skeleton documented in human families from diverse racial backgrounds. The condition is characterised by truncal shortening, extensive hemivertebrae and rib anomalies including malalignment, fusion and reduction in number. Mutations in the Notch signalling pathway genes DLL3, MESP2, LFNG, HES7 and TBX6 have been associated with this defect. In this study, spondylocostal dysostosis in an outbred family of miniature schnauzer dogs is described. Computed tomography demonstrated that the condition mirrors the skeletal defects observed in human cases, but unlike most human cases, the affected dogs were stillborn or died shortly after birth. Through gene mapping and whole genome sequencing, we identified a single-base deletion in the coding region of HES7. The frameshift mutation causes loss of functional domains essential for the oscillatory transcriptional autorepression of HES7 during somitogenesis. A restriction fragment length polymorphism test was applied within the immediate family and supported a highly penetrant autosomal recessive mode of inheritance. The mutation was not observed in wider testing of 117 randomly sampled adult miniature schnauzer and six adult standard schnauzer dogs; providing a significance of association of Praw = 4.759e-36 (genome-wide significant. Despite this apparently low frequency in the Australian population, the allele may be globally distributed based on its presence in two unrelated sires from geographically distant locations. While isolated hemivertebrae have been observed in a small number of other dog breeds, this is the first clinical and genetic diagnosis of spontaneously occurring spondylocostal dysostosis in a non-human mammal and offers an excellent model in which to study this devastating human disorder. The genetic test can be utilized by dog breeders to select away from the disease and avoid unnecessary neonatal losses.

  17. Canine disorder mirrors human disease: exonic deletion in HES7 causes autosomal recessive spondylocostal dysostosis in miniature Schnauzer dogs.

    Science.gov (United States)

    Willet, Cali E; Makara, Mariano; Reppas, George; Tsoukalas, George; Malik, Richard; Haase, Bianca; Wade, Claire M

    2015-01-01

    Spondylocostal dysostosis is a congenital disorder of the axial skeleton documented in human families from diverse racial backgrounds. The condition is characterised by truncal shortening, extensive hemivertebrae and rib anomalies including malalignment, fusion and reduction in number. Mutations in the Notch signalling pathway genes DLL3, MESP2, LFNG, HES7 and TBX6 have been associated with this defect. In this study, spondylocostal dysostosis in an outbred family of miniature schnauzer dogs is described. Computed tomography demonstrated that the condition mirrors the skeletal defects observed in human cases, but unlike most human cases, the affected dogs were stillborn or died shortly after birth. Through gene mapping and whole genome sequencing, we identified a single-base deletion in the coding region of HES7. The frameshift mutation causes loss of functional domains essential for the oscillatory transcriptional autorepression of HES7 during somitogenesis. A restriction fragment length polymorphism test was applied within the immediate family and supported a highly penetrant autosomal recessive mode of inheritance. The mutation was not observed in wider testing of 117 randomly sampled adult miniature schnauzer and six adult standard schnauzer dogs; providing a significance of association of Praw = 4.759e-36 (genome-wide significant). Despite this apparently low frequency in the Australian population, the allele may be globally distributed based on its presence in two unrelated sires from geographically distant locations. While isolated hemivertebrae have been observed in a small number of other dog breeds, this is the first clinical and genetic diagnosis of spontaneously occurring spondylocostal dysostosis in a non-human mammal and offers an excellent model in which to study this devastating human disorder. The genetic test can be utilized by dog breeders to select away from the disease and avoid unnecessary neonatal losses.

  18. Autosomal recessive polycystic kidney disorder due to two novel compound heterozygote mutations in PKHD1 gene: case report

    Directory of Open Access Journals (Sweden)

    Mohammad Miryounesi

    2017-01-01

    Full Text Available Background: Autosomal recessive polycystic kidney disorder (ARPCKD is one of the most prevalent hereditary disorders in neonates and children. Its frequency is between 1/6000 to 1/55000 births. In the most severe cases, it can be diagnosed prenatally by the presence of enlarged, echogenic kidneys and oligohydramnios. However, in the milder forms, clinical manifestations are usually detected in neonatal and childhood period. PKHD1 gene located on chromosome 6 is linked with this disorder. About half of detected mutations in this gene are missense ones. The largest protein product of this gene is called the FPC/polyductin complex (FPC. It is a single-membrane spanning protein whose absence leads to abnormal ciliogenesis in the kidneys. Case presentation: Here we present a 5-year-old female patient affected with ARPCKD. She has been born to a non-consanguineous healthy Iranian parents. No similar disorder has been seen in the family. Prenatal history has been normal. In order to find the genetic background, DNA was extracted from patient's peripheral blood lymphocytes. PKHD1 gene exons and exon-intron boundaries were sequenced using next generation sequencing platform. Two novel variants have been detected in compound heterozygote state in the patient (c.6591C>A, c.8222C>A. Bioinformatics tools predicted these variants to be pathogenic. Conclusion: In the present study, we detected two novel variants in PKHD1 gene in a patient with ARPCKD. The relatively mild phenotype of this patient is in accordance with the missense mutations found. Molecular genetic tools can help in accurate risk assessment as well as precise genotype-phenotype correlation establishment in families affected with such disorder to decrease the birth of affected individuals through preimplantation genetic diagnosis or better management of disorder.

  19. A novel gene encoding a TIG multiple domain protein is a positional candidate for autosomal recessive polycystic kidney disease.

    Science.gov (United States)

    Xiong, Huaqi; Chen, Yongxiong; Yi, Yajun; Tsuchiya, Karen; Moeckel, Gilbert; Cheung, Joseph; Liang, Dan; Tham, Kyi; Xu, Xiaohu; Chen, Xing-Zhen; Pei, York; Zhao, Zhizhuang Jeo; Wu, Guanqing

    2002-07-01

    Autosomal recessive polycystic kidney disease (ARPKD) is a common hereditary renal cystic disease in infants and children. By genetic linkage analyses, the gene responsible for this disease, termed polycystic kidney and hepatic disease 1 (PKHD1), was mapped on human chromosome 6p21.1-p12, and has been further localized to a 1-cM genetic interval flanked by the D6S1714/D6S243 (telomeric) and D6S1024 (centromeric) markers. We recently identified a novel gene in this genetic interval from kidney cDNA, using cloning strategies. The gene PKHD1 (PKHD1-tentative) encodes a novel 3396-amino-acid protein with no apparent homology with any known proteins. We named its gene product "tigmin" because it contains multiple TIG domains, which usually are seen in proteins containing immunoglobulin-like folds. PKHD1 encodes an 11.6-kb transcript and is composed of 61 exons spanning an approximately 365-kb genomic region on chromosome 6p12-p11.2 adjacent to the marker D6S1714. Northern blot analyses demonstrated that the gene has discrete bands with one peak signal at approximately 11 kb, indicating that PKHD1 is likely to have multiple alternative transcripts. PKHD1 is highly expressed in adult and infant kidneys and weakly expressed in liver in northern blot analysis. This expression pattern parallels the tissue involvement observed in ARPKD. In situ hybridization analysis further revealed that the expression of PKHD1 in the kidney is mainly localized to the epithelial cells of the collecting duct, the specific tubular segment involved in cyst formation in ARPKD. These features of PKHD1 make it a strong positional candidate gene for ARPKD.

  20. Homozygous SLC6A17 mutations cause autosomal-recessive intellectual disability with progressive tremor, speech impairment, and behavioral problems.

    Science.gov (United States)

    Iqbal, Zafar; Willemsen, Marjolein H; Papon, Marie-Amélie; Musante, Luciana; Benevento, Marco; Hu, Hao; Venselaar, Hanka; Wissink-Lindhout, Willemijn M; Vulto-van Silfhout, Anneke T; Vissers, Lisenka E L M; de Brouwer, Arjan P M; Marouillat, Sylviane; Wienker, Thomas F; Ropers, Hans Hilger; Kahrizi, Kimia; Nadif Kasri, Nael; Najmabadi, Hossein; Laumonnier, Frédéric; Kleefstra, Tjitske; van Bokhoven, Hans

    2015-03-05

    We report on Dutch and Iranian families with affected individuals who present with moderate to severe intellectual disability and additional phenotypes including progressive tremor, speech impairment, and behavioral problems in certain individuals. A combination of exome sequencing and homozygosity mapping revealed homozygous mutations c.484G>A (p.Gly162Arg) and c.1898C>G (p.Pro633Arg) in SLC6A17. SLC6A17 is predominantly expressed in the brain, encodes a synaptic vesicular transporter of neutral amino acids and glutamate, and plays an important role in the regulation of glutamatergic synapses. Prediction programs and 3D modeling suggest that the identified mutations are deleterious to protein function. To directly test the functional consequences, we investigated the neuronal subcellular localization of overexpressed wild-type and mutant variants in mouse primary hippocampal neuronal cells. Wild-type protein was present in soma, axons, dendrites, and dendritic spines. p.Pro633Arg altered SLC6A17 was found in soma and proximal dendrites but did not reach spines. p.Gly162Arg altered SLC6A17 showed a normal subcellular distribution but was associated with an abnormal neuronal morphology mainly characterized by the loss of dendritic spines. In summary, our genetic findings implicate homozygous SLC6A17 mutations in autosomal-recessive intellectual disability, and their pathogenic role is strengthened by genetic evidence and in silico and in vitro functional analyses. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  1. A novel COL4A3 mutation causes autosomal-recessive Alport syndrome in a large Turkish family.

    Science.gov (United States)

    Uzak, Asli Subasioglu; Tokgoz, Bulent; Dundar, Munis; Tekin, Mustafa

    2013-03-01

    Alport syndrome (AS) is a genetically heterogeneous disorder that is characterized by hematuria, progressive renal failure typically resulting in end-stage renal disease, sensorineural hearing loss, and variable ocular abnormalities. Only 15% of cases with AS are autosomal recessive and are caused by mutations in the COL4A3 or COL4A4 genes, encoding type IV collagen. Clinical data in a large consanguineous family with four affected members were reviewed, and genomic DNA was extracted. For mapping, 15 microsatellite markers flanking COL4A3, COL4A4, and COL4A5 in 16 family members were typed. For mutation screening, all coding exons of COL4A3 were polymerase chain reaction- amplified and Sanger-sequenced from genomic DNA. The disease locus was mapped to chromosome 2q36.3, where COL4A3 and COL4A4 reside. Sanger sequencing revealed a novel mis-sense mutation (c.2T>C; p.M1T) in exon 1 of COL4A3. The identified nucleotide change was not found in 100 healthy ethnicity-matched controls via Sanger sequencing. We present a large consanguineous Turkish family with AS that was found to have a COL4A3 mutation as the cause of the disease. Although the relationship between the various genotypes and phenotypes in AS has not been fully elucidated, detailed clinical and molecular analyses are helpful for providing data to be used in genetic counseling. It is important to identify new mutations to clarify their clinical importance, to assess the prognosis of the disease, and to avoid renal biopsy for final diagnosis.

  2. Autosomal Recessive Inheritance

    Science.gov (United States)

    ... NEI Intranet (Employees Only) *PDF files require the free Adobe® Reader® software for viewing. This website is maintained by the NEI Office of Science Communications, Public Liaison, and Education. Technical questions about this website can be addressed ...

  3. Skeletal muscle, but not cardiovascular function, is altered in a mouse model of autosomal recessive hypophosphatemic rickets

    Directory of Open Access Journals (Sweden)

    Michael J. Wacker

    2016-05-01

    Full Text Available Autosomal recessive hypophosphatemic rickets (ARHR is a heritable disorder characterized by hypophosphatemia, osteomalacia, and poor bone development. ARHR results from inactivating mutations in the DMP1 gene with the human phenotype being recapitulated in the Dmp1 null mouse model which displays elevated plasma fibroblast growth factor 23. While the bone phenotype has been well characterized, it is not known what effects ARHR may also have on skeletal, cardiac, or vascular smooth muscle function, which is critical to understand to treat patients suffering from this condition. In this study, the extensor digitorum longus (EDL- fast-twitch muscle, soleus (SOL- slow-twitch muscle, heart, and aorta were removed from Dmp1 null mice and ex-vivo functional tests were simultaneously performed in collaboration by three different laboratories. Dmp1 null EDL and SOL muscles produced less force than wildtype muscles after normalization for physiological cross sectional area of the muscles. Both EDL and SOL muscles from Dmp1 null mice also produced less force after the addition of caffeine (which releases calcium from the sarcoplasmic reticulum which may indicate problems in excitation contraction coupling in these mice. While the body weights of the Dmp1 null were smaller than wildtype, the heart weight to body weight ratio was higher. However, there were no differences in pathological hypertrophic gene expression compared to wildtype and maximal force of contraction was not different indicating that there may not be cardiac pathology under the tested conditions. We did observe a decrease in the rate of force development generated by cardiac muscle in the Dmp1 null which may be related to some of the deficits observed in skeletal muscle. There were no differences observed in aortic contractions induced by PGF2a or 5-HT or in endothelium-mediated acetylcholine-induced relaxations or endothelium-independent sodium nitroprusside-induced relaxations. In

  4. Highly prevalent LIPH founder mutations causing autosomal recessive woolly hair/hypotrichosis in Japan and the genotype/phenotype correlations.

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    Kana Tanahashi

    Full Text Available Mutations in LIPH cause of autosomal recessive woolly hair/hypotrichosis (ARWH, and the 2 missense mutations c.736T>A (p.Cys246Ser and c.742C>A (p.His248Asn are considered prevalent founder mutations for ARWH in the Japanese population. To reveal genotype/phenotype correlations in ARWH cases in Japan and the haplotypes in 14 Japanese patients from 14 unrelated Japanese families. 13 patients had woolly hair, and 1 patient had complete baldness since birth. An LIPH mutation search revealed homozygous c.736T>A mutations in 10 of the patients. Compound heterozygous c.736T>A and c.742C>A mutations were found in 3 of the patients, and homozygous c.742C>A mutation in 1 patient. The phenotype of mild hypotrichosis with woolly hair was restricted to the patients with the homozygous c.736T>A mutation. The severe phenotype of complete baldness was seen in only 1 patient with homozygous c.742C>A. Haplotype analysis revealed that the alleles containing the LIPH c.736T>A mutation had a haplotype identical to that reported previously, although 4 alleles out of 5 chromosomes containing the LIPH c.742C>A mutation had a different haplotype from the previously reported founder allele. These alleles with c.742C>A are thought to be the third founder LIPH mutation causing ARWH. To accurately determine the prevalence of the founder mutations, we investigated allele frequencies of those mutations in 819 Japanese controls. Heterozygous c.736T>A mutations were found in 13 controls (allele frequency: 0.0079; carrier rate: 0.016, and heterozygous c.742C>A mutations were found in 2 controls (allele frequency: 0.0012; carrier rate: 0.0024. In conclusion, this study confirms the more accurate allele frequencies of the pathogenic founder mutations of LIPH and shows that there is a third founder mutation in Japan. In addition, the present findings suggest that the mutation patterns of LIPH might be associated with hypotrichosis severity in ARWH.

  5. Outcome of ABCA4 disease-associated alleles in autosomal recessive retinal dystrophies: retrospective analysis in 420 Spanish families.

    Science.gov (United States)

    Riveiro-Alvarez, Rosa; Lopez-Martinez, Miguel-Angel; Zernant, Jana; Aguirre-Lamban, Jana; Cantalapiedra, Diego; Avila-Fernandez, Almudena; Gimenez, Ascension; Lopez-Molina, Maria-Isabel; Garcia-Sandoval, Blanca; Blanco-Kelly, Fiona; Corton, Marta; Tatu, Sorina; Fernandez-San Jose, Patricia; Trujillo-Tiebas, Maria-Jose; Ramos, Carmen; Allikmets, Rando; Ayuso, Carmen

    2013-11-01

    To provide a comprehensive overview of all detected mutations in the ABCA4 gene in Spanish families with autosomal recessive retinal disorders, including Stargardt's disease (arSTGD), cone-rod dystrophy (arCRD), and retinitis pigmentosa (arRP), and to assess genotype-phenotype correlation and disease progression in 10 years by considering the type of variants and age at onset. Case series. A total of 420 unrelated Spanish families: 259 arSTGD, 86 arCRD, and 75 arRP. Spanish families were analyzed through a combination of ABCR400 genotyping microarray, denaturing high-performance liquid chromatography, and high-resolution melting scanning. Direct sequencing was used as a confirmation technique for the identified variants. Screening by multiple ligation probe analysis was used to detect possible large deletions or insertions in the ABCA4 gene. Selected families were analyzed further by next generation sequencing. DNA sequence variants, mutation detection rates, haplotypes, age at onset, central or peripheral vision loss, and night blindness. Overall, we detected 70.5% and 36.6% of all expected ABCA4 mutations in arSTGD and arCRD patient cohorts, respectively. In the fraction of the cohort where the ABCA4 gene was sequenced completely, the detection rates reached 73.6% for arSTGD and 66.7% for arCRD. However, the frequency of possibly pathogenic ABCA4 alleles in arRP families was only slightly higher than that in the general population. Moreover, in some families, mutations in other known arRP genes segregated with the disease phenotype. An increasing understanding of causal ABCA4 alleles in arSTGD and arCRD facilitates disease diagnosis and prognosis and also is paramount in selecting patients for emerging clinical trials of therapeutic interventions. Because ABCA4-associated diseases are evolving retinal dystrophies, assessment of age at onset, accurate clinical diagnosis, and genetic testing are crucial. We suggest that ABCA4 mutations may be associated with a

  6. Congenital sensorineural deafness in Australian stumpy-tail cattle dogs is an autosomal recessive trait that maps to CFA10.

    Directory of Open Access Journals (Sweden)

    Susan Sommerlad

    2010-10-01

    speckling. Fine mapping was then performed on 45 of these 50 dogs and a further 48 dogs (n = 93. Sequencing candidate gene Sox10 in 6 hearing ASCD, 2 unilaterally deaf ASCD and 2 bilaterally deaf ASCD did not reveal any disease-associated mutations.Deafness in ASCD is an incompletely penetrant autosomal recessive inherited disease that maps to CFA10.

  7. Genetic Linkage Analysis of DFNB2 Locus with Autosomal Recessive Hearing Loss in Families Negative for GJB2 Mutations in Khuzestan Province

    Directory of Open Access Journals (Sweden)

    Parisa Tahmasebi

    2016-09-01

    Full Text Available Abstract Background: Hearing loss is a common sensory impairment in humans which half of its causes are genetic reasons. Genetic hearing loss can be divided into the two types of syndromic and non-syndromic, which 80% of non-syndromic cases is Autosomal Recessive Non-Syndromic Hearing Loss. The aim of the present research is to determine the contribution of DFNB2 locus (MYO7A gene in causing an autosomal recessive hearing loss in the one group of the deaf families of Khuzestan province. Materials and Methods: This study was conducted on 26 families with autosomal recessive hearing loss (with 4 patients and negative for GJB2 mutations in Khuzestan province. 22 families suffered from ARNSHL and 4 families suffered from Usher syndrome. Linkage analysis was performed by using STR (Short Tandem Repeat markers related to DFNB2 locus. Each family’s genotype was determined by PCR-PAGE method. Furthermore, haplotypes drawing and LOD score calculations were performed. Results: From 26 families with hearing loss participating in this research, following genetic linkage analysis and haplotypes drawing, two families (7.7% of the families showed linkage to DFNB2 locus. One family (4.5% suffered from ARNSHL and another family suffered from Usher syndrome. Conclusion: The results of the present research show that the contribution of DFNB2 locus in causing hearing loss in the population of Khuzestan province was similar to other studies conducted in Iran and this locus with other important loci should be considered to check in the hearing loss panel.

  8. Autosomal recessive hyper IgM syndrome associated with activation-induced cytidine deaminase gene in three Turkish siblings presented with tuberculosis lymphadenitis - Case report.

    Science.gov (United States)

    Patiroglu, Turkan; Akar, H Haluk; van der Burg, Mirjam; Unal, Ekrem

    2015-09-01

    The hyper-immunoglobulin M (HIGM) syndrome is a heterogeneous group of genetic disorders characterized by recurrent infections, decreased serum levels of immunoglobulin G (IgG) and IgA, and normal/increased serum levels of IgM. Herein, we describe three Turkish siblings with HIGM syndrome who had a homozygous missense mutation (c.70C>T, p.Arg24Trp) in the activation-induced cytidine deaminase gene which results in autosomal recessive HIGM syndrome. Two of the siblings, sibling 1 and sibling 3, presented with cervical deep abscess and cervical tuberculosis lymphadenitis, respectively.

  9. A novel c.5308_5311delGAGA mutation in Senataxin in a Cypriot family with an autosomal recessive cerebellar ataxia

    Directory of Open Access Journals (Sweden)

    Zamba-Papanicolaou Eleni

    2008-04-01

    Full Text Available Abstract Background Senataxin (chromosome 9q34 was recently identified as the causative gene for an autosomal recessive form of Ataxia (ARCA, termed as Ataxia with Oculomotor Apraxia, type 2 (AOA2 and characterized by generalized incoordination, cerebellar atrophy, peripheral neuropathy, "oculomotor apraxia" and increased alpha-fetoprotein (AFP. Here, we report a novel Senataxin mutation in a Cypriot ARCA family. Methods We studied several Cypriot autosomal recessive cerebellar ataxia (ARCA families for linkage to known ARCA gene loci. We linked one family (909 to the SETX locus on chromosome 9q34 and screened the proband for mutations by direct sequencing. Results Sequence analysis revealed a novel c.5308_5311delGAGA mutation in exon 11 of the SETX gene. The mutation has not been detected in 204 control chromosomes from the Cypriot population, the remaining Cypriot ARCA families and 37 Cypriot sporadic cerebellar ataxia patients. Conclusion We identified a novel SETX homozygous c.5308_5311delGAGA mutation that co-segregates with ARCA with cerebellar atrophy and raised AFP.

  10. A Rare Variant in PGAP2 Causes Autosomal Recessive Hyperphosphatasia with Mental Retardation Syndrome, with a Mild Phenotype in Heterozygous Carriers

    Directory of Open Access Journals (Sweden)

    Yonatan Perez

    2017-01-01

    Full Text Available Mutations in genes involved in the biosynthesis of the glycosylphosphatidylinositol (GPI anchor cause autosomal recessive glycosylation defects, with a wide phenotypic spectrum of intellectual disability, seizures, minor facial dysmorphism, hypotonia, and elevated serum alkaline phosphatase. We now describe consanguineous Bedouin kindred presenting with an autosomal recessive syndrome of intellectual disability and elevated serum alkaline phosphatase. Genome-wide linkage analysis identified 6 possible disease-associated loci. Whole-exome sequencing followed by Sanger sequencing validation identified a single variant in PGAP2 as the disease-causing mutation (C.554G>A; p.185(R>Q, segregating as expected within the kindred and not found in 150 Bedouin controls. The mutation replaces a highly conserved arginine residue with glutamine within the Frag1 (FGF receptor activating domain of PGAP2. Interestingly, this mutation is a known dbSNP variant (rs745521288, build 147 with a very low allele frequency (0.00000824 in dbSNP, no homozygotes reported, highlighting the fact that dbSNP variants should not be automatically ruled out as disease-causing mutations. We further showed that PGAP2 is ubiquitously expressed, but in line with the disease phenotype, it is highly transcribed in human brain, skeletal muscle, and liver. Interestingly, a mild phenotype of slightly elevated serum levels of alkaline phosphatase and significant learning disabilities was observed in heterozygous carriers.

  11. Microarray-based mutation analysis of the ABCA4 (ABCR) gene in autosomal recessive cone-rod dystrophy and retinitis pigmentosa.

    Science.gov (United States)

    Klevering, B Jeroen; Yzer, Suzanne; Rohrschneider, Klaus; Zonneveld, Marijke; Allikmets, Rando; van den Born, L Ingeborgh; Maugeri, Alessandra; Hoyng, Carel B; Cremers, Frans P M

    2004-12-01

    Mutations in the ABCA4 gene have been associated with autosomal recessive Stargardt disease (STGD1), cone-rod dystrophy (CRD), and retinitis pigmentosa (RP). We employed a recently developed genotyping microarray, the ABCR400-chip, to search for known ABCA4 mutations in patients with isolated or autosomal recessive CRD (54 cases) or RP (90 cases). We performed detailed ophthalmologic examinations and identified at least one ABCA4 mutation in 18 patients (33%) with CRD and in five patients (5.6%) with RP. Single-strand conformation polymorphism (SSCP) analysis and subsequent DNA sequencing revealed four novel missense mutations (R24C, E161K, P597S, G618E) and a novel 1-bp deletion (5888delG). Ophthalmoscopic abnormalities in CRD patients ranged from minor granular pigmentary changes in the posterior pole to widespread atrophy. In 12 patients with recordable electroretinogram (ERG) tracings, a cone-rod pattern was detected. Three patients demonstrated progression from a retinal dystrophy resembling STGD1 to a more widespread degeneration, and were subsequently diagnosed as CRD. In addition to a variable degree of atrophy, all RP patients displayed ophthalmologic characteristics of classic RP. When detectable, ERG recordings in these patients demonstrated rod-cone patterns of photoreceptor degeneration. In conclusion, in this study, we show that the ABCA4 mutation chip is an efficient first screening tool for arCRD.

  12. Inhibitory action of chlorophyllin of autosome recessive lethals induced by irradiation; Accion inhibidora de la clorofilina de letales recesivos autosonicos inducidos por irradiacion

    Energy Technology Data Exchange (ETDEWEB)

    Salceda, V M; Pimentel, P A.E.; Cruces, M P [ININ, 52045 Ocoyoacac, Estado de Mexico (Mexico)

    2006-07-01

    The chlorolin is a sodium salt of the chlorophyll that has a strong protective action of the damage induced by different agents so much physical as chemical. In Drosophila there is reported this effect in somatic cells. In contrast, in germinal cells using tests with the sexual chromosomes has not been found such inhibitory action. For this reason, in this occasion we will refer to the effect of the lethality induced in autosome chromosomes, in particular to the chromosome II of this species. For such effect groups of males of the line Canton-S its were pre-treated for 24h with or without 69 mm of CCS and later on treaties with or without 40 Gy of gamma irradiation. The males were then subjected to the technical Cy L / Pm for the detection of recessive lethals. In the third generation the respective counts of the descendant of each one of them to determine the corresponding categories for each extracted chromosome were made. To be mendelian crosses it is expected for a normal chromosome a proportion 2:1 of individuals with genotype Cy L / +: +/+. The absence of individuals +/+ it is indicative of a lethal gene, until 10% of these individuals of each male's total descendant, it is considered that is carrying of a semi lethal gene. The sum of lethal and semi lethals constitutes the category detrimental. The obtained results indicated that the pre-treatment with CCS reduces in a significant way the frequency of induced lethals by 40 Gy of gamma rays. The fact that an effect inhibitor has not been observed in the test of recessive lethal bound to the sex obtained previously, it contrasts with the effect observed in the chromosome II, results of this study and with the one observed in the chromosome III in somatic cells. The above-mentioned shows a differential action of the CCS between sexual chromosomes and autosomal before the effect of the gamma radiation. At the moment we don't have an explanation to these evidences. To evaluate the action of the chlorophyllin on

  13. Inhibitory action of chlorophyllin of autosome recessive lethals induced by irradiation; Accion inhibidora de la clorofilina de letales recesivos autosonicos inducidos por irradiacion

    Energy Technology Data Exchange (ETDEWEB)

    Salceda, V.M.; Pimentel, P.A.E.; Cruces, M.P. [ININ, 52045 Ocoyoacac, Estado de Mexico (Mexico)]. e-mail: vmss@nuclear.inin.mx

    2006-07-01

    The chlorolin is a sodium salt of the chlorophyll that has a strong protective action of the damage induced by different agents so much physical as chemical. In Drosophila there is reported this effect in somatic cells. In contrast, in germinal cells using tests with the sexual chromosomes has not been found such inhibitory action. For this reason, in this occasion we will refer to the effect of the lethality induced in autosome chromosomes, in particular to the chromosome II of this species. For such effect groups of males of the line Canton-S its were pre-treated for 24h with or without 69 mm of CCS and later on treaties with or without 40 Gy of gamma irradiation. The males were then subjected to the technical Cy L / Pm for the detection of recessive lethals. In the third generation the respective counts of the descendant of each one of them to determine the corresponding categories for each extracted chromosome were made. To be mendelian crosses it is expected for a normal chromosome a proportion 2:1 of individuals with genotype Cy L / +: +/+. The absence of individuals +/+ it is indicative of a lethal gene, until 10% of these individuals of each male's total descendant, it is considered that is carrying of a semi lethal gene. The sum of lethal and semi lethals constitutes the category detrimental. The obtained results indicated that the pre-treatment with CCS reduces in a significant way the frequency of induced lethals by 40 Gy of gamma rays. The fact that an effect inhibitor has not been observed in the test of recessive lethal bound to the sex obtained previously, it contrasts with the effect observed in the chromosome II, results of this study and with the one observed in the chromosome III in somatic cells. The above-mentioned shows a differential action of the CCS between sexual chromosomes and autosomal before the effect of the gamma radiation. At the moment we don't have an explanation to these evidences. To evaluate the action of the

  14. Autosomal-recessive posterior microphthalmos is caused by mutations in PRSS56, a gene encoding a trypsin-like serine protease

    DEFF Research Database (Denmark)

    Gal, Andreas; Rau, Isabella; El Matri, Leila

    2011-01-01

    Posterior microphthalmos (MCOP) is a rare isolated developmental anomaly of the eye characterized by extreme hyperopia due to short axial length. The population of the Faroe Islands shows a high prevalence of an autosomal-recessive form (arMCOP) of the disease. Based on published linkage data, we...... the affinity and reactivity of the enzyme toward in vivo protein substrates are likely to be substantially reduced....... heterogeneity of the trait. Using RT-PCR, PRSS56 transcripts were detected in samples derived from the human adult retina, cornea, sclera, and optic nerve. The expression of the mouse ortholog could be first detected in the eye at E17 and was maintained into adulthood. The predicted PRSS56 protein is a 603...

  15. Additional case of Marden-Walker syndrome: support for the autosomal-recessive inheritance adn refinement of phenotype in a surviving patient.

    Science.gov (United States)

    Orrico, A; Galli, L; Zappella, M; Orsi, A; Hayek, G

    2001-02-01

    In this report, we present a 14-year-old girl, born to consanguineous parents, who presented with severe mental retardation, hypotonia, short stature, and congenital joint contractures. The craniofacial features were scaphocephaly, thin/long and immobile face, marked hypoplasia of the midface, temporal narrowness, blepharophimosis, palpebral ptosis, and strabismus. The combination of such a distinctive craniofacial appearance and psychomotor retardation allows us to recognize a new case of the Marden-Walker syndrome. Our patient represents one of the rare cases in which consanguineous mating supports the autosomal-recessive pattern of inheritance of this condition. Furthermore, through refining the phenotype of a surviving patient, this report may contribute to a better recognition of this disorder in older affected children.

  16. Simultaneous Occurence of an Autosomal Dominant Inherited MSX1 Mutation and an X-linked Recessive Inherited EDA Mutation in One Chinese Family with Non-syndromic Oligodontia.

    Science.gov (United States)

    Zhang, Xiao Xia; Wong, Sing Wai; Han, Dong; Feng, Hai Lan

    2015-01-01

    To describe the simultaneous occurence of an autosomal dominant inherited MSX1 mutation and an X-linked recessive inherited EDA mutation in one Chinese family with nonsyndromic oligodontia. Clinical data of characteristics of tooth agenesis were collected. MSX1 and EDA gene mutations were detected in a Chinese family of non-syndromic oligodontia. Mild hypodontia in the parents and severe oligodontia in the son was recorded. A novel missense heterozygous mutation c.517C>A (p.Arg173Ser) was detected in the MSX1 gene in the boy and the father. A homozygous missense mutation c.1001G>A (p.Arg334His) was detected in the EDA gene in the boy and the same mutant occurred heterozygously in the mother. Simultaneous occurence of two different gene mutations with different inheritence patterns, which both caused oligodontia, which occurred in one subject and in one family, was reported.

  17. Autosomal-recessive posterior microphthalmos is caused by mutations in PRSS56, a gene encoding a trypsin-like serine protease

    DEFF Research Database (Denmark)

    Gal, Andreas; Rau, Isabella; El Matri, Leila

    2011-01-01

    heterogeneity of the trait. Using RT-PCR, PRSS56 transcripts were detected in samples derived from the human adult retina, cornea, sclera, and optic nerve. The expression of the mouse ortholog could be first detected in the eye at E17 and was maintained into adulthood. The predicted PRSS56 protein is a 603......Posterior microphthalmos (MCOP) is a rare isolated developmental anomaly of the eye characterized by extreme hyperopia due to short axial length. The population of the Faroe Islands shows a high prevalence of an autosomal-recessive form (arMCOP) of the disease. Based on published linkage data, we...... amino acid long secreted trypsin-like serine peptidase. The c.1066dupC is likely to result in a functional null allele, whereas the two point mutations predict the replacement of evolutionary conserved and functionally important residues. Molecular modeling of the p.Trp309Ser mutant suggests that both...

  18. Kidney Versus Combined Kidney and Liver Transplantation in Young People With Autosomal Recessive Polycystic Kidney Disease: Data From the European Society for Pediatric Nephrology/European Renal Association-European Dialysis and Transplant (ESPN/ERA-EDTA) Registry

    NARCIS (Netherlands)

    Mekahli, Djalila; van Stralen, Karlijn J.; Bonthuis, Marjolein; Jager, Kitty J.; Balat, Ayşe; Benetti, Elisa; Godefroid, Nathalie; Edvardsson, Vidar O.; Heaf, James G.; Jankauskiene, Augustina; Kerecuk, Larissa; Marinova, Svetlana; Puteo, Flora; Seeman, Tomas; Zurowska, Aleksandra; Pirenne, Jacques; Schaefer, Franz; Groothoff, Jaap W.; Levtchenko, E.; Haffner, D.; Bjerre, A.; Massy, Z.; Shtiza, D.; Kramar, R.; Oberbauer, R.; Baiko, S.; Sukalo, A.; van Hoeck, K.; Collart, F.; des Grottes, J. M.; Pokrajac, D.; Roussinov, D.; Batinić , D.; Lemac, M.; Slavicek, J.; Seeman, T.; Vondrak, K.; Heaf, J. G.; Toots, U.; Finne, P.; Grö nhagen-Riska, C.; Couchoud, C.; Lasalle, M.; Sahpazova, E.; Abazi, N.; Ristoka Bojkovska, N.; von Gersdorff, G.; Scholz, C.; Tö nshoff, B.; Krupka, K.

    2016-01-01

    The choice for either kidney or combined liver-kidney transplantation in young people with kidney failure and liver fibrosis due to autosomal recessive polycystic kidney disease (ARPKD) can be challenging. We aimed to analyze the characteristics and outcomes of transplantation type in these

  19. Kidney Versus Combined Kidney and Liver Transplantation in Young People With Autosomal Recessive Polycystic Kidney Disease: Data From the European Society for Pediatric Nephrology/European Renal Association-European Dialysis and Transplant (ESPN/ERA-EDTA) Registry

    NARCIS (Netherlands)

    Mekahli, D.; Stralen, K.J. van; Bonthuis, M.; Jager, K.J.; Balat, A.; Benetti, E.; Godefroid, N.; Edvardsson, V.O.; Heaf, J.G.; Jankauskiene, A.; Kerecuk, L.; Marinova, S.; Puteo, F.; Seeman, T.; Zurowska, A.; Pirenne, J.; Schaefer, F.; Groothoff, J.W.; Hoitsma, A.J.; et al.,

    2016-01-01

    BACKGROUND: The choice for either kidney or combined liver-kidney transplantation in young people with kidney failure and liver fibrosis due to autosomal recessive polycystic kidney disease (ARPKD) can be challenging. We aimed to analyze the characteristics and outcomes of transplantation type in

  20. SLC3A1 and SLC7A9 mutations in autosomal recessive or dominant canine cystinuria: a new classification system.

    Science.gov (United States)

    Brons, A-K; Henthorn, P S; Raj, K; Fitzgerald, C A; Liu, J; Sewell, A C; Giger, U

    2013-01-01

    Cystinuria, one of the first recognized inborn errors of metabolism, has been reported in many dog breeds. To determine urinary cystine concentrations, inheritance, and mutations in the SLC3A1 and SLC7A9 genes associated with cystinuria in 3 breeds. Mixed and purebred Labrador Retrievers (n = 6), Australian Cattle Dogs (6), Miniature Pinschers (4), and 1 mixed breed dog with cystine urolithiasis, relatives and control dogs. Urinary cystinuria and aminoaciduria was assessed and exons of the SLC3A1 and SLC7A9 genes were sequenced from genomic DNA. In each breed, male and female dogs, independent of neuter status, were found to form calculi. A frameshift mutation in SLC3A1 (c.350delG) resulting in a premature stop codon was identified in autosomal-recessive (AR) cystinuria in Labrador Retrievers and mixed breed dogs. A 6 bp deletion (c.1095_1100del) removing 2 threonines in SLC3A1 was found in autosomal-dominant (AD) cystinuria with a more severe phenotype in homozygous than in heterozygous Australian Cattle Dogs. A missense mutation in SLC7A9 (c.964G>A) was discovered in AD cystinuria in Miniature Pinschers with only heterozygous affected dogs observed to date. Breed-specific DNA tests were developed, but the prevalence of each mutation remains unknown. These studies describe the first AD inheritance and the first putative SLC7A9 mutation to cause cystinuria in dogs and expand our understanding of this phenotypically and genetically heterogeneous disease, leading to a new classification system for canine cystinuria and better therapeutic management and genetic control in these breeds. Copyright © 2013 by the American College of Veterinary Internal Medicine.

  1. Homozygosity mapping reveals new nonsense mutation in the FAM161A gene causing autosomal recessive retinitis pigmentosa in a Palestinian family.

    Science.gov (United States)

    Zobor, Ditta; Balousha, Ghassan; Baumann, Britta; Wissinger, Bernd

    2014-01-01

    Retinitis pigmentosa (RP) is a heterogenous group of inherited retinal degenerations caused by mutations in at least 45 genes. Recently, the FAM161A gene was identified as the causative gene for RP28, an autosomal recessive form of RP. We performed a clinical and molecular genetic study of a consanguineous Palestinian family with two three siblings affected with retinitis pigmentosa. DNA samples were collected from the index patient, his father, his affected sister, and two non-affected brothers. DNA sample from the index was subjected to high resolution genome-wide SNP array. Assuming identity-by-descent in this consanguineous family we applied homozygosity mapping to identify disease causing genes. The index patient reported night blindness since the age of 20 years, followed by moderate disease progression with decrease of peripheral vision, the development of photophobia and later on reduced central vision. At the age of 40 his visual acuity was counting fingers (CF) for both eyes, color discrimination was not possible and his visual fields were severely constricted. Funduscopic examination revealed a typical appearance of advanced RP with optic disc pallor, narrowed retinal vessels, bone-spicule like pigmentary changes in the mid-periphery and atrophic changes in the macula. His younger affected brother (37 years) was reported with overall milder symptoms, while the youngest sister (21 years) reported problems only with night vision. Applying high-density SNP arrays we identified several homozygous genomic regions one of which included the recently identified FAM161A gene mutated in RP28-linked autosomal recessive RP. Sequencing analysis revealed the presence of a novel homozygous nonsense mutation, c.1003C>T/p.R335X in the index patient and the affected sister. We identified an RP28-linked RP family in the Palestinian population caused by a novel nonsense mutation in FAM161A. RP in this family shows a typical disease onset with moderate to rapid progression

  2. Digenic inheritance in autosomal recessive non-syndromic hearing loss cases carrying GJB2 heterozygote mutations: assessment of GJB4, GJA1, and GJC3.

    Science.gov (United States)

    Kooshavar, Daniz; Tabatabaiefar, Mohammad Amin; Farrokhi, Effat; Abolhasani, Marziye; Noori-Daloii, Mohammad-Reza; Hashemzadeh-Chaleshtori, Morteza

    2013-02-01

    Autosomal recessive non-syndromic hearing loss (ARNSHL) can be caused by many genes. However, mutations in the GJB2 gene, which encodes the gap-junction (GJ) protein connexin (Cx) 26, constitute a considerable proportion differing among population. Between 10 and 42 percent of patients with recessive GJB2 mutations carry only one mutant allele. Mutations in GJB4, GJA1, and GJC3 encoding Cx30.3, Cx43, and Cx29, respectively, can lead to HL. Combination of different connexins in heteromeric and heterotypic GJ assemblies is possible. This study aims to determine whether variations in any of the genes GJB4, GJA1 or GJC3 can be the second mutant allele causing the disease in the digenic mode of inheritance in the studied GJB2 heterozygous cases. We examined 34 unrelated GJB2 heterozygous ARNSHL subjects from different geographic and ethnic areas in Iran, using polymerase chain reaction (PCR) followed by direct DNA sequencing to identify any sequence variations in these genes. Restriction fragment length polymorphism (RFLP) assays were performed on 400 normal hearing individuals. Sequence analysis of GJB4 showed five heterozygous variations including c.451C>A, c.219C>T, c.507C>G, c.155_158delTCTG and c.542C>T, with only the latter variation not being detected in any of control samples. There were three heterozygous variations including c.758C>T, c.717G>A and c.3*dupA in GJA1 in four cases. We found no variations in GJC3 gene sequence. Our data suggest that GJB4 c.542C>T variant and less likely some variations of GJB4 and GJA1, but not possibly GJC3, can be assigned to ARNSHL in GJB2 heterozygous mutation carriers providing clues of the digenic pattern. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  3. Four siblings with distal renal tubular acidosis and nephrocalcinosis, neurobehavioral impairment, short stature, and distinctive facial appearance: a possible new autosomal recessive syndrome.

    Science.gov (United States)

    Faqeih, Eissa; Al-Akash, Samhar I; Sakati, Nadia; Teebi, Prof Ahmad S

    2007-09-01

    We report on four siblings (three males, one female) born to first cousin Arab parents with the constellation of distal renal tubular acidosis (RTA), small kidneys, nephrocalcinosis, neurobehavioral impairment, short stature, and distinctive facial features. They presented with early developmental delay with subsequent severe mental, behavioral and social impairment and autistic-like features. Their facial features are unique with prominent cheeks, well-defined philtrum, large bulbous nose, V-shaped upper lip border, full lower lip, open mouth with protruded tongue, and pits on the ear lobule. All had proteinuria, hypercalciuria, hypercalcemia, and normal anion-gap metabolic acidosis. Renal ultrasound examinations revealed small kidneys, with varying degrees of hyperechogenicity and nephrocalcinosis. Additional findings included dilated ventricles and cerebral demyelination on brain imaging studies. Other than distal RTA, common causes of nephrocalcinosis were excluded. The constellation of features in this family currently likely represents a possibly new autosomal recessive syndrome providing further evidence of heterogeneity of nephrocalcinosis syndromes. Copyright 2007 Wiley-Liss, Inc.

  4. Clinical Application of Screening for GJB2 Mutations before Cochlear Implantation in a Heterogeneous Population with High Rate of Autosomal Recessive Nonsyndromic Hearing Loss

    Directory of Open Access Journals (Sweden)

    Masoud Motasaddi Zarandy

    2011-01-01

    Full Text Available Clinical application of mutation screening and its effect on the outcome of cochlear implantation is widely debated. We investigated the effect of mutations in GJB2 gene on the outcome of cochlear implantation in a population with a high rate of consanguineous marriage and autosomal recessive nonsyndromic hearing loss. Two hundred and one children with profound prelingual sensorineural hearing loss were included. Forty-six patients had 35delG in GJB2. Speech awareness thresholds (SATs and speech recognition thresholds (SRTs improved following implantation, but there was no difference in performance between patients with GJB2-related deafness versus control (all >0.10. Both groups had produced their first comprehensible words within the same period of time following implantation (2.27 months in GJB2-related deaf versus 2.62 months in controls, =0.22. Although our findings demonstrate the need to uncover unidentified genetic causes of hereditary deafness, they do not support the current policy for genetic screening before cochlear implantation, nor prove a prognostic value.

  5. New evidence for the role of calpain 10 in autosomal recessive intellectual disability: identification of two novel nonsense variants by exome sequencing in Iranian families.

    Science.gov (United States)

    Oladnabi, Morteza; Musante, Luciana; Larti, Farzaneh; Hu, Hao; Abedini, Seyedeh Sedigheh; Wienker, Thomas; Ropers, Hans Hilger; Kahrizi, Kimia; Najmabadi, Hossein

    2015-03-01

    Knowledge of the genes responsible for intellectual disability, particularly autosomal recessive forms, is rapidly expanding. Increasing numbers of the gene show great heterogeneity and supports the hypothesis that human genome may contain over 2000 causative genes with a critical role in brain development. Since 2004, we have applied genome-wide SNP genotyping and next-generation sequencing in large consanguineous Iranian families with intellectual disability, to identify the genes harboring disease-causing mutations. The current study paved the way for identification of responsible genes in two unrelated Iranian families. We found two novel nonsense mutations, p.C77* and p.Q115*, in the calpain catalytic domain of CAPN10, which is a cysteine protease known to be involved in pathogenesis of noninsulin-dependent diabetes mellitus. Another different mutation in this gene (p.S138_R139ins5) has previously been reported in an Iranian family. All of these patients have common clinical features in spite of specific brain structural abnormalities on MRI. Different mutations in CAPN10 have already been found in three independent Iranian families. These results have strongly supported the possible role of CAPN10 in human brain development. Altogether, we proposed CAPN10 as a promising candidate gene for intellectual disability, which should be considered in diagnostic gene panels.

  6. Autosomal-Recessive Intellectual Disability with Cerebellar Atrophy Syndrome Caused by Mutation of the Manganese and Zinc Transporter Gene SLC39A8

    Science.gov (United States)

    Boycott, Kym M.; Beaulieu, Chandree L.; Kernohan, Kristin D.; Gebril, Ola H.; Mhanni, Aziz; Chudley, Albert E.; Redl, David; Qin, Wen; Hampson, Sarah; Küry, Sébastien; Tetreault, Martine; Puffenberger, Erik G.; Scott, James N.; Bezieau, Stéphane; Reis, André; Uebe, Steffen; Schumacher, Johannes; Hegele, Robert A.; McLeod, D. Ross; Gálvez-Peralta, Marina; Majewski, Jacek; Ramaekers, Vincent T.; Nebert, Daniel W.; Innes, A. Micheil; Parboosingh, Jillian S.; Abou Jamra, Rami

    2015-01-01

    Manganese (Mn) and zinc (Zn) are essential divalent cations used by cells as protein cofactors; various human studies and animal models have demonstrated the importance of Mn and Zn for development. Here we describe an autosomal-recessive disorder in six individuals from the Hutterite community and in an unrelated Egyptian sibpair; the disorder is characterized by intellectual disability, developmental delay, hypotonia, strabismus, cerebellar atrophy, and variable short stature. Exome sequencing in one affected Hutterite individual and the Egyptian family identified the same homozygous variant, c.112G>C (p.Gly38Arg), affecting a conserved residue of SLC39A8. The affected Hutterite and Egyptian individuals did not share an extended common haplotype, suggesting that the mutation arose independently. SLC39A8 is a member of the solute carrier gene family known to import Mn, Zn, and other divalent cations across the plasma membrane. Evaluation of these two metal ions in the affected individuals revealed variably low levels of Mn and Zn in blood and elevated levels in urine, indicating renal wasting. Our findings identify a human Mn and Zn transporter deficiency syndrome linked to SLC39A8, providing insight into the roles of Mn and Zn homeostasis in human health and development. PMID:26637978

  7. A mutation in KIF7 is responsible for the autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance

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    Ali Bassam R

    2012-05-01

    Full Text Available Abstract Background We previously reported the existence of a unique autosomal recessive syndrome consisting of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance mapping to chromosome 15q26. Methods In this manuscript, we have used whole exome sequencing on two affected members of a consanguineous family with this condition and carried out detailed bioinformatics analysis to elucidate the causative mutation. Results Our analysis resulted in the identification of a homozygous p.N1060S missense mutation in a highly conserved residue in KIF7, a regulator of Hedgehog signaling that has been recently found to be causing Joubert syndrome, fetal hydrolethalus and acrocallosal syndromes. The phenotype in our patients partially overlaps with the phenotypes associated with those syndromes but they also exhibit some distinctive features including multiple epiphyseal dysplasia. Conclusions We report the first missense homozygous disease-causing mutation in KIF7 and expand the clinical spectrum associated with mutations in this gene to include multiple epiphyseal dysplasia. The missense nature of the mutation might account for the unique presentation in our patients.

  8. A missense mutation in ALDH18A1, encoding Delta1-pyrroline-5-carboxylate synthase (P5CS), causes an autosomal recessive neurocutaneous syndrome.

    Science.gov (United States)

    Bicknell, Louise S; Pitt, James; Aftimos, Salim; Ramadas, Ram; Maw, Marion A; Robertson, Stephen P

    2008-10-01

    There are several rare syndromes combining wrinkled, redundant skin and neurological abnormalities. Although phenotypic overlap between conditions has suggested that some might be allelic to one another, the aetiology for many of them remains unknown. A consanguineous New Zealand Maori family has been characterised that segregates an autosomal recessive connective tissue disorder (joint dislocations, lax skin) associated with neurological abnormalities (severe global developmental delay, choreoathetosis) without metabolic abnormalities in four affected children. A genome-screen performed under a hypothesis of homozygosity by descent for an ancestral mutation, identified a locus at 10q23 (Z = 3.63). One gene within the candidate interval, ALDH18A1, encoding Delta1-pyrroline-5-carboxylate synthase (P5CS), was considered a plausible disease gene since a missense mutation had previously been shown to cause progressive neurodegeneration, cataracts, skin laxity, joint dislocations and metabolic derangement in a consanguineous Algerian family. A missense mutation, 2350C>T, was identified in ALDH18A1, which predicts the substitution H784Y. H784 is invariant across all phyla and lies within a previously unrecognised, conserved C-terminal motif in P5CS. In an in vivo assay of flux through this metabolic pathway using dermal fibroblasts obtained from an affected individual, proline and ornithine biosynthetic activity of P5CS was not affected by the H784Y substitution. These data suggest that P5CS may possess additional uncharacterised functions that affect connective tissue and central nervous system function.

  9. Validation of a clinical practice-based algorithm for the diagnosis of autosomal recessive cerebellar ataxias based on NGS identified cases.

    Science.gov (United States)

    Mallaret, Martial; Renaud, Mathilde; Redin, Claire; Drouot, Nathalie; Muller, Jean; Severac, Francois; Mandel, Jean Louis; Hamza, Wahiba; Benhassine, Traki; Ali-Pacha, Lamia; Tazir, Meriem; Durr, Alexandra; Monin, Marie-Lorraine; Mignot, Cyril; Charles, Perrine; Van Maldergem, Lionel; Chamard, Ludivine; Thauvin-Robinet, Christel; Laugel, Vincent; Burglen, Lydie; Calvas, Patrick; Fleury, Marie-Céline; Tranchant, Christine; Anheim, Mathieu; Koenig, Michel

    2016-07-01

    Establishing a molecular diagnosis of autosomal recessive cerebellar ataxias (ARCA) is challenging due to phenotype and genotype heterogeneity. We report the validation of a previously published clinical practice-based algorithm to diagnose ARCA. Two assessors performed a blind analysis to determine the most probable mutated gene based on comprehensive clinical and paraclinical data, without knowing the molecular diagnosis of 23 patients diagnosed by targeted capture of 57 ataxia genes and high-throughput sequencing coming from a 145 patients series. The correct gene was predicted in 61 and 78 % of the cases by the two assessors, respectively. There was a high inter-rater agreement [K = 0.85 (0.55-0.98) p < 0.001] confirming the algorithm's reproducibility. Phenotyping patients with proper clinical examination, imaging, biochemical investigations and nerve conduction studies remain crucial for the guidance of molecular analysis and to interpret next generation sequencing results. The proposed algorithm should be helpful for diagnosing ARCA in clinical practice.

  10. Whole-exome sequencing in a single proband reveals a mutation in the CHST8 gene in autosomal recessive peeling skin syndrome.

    Science.gov (United States)

    Cabral, Rita M; Kurban, Mazen; Wajid, Muhammad; Shimomura, Yutaka; Petukhova, Lynn; Christiano, Angela M

    2012-04-01

    Generalized peeling skin syndrome (PSS) is an autosomal recessive genodermatosis characterized by lifelong, continuous shedding of the upper epidermis. Using whole-genome homozygozity mapping and whole-exome sequencing, we identified a novel homozygous missense mutation (c.229C>T, R77W) within the CHST8 gene, in a large consanguineous family with non-inflammatory PSS type A. CHST8 encodes a Golgi transmembrane N-acetylgalactosamine-4-O-sulfotransferase (GalNAc4-ST1), which we show by immunofluorescence staining to be expressed throughout normal epidermis. A colorimetric assay for total sulfated glycosaminoglycan (GAG) quantification, comparing human keratinocytes (CCD1106 KERTr) expressing wild type and mutant recombinant GalNAc4-ST1, revealed decreased levels of total sulfated GAGs in cells expressing mutant GalNAc4-ST1, suggesting loss of function. Western blotting revealed lower expression levels of mutant recombinant GalNAc4-ST1 compared to wild type, suggesting that accelerated degradation may result in loss of function, leading to PSS type A. This is the first report describing a mutation as the cause of PSS type A. Copyright © 2012 Elsevier Inc. All rights reserved.

  11. The human intrinsic factor-vitamin B12 receptor, cubilin: molecular characterization and chromosomal mapping of the gene to 10p within the autosomal recessive megaloblastic anemia (MGA1) region

    DEFF Research Database (Denmark)

    Kozyraki, R; Kristiansen, M; Silahtaroglu, A

    1998-01-01

    -5445 on the short arm of chromosome 10. This is within the autosomal recessive megaloblastic anemia (MGA1) 6-cM region harboring the unknown recessive-gene locus of juvenile megaloblastic anemia caused by intestinal malabsorption of cobalamin (Imerslund-Gräsbeck's disease). In conclusion, the present...... molecular and genetic information on human cubilin now provides circumstantial evidence that an impaired synthesis, processing, or ligand binding of cubilin is the molecular background of this hereditary form of megaloblastic anemia. Udgivelsesdato: 1998-May-15...

  12. AUTOSOMAL RECESSIVE PERIPHERAL NEUROPATHY WITH NEUROMYOTONIA (ARAN-NM: DESCRIPTION OF A CLINICAL CASE CONFIRMED BY A MUTATION IN THE HINT1 GENE

    Directory of Open Access Journals (Sweden)

    Olga A. Klochkova

    2017-01-01

    Full Text Available Autosomal recessive  peripheral neuropathy with neuromyotonia  (ARAN-NM  is a relatively newly described  disease associated  with mutations  in the HINT1 gene.  It accounts  for a significant  part of the poorly  differentiated  forms  of axonal polyneuropathies.  We present the first in Russia description of the genetically confirmed case of ARAN-NM in a boy aged 14 years and 11 months without the hereditary-tainted anamnesis. On presentation,  the patient experienced  progressive  distal muscular weakness, asymmetric foot deformity,  gait disorders  and minimal manifestations  of neuromyotonia  (stiffness  in the fingers.  During examination,  we detected an increase in the level of creatine phosphokinase up to 635 U/l, a disturbance of conduction of motor and, to a lesser extent, sensory fibers  of  the  peripheral  nerves  (according  to  the  stimulation  electromyography,  EMG,  denervation-reinnervation  changes,  single positive acute waves, fibrillation potentials, complex repeated discharge (according to the data of needle EMG. In the study of exome, a homozygous mutation c.110G>C, p.R37P was determined in exon 01 of the HINT1 gene, which confirmed the presence of ARAN-NM. A molecular-genetic  examination of the patient's immediate relatives was carried out. The described case is compared with literature data. An overview of currently available information on ARAN-NM is provided. Diagnostic criteria of the disease are presented.

  13. Application of a high-throughput genotyping method for loci exclusion in non-consanguineous Australian pedigrees with autosomal recessive retinitis pigmentosa.

    Science.gov (United States)

    Paterson, Rachel L; De Roach, John N; McLaren, Terri L; Hewitt, Alex W; Hoffmann, Ling; Lamey, Tina M

    2012-01-01

    Retinitis pigmentosa (RP) is the most common form of inherited blindness, caused by progressive degeneration of photoreceptor cells in the retina, and affects approximately 1 in 3,000 people. Over the past decade, significant progress has been made in gene therapy for RP and related diseases, making genetic characterization increasingly important. Recently, high-throughput technologies have provided an option for reasonably fast, cost-effective genetic characterization of autosomal recessive RP (arRP). The current study used a single nucleotide polymorphism (SNP) genotyping method to exclude up to 28 possible disease-causing genes in 31 non-consanguineous Australian families affected by arRP. DNA samples were collected from 59 individuals affected with arRP and 74 unaffected family members from 31 Australian families. Five to six SNPs were genotyped for 28 genes known to cause arRP or the related disease Leber congenital amaurosis (LCA). Cosegregation analyses were used to exclude possible causative genes from each of the 31 families. Bidirectional sequencing was used to identify disease-causing mutations in prioritized genes that were not excluded with cosegregation analyses. Two families were excluded from analysis due to identification of false paternity. An average of 28.9% of genes were excluded per family when only one affected individual was available, in contrast to an average of 71.4% or 89.8% of genes when either two, or three or more affected individuals were analyzed, respectively. A statistically significant relationship between the proportion of genes excluded and the number of affected individuals analyzed was identified using a multivariate regression model (pA) and USH2A in two families (c.2276 G>T). This study has shown that SNP genotyping cosegregation analysis can be successfully used to refine and expedite the genetic characterization of arRP in a non-consanguineous population; however, this method is effective only when DNA samples are

  14. An autosomal recessive leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa maps to chromosome 17q24.2-25.3

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    Bouhouche Ahmed

    2012-03-01

    Full Text Available Abstract Background Single-gene disorders related to ischemic stroke seem to be an important cause of stroke in young patients without known risk factors. To identify new genes responsible of such diseases, we studied a consanguineous Moroccan family with three affected individuals displaying hereditary leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa that appears to segregate in autosomal recessive pattern. Methods All family members underwent neurological and radiological examinations. A genome wide search was conducted in this family using the ABI PRISM linkage mapping set version 2.5 from Applied Biosystems. Six candidate genes within the region linked to the disease were screened for mutations by direct sequencing. Results Evidence of linkage was obtained on chromosome 17q24.2-25.3. Analysis of recombination events and LOD score calculation suggests linkage of the responsible gene in a genetic interval of 11 Mb located between D17S789 and D17S1806 with a maximal multipoint LOD score of 2.90. Sequencing of seven candidate genes in this locus, ATP5H, FDXR, SLC25A19, MCT8, CYGB, KCNJ16 and GRIN2C, identified three missense mutations in the FDXR gene which were also found in a homozygous state in three healthy controls, suggesting that these variants are not disease-causing mutations in the family. Conclusion A novel locus for leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa has been mapped to chromosome 17q24.2-25.3 in a consanguineous Moroccan family.

  15. Compound Heterozygous Inheritance of Mutations in Coenzyme Q8A Results in Autosomal Recessive Cerebellar Ataxia and Coenzyme Q10 Deficiency in a Female Sib-Pair.

    Science.gov (United States)

    Jacobsen, Jessie C; Whitford, Whitney; Swan, Brendan; Taylor, Juliet; Love, Donald R; Hill, Rosamund; Molyneux, Sarah; George, Peter M; Mackay, Richard; Robertson, Stephen P; Snell, Russell G; Lehnert, Klaus

    2017-11-21

    Autosomal recessive ataxias are characterised by a fundamental loss in coordination of gait with associated atrophy of the cerebellum. There is significant clinical and genetic heterogeneity amongst inherited ataxias; however, an early molecular diagnosis is essential with low-risk treatments available for some of these conditions. We describe two female siblings who presented early in life with unsteady gait and cerebellar atrophy. Whole exome sequencing revealed compound heterozygous inheritance of two pathogenic mutations (p.Leu277Pro, c.1506+1G>A) in the coenzyme Q8A gene (COQ8A), a gene central to biosynthesis of coenzyme Q (CoQ). The paternally derived p.Leu277Pro mutation is predicted to disrupt a conserved motif in the substrate-binding pocket of the protein, resulting in inhibition of CoQ 10 production. The maternal c.1506+1G>A mutation destroys a canonical splice donor site in exon 12 affecting transcript processing and subsequent protein translation. Mutations in this gene can result in primary coenzyme Q 10 deficiency type 4, which is characterized by childhood onset of cerebellar ataxia and exercise intolerance, both of which were observed in this sib-pair. Muscle biopsies revealed unequivocally low levels of CoQ 10, and the siblings were subsequently established on a therapeutic dose of CoQ 10 with distinct clinical evidence of improvement after 1 year of treatment. This case emphasises the importance of an early and accurate molecular diagnosis for suspected inherited ataxias, particularly given the availability of approved treatments for some subtypes.

  16. Al-Aqeel Sewairi Syndrome, a new autosomal recessive disorder with multicentric osteolysis, nodulosis and arthropathy. The first genetic defect of matrix metalloproteinase 2 gene

    International Nuclear Information System (INIS)

    Al-Aqeel, Aida I.

    2005-01-01

    We report a distinctive autosomal recessive multicentric osteolysis in Saudi Arabian families with distal arthropathy of the metacarpal, metatarsal and interphalangeal joints, with ultimate progression to the proximal joints with decreased range of movements and deformities with ankylosis and generalized osteopenia. In addition, they had large, painful to touch palmar and plantar pads. Hirsutism and mild dysmorphic facial features including proptosis, a narrow nasal bridge, bulbous nose and micrognathia. Using a genome-wide search for microsatellite markers from 11 members of the family from the Armed Forces Hospital and King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia, localized the disease gene to chromosome 16q12-21. Haplotype analysis with additional markers narrowed the critical region to 1.2cM and identified the matrix metalloproteinase 2 (MMP-2), (gelatinase A, collagenase type IV, EC 3.4, 24,24) gene as a disease candidate at Mount Sinai School of Medicine, New York, United States of America in April 2000. Some affected individuals were homoallelic for a nonsense mutation (TCA>TAA) in codon 244 of exon 5, predicting the replacement of a tyrosine residue by a stop codon in the first fibronectin type II domain (Y244X). Other affected members had a missense mutation in exon 2 arginine 101-histidine (R101H) leading to no MMP-2 enzyme activity in serum or fibroblast or both of affected individuals. In other affected members, a non-pathogenic homoallelic GT transversion resulted in the substitution of an aspartate with a tyrosine residue in codon 210 of exon 4 (D210Y). The MMP-2-null mouse has no developmental defects, but are small, which may reflect genetic redundancy. The discovery that deficiency of this well-characterized gelatinase/collagenase results in an inherited form of an osteolytic and arthritic disorder provides an invaluable insights for the understanding of osteolysis and arthritis and is the first genetic

  17. Whole-exome sequencing identifies novel compound heterozygous mutations in USH2A in Spanish patients with autosomal recessive retinitis pigmentosa.

    Science.gov (United States)

    Méndez-Vidal, Cristina; González-Del Pozo, María; Vela-Boza, Alicia; Santoyo-López, Javier; López-Domingo, Francisco J; Vázquez-Marouschek, Carmen; Dopazo, Joaquin; Borrego, Salud; Antiñolo, Guillermo

    2013-01-01

    Retinitis pigmentosa (RP) is an inherited retinal dystrophy characterized by extreme genetic and clinical heterogeneity. Thus, the diagnosis is not always easily performed due to phenotypic and genetic overlap. Current clinical practices have focused on the systematic evaluation of a set of known genes for each phenotype, but this approach may fail in patients with inaccurate diagnosis or infrequent genetic cause. In the present study, we investigated the genetic cause of autosomal recessive RP (arRP) in a Spanish family in which the causal mutation has not yet been identified with primer extension technology and resequencing. We designed a whole-exome sequencing (WES)-based approach using NimbleGen SeqCap EZ Exome V3 sample preparation kit and the SOLiD 5500×l next-generation sequencing platform. We sequenced the exomes of both unaffected parents and two affected siblings. Exome analysis resulted in the identification of 43,204 variants in the index patient. All variants passing filter criteria were validated with Sanger sequencing to confirm familial segregation and absence in the control population. In silico prediction tools were used to determine mutational impact on protein function and the structure of the identified variants. Novel Usher syndrome type 2A (USH2A) compound heterozygous mutations, c.4325T>C (p.F1442S) and c.15188T>G (p.L5063R), located in exons 20 and 70, respectively, were identified as probable causative mutations for RP in this family. Family segregation of the variants showed the presence of both mutations in all affected members and in two siblings who were apparently asymptomatic at the time of family ascertainment. Clinical reassessment confirmed the diagnosis of RP in these patients. Using WES, we identified two heterozygous novel mutations in USH2A as the most likely disease-causing variants in a Spanish family diagnosed with arRP in which the cause of the disease had not yet been identified with commonly used techniques. Our data

  18. Aberrant Smad3 phosphoisoforms in cyst-lining epithelial cells in the cpk mouse, a model of autosomal recessive polycystic kidney disease.

    Science.gov (United States)

    Hama, Taketsugu; Nakanishi, Koichi; Sato, Masashi; Mukaiyama, Hironobu; Togawa, Hiroko; Shima, Yuko; Miyajima, Masayasu; Nozu, Kandai; Nagao, Shizuko; Takahashi, Hisahide; Sako, Mayumi; Iijima, Kazumoto; Yoshikawa, Norishige; Suzuki, Hiroyuki

    2017-12-01

    Cystic epithelia acquire mesenchymal-like features in polycystic kidney disease (PKD). In this phenotypic alteration, it is well known that transforming growth factor (TGF)-β/Smad3 signaling is involved; however, there is emerging new data on Smad3 phosphoisoforms: Smad3 phosphorylated at linker regions (pSmad3L), COOH-terminal regions (pSmad3C), and both (pSmad3L/C). pSmad3L/C has a pathological role in colorectal cancer. Mesenchymal phenotype-specific cell responses in the TGF-β/Smad3 pathway are implicated in carcinomas. In this study, we confirmed mesenchymal features and examined Smad3 phosphoisoforms in the cpk mouse, a model of autosomal recessive PKD. Kidney sections were stained with antibodies against mesenchymal markers and domain-specific phospho-Smad3. TGF-β, pSmad3L, pSmad3C, JNK, cyclin-dependent kinase (CDK) 4, and c-Myc were evaluated by Western blotting. Cophosphorylation of pSmad3L/C was assessed by immunoprecipitation. α-Smooth muscle actin, which indicates mesenchymal features, was expressed higher in cpk mice. pSmad3L expression was increased in cpk mice and was predominantly localized in the nuclei of tubular epithelial cells in cysts; however, pSmad3C was equally expressed in both cpk and control mice. Levels of pSmad3L, JNK, CDK4, and c-Myc protein in nuclei were significantly higher in cpk mice than in controls. Immunoprecipitation showed that Smad3 was cophosphorylated (pSmad3L/C) in cpk mice. Smad3 knockout/ cpk double-mutant mice revealed amelioration of cpk abnormalities. These findings suggest that upregulating c-Myc through the JNK/CDK4-dependent pSmad3L pathway may be key to the pathophysiology in cpk mice. In conclusion, a qualitative rather than a quantitative abnormality of the TGF-β/Smad3 pathway is involved in PKD and may be a target for disease-specific intervention. Copyright © 2017 the American Physiological Society.

  19. Do consanguineous parents of a child affected by an autosomal recessive disease have more DNA identical-by-descent than similarly-related parents with healthy offspring? Design of a case-control study

    Directory of Open Access Journals (Sweden)

    Cornel Martina C

    2010-07-01

    Full Text Available Abstract Background The offspring of consanguineous relations have an increased risk of congenital/genetic disorders and early mortality. Consanguineous couples and their offspring account for approximately 10% of the global population. The increased risk for congenital/genetic disorders is most marked for autosomal recessive disorders and depends on the degree of relatedness of the parents. For children of first cousins the increased risk is 2-4%. For individual couples, however, the extra risk can vary from zero to 25% or higher, with only a minority of these couples having an increased risk of at least 25%. It is currently not possible to differentiate between high-and low-risk couples. The quantity of DNA identical-by-descent between couples with the same degree of relatedness shows a remarkable variation. Here we hypothesize that consanguineous partners with children affected by an autosomal recessive disease have more DNA identical-by-descent than similarly-related partners who have only healthy children. The aim of the study is thus to establish whether the amount of DNA identical-by-descent in consanguineous parents of children with an autosomal recessive disease is indeed different from its proportion in consanguineous parents who have healthy children only. Methods/Design This project is designed as a case-control study. Cases are defined as consanguineous couples with one or more children with an autosomal recessive disorder and controls as consanguineous couples with at least three healthy children and no affected child. We aim to include 100 case couples and 100 control couples. Control couples are matched by restricting the search to the same family, clan or ethnic origin as the case couple. Genome-wide SNP arrays will be used to test our hypothesis. Discussion This study contains a new approach to risk assessment in consanguineous couples. There is no previous study on the amount of DNA identical-by-descent in consanguineous

  20. Monogenic diabetes mellitus in Norway

    OpenAIRE

    Oddmund Søvika; Henrik Underthun Irgens; Janne Molnes; Jørn V. Sagena; Lise Bjørkhaug; Helge Ræder; Anders Molveng; Pål R. Njølstad

    2013-01-01

    Here, we review data on monogenic diabetes mellitus in Norway based on the Norwegian MODY Registry at Haukeland University Hospital, Bergen. This registry comprises established or suspected cases of maturity-onset diabetes of the young (MODY) referred to our laboratory for genetic testing. We also present data on neonatal diabetes, another group of monogenic diabetes. To date, we have genetically diagnosed nearly 500 MODY cases in Norway. Mutations in the HNF1A gene (MODY3) were detected in a...

  1. Addressing key issues in the consanguinity-related risk of autosomal recessive disorders in consanguineous communities: lessons from a qualitative study of British Pakistanis.

    Science.gov (United States)

    Darr, A; Small, N; Ahmad, W I U; Atkin, K; Corry, P; Modell, B

    2016-01-01

    Currently, there is no consensus regarding services required to help families with consanguineous marriages manage their increased genetic reproductive risk. Genetic services for communities with a preference for consanguineous marriage in the UK remain patchy, often poor. Receiving two disparate explanations of the cause of recessive disorders (cousin marriage and recessive inheritance) leads to confusion among families. Further, the realisation that couples in non-consanguineous relationships have affected children leads to mistrust of professional advice. British Pakistani families at-risk for recessive disorders lack an understanding of recessive disorders and their inheritance. Such an understanding is empowering and can be shared within the extended family to enable informed choice. In a three-site qualitative study of British Pakistanis, we explored family and health professional perspectives on recessively inherited conditions. Our findings suggest, firstly, that family networks hold strong potential for cascading genetic information, making the adoption of a family-centred approach an efficient strategy for this community. However, this is dependent on provision of high-quality and timely information from health care providers. Secondly, families' experience was of ill-coordinated and time-starved services, with few having access to specialist provision from Regional Genetics Services; these perspectives were consistent with health professionals' views of services. Thirdly, we confirm previous findings that genetic information is difficult to communicate and comprehend, further complicated by the need to communicate the relationship between cousin marriage and recessive disorders. A communication tool we developed and piloted is described and offered as a useful resource for communicating complex genetic information.

  2. Clinical and molecular diagnosis of a Costa Rican family with autosomal recessive myotonia congenita (Becker disease carrying a new mutation in the CLCN1 gene

    Directory of Open Access Journals (Sweden)

    Fernando Morales

    2008-03-01

    Full Text Available Myotonia congenita is a muscular disease characterized by myotonia, hypertrophy, and stiffness. It is inherited as either autosomal dominant or recessive known as Thomsen and Becker diseases, respectively. Here we confirm the clinical diagnosis of a family diagnosed with a myotonic condition many years ago and report a new mutation in the CLCN1 gene. The clinical diagnosis was established using ocular, cardiac, neurological and electrophysiological tests and the molecular diagnosis was done by PCR, SSCP and sequencing of the CLCN1 gene. The proband and the other affected individuals exhibited proximal and distal muscle weakness but no hypertrophy or muscular pain was found. The myotatic reflexes were lessened and sensibility was normal. Electrical and clinical myotonia was found only in the sufferers. Slit lamp and electrocardiogram tests were normal. Two affected probands presented diminution of the sensitive conduction velocities and prolonged sensory distal latencies. The clinical spectrum for this family is in agreement with a clinical diagnosis of Becker myotonia. This was confirmed by molecular diagnosis where a new disease-causing mutation (Q412P was found in the family and absent in 200 unaffected chromosomes. No latent myotonia was found in this family; therefore the ability to cause this subclinical sign might be intrinsic to each mutation. Implications of the structure-function-genotype relationship for this and other mutations are discussed. Adequate clinical diagnosis of a neuromuscular disorder would allow focusing the molecular studies toward the confirmation of the initial diagnosis, leading to a proper clinical management, genetic counseling and improving in the quality of life of the patients and relatives. Rev. Biol. Trop. 56 (1: 1-11. Epub 2008 March 31.La miotonía congénita es una enfermedad muscular caracterizada por miotonía, hipertrofia y rigidez. Se presenta con dos patrones de herencia, autosómica dominante en cuyo

  3. Monogenic diseases of DNA repair

    DEFF Research Database (Denmark)

    Keijzers, Guido; Bakula, Daniela; Scheibye-Knudsen, Morten

    2017-01-01

    Maintaining the stability of the genome is essential for all organisms, and it is not surprising that damage to DNA has been proposed as an explanation for multiple chronic diseases.1-5 Conserving a pristine genome is therefore of central importance to our health. To overcome the genotoxic stress...... of a growing number of human diseases. Notably, many of these monogenic DNA-repair disorders display features of accelerated aging, supporting the notion that genome maintenance is a key factor for organismal longevity. This review focuses on the physiological consequences of loss of DNA repair, particularly...... in the context of monogenic DNA-repair diseases....

  4. The first USH2A mutation analysis of Japanese autosomal recessive retinitis pigmentosa patients: a totally different mutation profile with the lack of frequent mutations found in Caucasian patients.

    Science.gov (United States)

    Zhao, Yang; Hosono, Katsuhiro; Suto, Kimiko; Ishigami, Chie; Arai, Yuuki; Hikoya, Akiko; Hirami, Yasuhiko; Ohtsubo, Masafumi; Ueno, Shinji; Terasaki, Hiroko; Sato, Miho; Nakanishi, Hiroshi; Endo, Shiori; Mizuta, Kunihiro; Mineta, Hiroyuki; Kondo, Mineo; Takahashi, Masayo; Minoshima, Shinsei; Hotta, Yoshihiro

    2014-09-01

    Retinitis pigmentosa (RP) is a highly heterogeneous genetic disease. The USH2A gene, which accounts for approximately 74-90% of Usher syndrome type 2 (USH2) cases, is also one of the major autosomal recessive RP (arRP) causative genes among Caucasian populations. To identify disease-causing USH2A gene mutations in Japanese RP patients, all 73 exons were screened for mutations by direct sequencing. In total, 100 unrelated Japanese RP patients with no systemic manifestations were identified, excluding families with obvious autosomal dominant inheritance. Of these 100 patients, 82 were included in this present study after 18 RP patients with very likely pathogenic EYS (eyes shut homolog) mutations were excluded. The mutation analysis of the USH2A revealed five very likely pathogenic mutations in four patients. A patient had only one very likely pathogenic mutation and the others had two of them. Caucasian frequent mutations p.C759F in arRP and p.E767fs in USH2 were not found. All the four patients exhibited typical clinical features of RP. The observed prevalence of USH2A gene mutations was approximately 4% among Japanese arRP patients, and the profile of the USH2A gene mutations differed largely between Japanese patients and previously reported Caucasian populations.

  5. CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila

    DEFF Research Database (Denmark)

    Zweier, Christiane; de Jong, Eiko K; Zweier, Markus

    2009-01-01

    , phenotypically overlapping with Pitt-Hopkins syndrome. With a frequency of at least 1% in our cohort of 179 patients, recessive defects in CNTNAP2 appear to significantly contribute to severe MR. Whereas the established synaptic role of NRXN1 suggests that synaptic defects contribute to the associated...... protein can reorganize synaptic morphology and induce increased density of active zones, the synaptic domains of neurotransmitter release. Moreover, both Nrx-I and Nrx-IV determine the level of the presynaptic active-zone protein bruchpilot, indicating a possible common molecular mechanism in Nrx...

  6. Estimation of the frequency of occult mutations for an autosomal recessive disease in the presence of genetic heterogeneity: application to genetic hearing loss disorders.

    Science.gov (United States)

    Kimberling, William J

    2005-11-01

    The routine testing for pathologic mutation(s) in a patient's DNA has become the foundation of modern molecular genetic diagnosis. It is especially valuable when the phenotype shows genetic heterogeneity, and its importance will grow as treatments become genotype specific. However, the technology of mutation detection is imperfect and mutations are often missed. This can be especially troublesome when dealing with a recessive disorder where the combination of genetic heterogeneity and missed mutation creates an imprecision in the genotypic assessment of individuals who do not appear to have the expected complement of two pathologic mutations. This article describes a statistical approach to the estimation of the likelihood of a genetic diagnosis under these conditions. In addition to providing a means of testing for missed mutations, it also provides a method of estimating and testing for the presence of genetic heterogeneity in the absence of linkage data. Gene frequencies as well as estimates of sensitivity and specificity can be obtained as well. The test is applied to GJB2 recessive nonsyndromic deafness, Usher syndrome types Ib and IIa, and Pendred-enlarged vestibular aqueduct syndrome. Copyright 2005 Wiley-Liss, Inc.

  7. Emergence of hepatic fibrosis and portal hypertension in infants and children with autosomal recessive polycystic kidney disease. Initial and follow-up sonographic and radiographic findings

    Energy Technology Data Exchange (ETDEWEB)

    Premkumar, A; Berdon, W E; Abramson, S J; Newhouse, J H; Levy, J

    1988-02-01

    Long-term imaging and clinical findings are reported in six children whose polycystic kidney disease was detected in infancy or early childhood. Over time (2 years to 20 years) all patients developed portal hypertension from hepatic fibrosis, a problem primarily noted in recessive pattern polycystic kidney disease. Mild renal failure (two patients) was accompanied by serious systemic hypertension in the same patients. In one family, one of the babies also showed dilated right hepatic ducts. Imaging studies included urography and CT although recently ultrasonography was the method of choice. The relative renal and hepatic manifestations in these patients so changed with time that it would seem fallacious to attempt to use rigid classifications based on findings at initial diagnosis.

  8. Mutations in UNC80, Encoding Part of the UNC79-UNC80-NALCN Channel Complex, Cause Autosomal-Recessive Severe Infantile Encephalopathy

    Science.gov (United States)

    Shamseldin, Hanan E.; Faqeih, Eissa; Alasmari, Ali; Zaki, Maha S.; Gleeson, Joseph G.; Alkuraya, Fowzan S.

    2016-01-01

    Brain channelopathies represent a growing class of brain disorders that usually result in paroxysmal disorders, although their role in other neurological phenotypes, including the recently described NALCN-related infantile encephalopathy, is increasingly recognized. In three Saudi Arabian families and one Egyptian family all affected by a remarkably similar phenotype (infantile encephalopathy and largely normal brain MRI) to that of NALCN-related infantile encephalopathy, we identified a locus on 2q34 in which whole-exome sequencing revealed three, including two apparently loss-of-function, recessive mutations in UNC80. UNC80 encodes a large protein that is necessary for the stability and function of NALCN and for bridging NALCN to UNC79 to form a functional complex. Our results expand the clinical relevance of the UNC79-UNC80-NALCN channel complex. PMID:26708753

  9. Monogenic diabetes mellitus in Norway

    Directory of Open Access Journals (Sweden)

    Oddmund Søvika

    2013-06-01

    Full Text Available Here, we review data on monogenic diabetes mellitus in Norway based on the Norwegian MODY Registry at Haukeland University Hospital, Bergen. This registry comprises established or suspected cases of maturity-onset diabetes of the young (MODY referred to our laboratory for genetic testing. We also present data on neonatal diabetes, another group of monogenic diabetes. To date, we have genetically diagnosed nearly 500 MODY cases in Norway. Mutations in the HNF1A gene (MODY3 were detected in about 50% of families with clinical MODY. GCK-MODY (MODY2 was the second most prevalent type, but may be underreported. We have also found mutations in the monogenic genes ABCC8, CEL, HNF1B, HNF4A, INS, KCNJ11 and NEUROD1. Based on genetic screening in the Norwegian MODY Registry and HUNT2, we estimate the number of MODY cases in Norway to be at least 2500-5000. Founder effects may determine the geographical distribution of MODY mutations in Norway. The molecular genetic testing of MODY and neonatal diabetes is mandatory for correct diagnosis and prognosis as well as choice of therapy

  10. Exclusion of the GNAS locus in PHP-Ib patients with broad GNAS methylation changes: evidence for an autosomal recessive form of PHP-Ib?

    Science.gov (United States)

    Fernández-Rebollo, Eduardo; Pérez de Nanclares, Guiomar; Lecumberri, Beatriz; Turan, Serap; Anda, Emma; Pérez-Nanclares, Gustavo; Feig, Denice; Nik-Zainal, Serena; Bastepe, Murat; Jüppner, Harald

    2011-08-01

    Most patients with autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP-Ib) carry maternally inherited microdeletions upstream of GNAS that are associated with loss of methylation restricted to GNAS exon A/B. Only few AD-PHP-Ib patients carry microdeletions within GNAS that are associated with loss of all maternal methylation imprints. These epigenetic changes are often indistinguishable from those observed in patients affected by an apparently sporadic PHP-Ib form that has not yet been defined genetically. We have now investigated six female patients affected by PHP-Ib (four unrelated and two sisters) with complete or almost complete loss of GNAS methylation, whose healthy children (11 in total) showed no epigenetic changes at this locus. Analysis of several microsatellite markers throughout the 20q13 region made it unlikely that PHP-Ib is caused in these patients by large deletions involving GNAS or by paternal uniparental isodisomy or heterodisomy of chromosome 20 (patUPD20). Microsatellite and single-nucleotide variation (SNV) data revealed that the two affected sisters share their maternally inherited GNAS alleles with unaffected relatives that lack evidence for abnormal GNAS methylation, thus excluding linkage to this locus. Consistent with these findings, healthy children of two unrelated sporadic PHP-Ib patients had inherited different maternal GNAS alleles, also arguing against linkage to this locus. Based on our data, it appears plausible that some forms of PHP-Ib are caused by homozygous or compound heterozygous mutation(s) in an unknown gene involved in establishing or maintaining GNAS methylation. Copyright © 2011 American Society for Bone and Mineral Research.

  11. [Identification of the genetic sex chromosomes in the monogenic blowfly Chrysomya rufifacies (Calliphoridae, Diptera)].

    Science.gov (United States)

    Ullerich, F H

    1975-01-01

    Previous investigations have shown the sex determination in the monogenic blowfly Chrysomya rufifacies to be controlled by a cytologically not discernible homogametry-heterogamety mechanism in the female. Female-producing (thelygenic) females are assumed to be heterozygous for a dominant female sex realizer (F') with sex-predetermining properties, while male-producing (arrhenogenic) females as well as males are supposed to be homozygous for the recessive allele (f). In order to identify the genetic sex chromosomes of C. rufifacies among its five pairs of long euchromatic chromosomes (nos. 1-5) plus one pair of small heterochromatic ones (no. 6), all chromosomes were marked by reciprocal translocations induced by X-ray treatment of adult males. The inheritance of thirteen different heteroxygous translocations has been analyzed. All of the translocations (eleven) between two of the four longer chromosomes did not show sex-linked inheritance, thus demonstrating the autosomal character of the chromosomes nos 1, 2, 3 and 4. The same is true for the translocation T6 (2/6). Therefore the small heterochromatic chromosome no. 6, corresponding to the morphlogically differentiated six chromosomes within the amphogenic calliphorid species, remains without sex determining function in the monogenic fly. This could be confirmed by the analysis of monosomic (monosomy-6) and trisomic (trisomy-6) individuals, which resulted from meiotic non-disfunction in T6/+ translocation heterozygotes. Contrary to these translocations, the heteroxygous 5/2 translocation (T14) exhibited sex-linked inheritance: There was but a very low frequency (0,76 per cent) of recombinants resulting from crossing-over between F'/f and the translocation breakage point in theylgenic F1 T14/+females. The sex-linked inheritance of T14 was confirmed by the progeny of a thelygenic F1 T14/+ female crossed to a homozygous T14/T14 translocation male.Among the offspring of that F1 T14/+ female, which had received the

  12. Monogenic functions with parameters in Clifford analysis

    International Nuclear Information System (INIS)

    Le Hung Son.

    1990-02-01

    In this paper we study some properties of monogenic functions taking values in a Clifford algebra and depending on several parameters. It is proved that the Hartogs extension theorems are valid for these functions and for the multi-monogenic functions, which contain solutions of many important systems of partial differential equations in Theoretical Physics. (author). 4 refs

  13. Novel Insights into the Pathogenesis of Monogenic Congenital Anomalies of the Kidney and Urinary Tract.

    Science.gov (United States)

    van der Ven, Amelie T; Vivante, Asaf; Hildebrandt, Friedhelm

    2018-01-01

    Congenital anomalies of the kidneys and urinary tract (CAKUT) comprise a large spectrum of congenital malformations ranging from severe manifestations, such as renal agenesis, to potentially milder conditions, such as vesicoureteral reflux. CAKUT causes approximately 40% of ESRD that manifests within the first three decades of life. Several lines of evidence indicate that CAKUT is often caused by recessive or dominant mutations in single (monogenic) genes. To date, approximately 40 monogenic genes are known to cause CAKUT if mutated, explaining 5%-20% of patients. However, hundreds of different monogenic CAKUT genes probably exist. The discovery of novel CAKUT-causing genes remains challenging because of this pronounced heterogeneity, variable expressivity, and incomplete penetrance. We here give an overview of known genetic causes for human CAKUT and shed light on distinct renal morphogenetic pathways that were identified as relevant for CAKUT in mice and humans. Copyright © 2018 by the American Society of Nephrology.

  14. Blepharophimosis-mental retardation (BMR) syndromes: A proposed clinical classification of the so-called Ohdo syndrome, and delineation of two new BMR syndromes, one X-linked and one autosomal recessive.

    Science.gov (United States)

    Verloes, Alain; Bremond-Gignac, Dominique; Isidor, Bertrand; David, Albert; Baumann, Clarisse; Leroy, Marie-Anne; Stevens, René; Gillerot, Yves; Héron, Delphine; Héron, Bénédicte; Benzacken, Brigitte; Lacombe, Didier; Brunner, Han; Bitoun, Pierre

    2006-06-15

    We report on 11 patients from 8 families with a blepharophimosis and mental retardation syndrome (BMRS) phenotype. Using current nosology, five sporadic patients have Ohdo syndrome, associated with congenital hypothyroidism in two of them (thus also compatible with a diagnosis of Young-Simpson syndrome). In two affected sibs with milder phenotype, compensated hypothyroidism was demonstrated. In another family, an affected boy was born to the unaffected sister of a previously reported patient. Finally, in the last sibship, two affected boys in addition had severe microcephaly and neurological anomalies. A definitive clinical and etiologic classification of BMRS is lacking, but closer phenotypic analysis should lead to a more useful appraisal of the BMRS phenotype. We suggest discontinuing the systematic use of the term "Ohdo syndrome" when referring to patients with BMRS. We propose a classification of BMRS into five groups: (1) del(3p) syndrome, (possibly overlooked in older reports); (2) BMRS, Ohdo type, limited to the original patients of Ohdo; (3) BMRS SBBYS (Say-Barber/Biesecker/Young-Simpson) type, with distinctive dysmorphic features and inconstant anomalies including heart defect, optic atrophy, deafness, hypoplastic teeth, cleft palate, joint limitations, and hypothyroidism. BMRS type SBBYS is probably an etiologically heterogeneous phenotype, as AD and apparently AR forms exist; (4) BMRS, MKB (Maat-Kievit-Brunner) type, with coarse, triangular face, which is probably sex-linked; (5) BMRS V (Verloes) type, a probable new type with severe microcephaly, hypsarrhythmia, adducted thumbs, cleft palate, and abnormal genitalia, which is likely autosomal recessive. Types MKB and V are newly described here. Copyright 2006 Wiley-Liss, Inc.

  15. Analysis of TGM1, ALOX12B, ALOXE3, NIPAL4 and CYP4F22 in autosomal recessive congenital ichthyosis from Galicia (NW Spain): evidence of founder effects.

    Science.gov (United States)

    Rodríguez-Pazos, L; Ginarte, M; Fachal, L; Toribio, J; Carracedo, A; Vega, A

    2011-10-01

      Mutations in six genes have been identified in autosomal recessive congenital ichthyosis (ARCI). To date, few studies have analysed the spectrum of these mutations in specific populations. We have studied the characteristics of patients with ARCI in Galicia (NW Spain). Methods  We recruited patients by contacting all dermatology departments of Galicia and the Spanish patient organization for ichthyosis. TGM1, ALOX12B, ALOXE3, NIPAL4 and CYP4F22 were analysed in the patients and their relatives. We identified 23 patients with ARCI and estimated a prevalence of 1 : 122 000. Twenty of the patients were studied. Seventeen of them were clinically categorized as having lamellar ichthyosis (LI) and three as having congenital ichthyosiform erythroderma (CIE). TGM1 and ALOXE3 mutations were identified in 12/16 (75%) probands whereas no ALOX12B, NIPAL4 and CYP4F22 mutations were found. TGM1 mutations were found in 11/13 (85%) of LI probands. ALOXE3 mutations were identified in a single patient with CIE. Remarkably, mutations p.Arg760X, p.Asp408ValfsX21 and c.984+1G>A of TGM1 were present in six, four and two families, accounting for 41%, 23% and 14% of all TGM1 mutant alleles, respectively. The high percentage of patients with the same TGM1 mutations, together with the high number of homozygous probands (64%), indicates the existence of a strong founder effect in our population. © 2011 The Authors. BJD © 2011 British Association of Dermatologists 2011.

  16. Autosomal recessive deafness 1A (DFNB1A) in Yakut population isolate in Eastern Siberia: extensive accumulation of the splice site mutation IVS1+1G>A in GJB2 gene as a result of founder effect.

    Science.gov (United States)

    Barashkov, Nikolay A; Dzhemileva, Lilya U; Fedorova, Sardana A; Teryutin, Fedor M; Posukh, Olga L; Fedotova, Elvira E; Lobov, Simeon L; Khusnutdinova, Elza K

    2011-09-01

    Hereditary forms of hearing impairment (HI) caused by GJB2 (Cx26) mutations are the frequent sensory disorders registered among newborns in various human populations. In this study, we present data on the molecular, audiological and population features of autosomal recessive deafness 1A (DFNB1A) associated with the donor splicing site IVS1+1G>A mutation of GJB2 gene in Yakut population isolate of the Sakha Republic (Yakutia) located in Eastern Siberia (Russian Federation). The Yakut population exhibits high frequency of some Mendelian disorders, which are rare in other populations worldwide. Mutational analysis of GJB2 gene in 86 unrelated Yakut patients with congenital HI without other clinical features has been performed. In this study, we registered a large cohort of Yakut patients homozygous for the IVS1+1G>A mutation (70 unrelated deaf subjects in total). Detailed audiological analysis of 40 deaf subjects with genotype IVS1+1G>A/IVS1+1G>A revealed significant association of this genotype with mostly symmetrical bilateral severe to profound HI (85% severe-to-profound HI versus 15% mild-to-moderate HI, PA mutation (11.7%) has been found in Yakut population. Reconstruction of 140 haplotypes with IVS1+1G>A mutation demonstrates the common origin of all mutant chromosomes found in Yakuts. The age of mutation was estimated to be approximately 800 years. These findings characterize Eastern Siberia as the region with the most extensive accumulation of the IVS1+1G>A mutation in the world as a result of founder effect.

  17. Diverse pattern of gap junction beta-2 and gap junction beta-4 genes mutations and lack of contribution of DFNB21, DFNB24, DFNB29, and DFNB42 loci in autosomal recessive nonsyndromic hearing loss patients in Hormozgan, Iran

    Directory of Open Access Journals (Sweden)

    Masoud Akbarzadeh Laleh

    2017-01-01

    Full Text Available Background: We aimed to determine the contribution of four DFNB loci and mutation analysis of gap junction beta-2 (GJB2 and GJB4 genes in autosomal recessive nonsyndromic hearing loss (ARNSHL in South of Iran. Materials and Methods: A total of 36 large ARNSHL pedigrees with at least two affected subjects were enrolled in the current study. The GJB2 and GJB4 genes mutations were screened using direct sequencing method. The GJB2 and GJB4 negative families were analyzed for the linkage to DFNB21, DFNB24, DFNB29, and DFNB42 loci by genotyping the corresponding STR markers using polymerase chain reaction-PAGE method. Results: We found a homozygous nonsense mutation W77X and a homozygous missense mutation C169W in 5.55% of studied families in GJB2 and GJB4 genes, respectively. Five heterozygous mutations including V63G, A78T, and R127H in GJB2 gene, and R103C and R227W in GJB4 gene were detected. We identified two novel variations V63G in GJB2 and R227W in GJB4. In silico analysis predicted that both novel variations are deleterious mutations. We did not unveil any linkage between DFNB21, DFNB24, DFNB29, and DFNB42 loci and ARNSHL among studied families. Conclusion: This is the first report of GJB2 and GJB4 mutations from Hormozgan population. According to the previous publications regarding GJB2 and GJB4 mutations, the distribution of the mutations is different from other parts of Iran that should be considered in primary health-care programs. Further investigations are needed to evaluate the contribution of other loci in ARNSHL subjects in South of Iran.

  18. Genetics Home Reference: autosomal recessive primary microcephaly

    Science.gov (United States)

    ... microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings. Am J Hum Genet. 2005 May;76( ... genome editing and CRISPR-Cas9? What is precision medicine? What is newborn screening? New Pages Alopecia areata ...

  19. Genetics Home Reference: autosomal recessive hypotrichosis

    Science.gov (United States)

    ... in the growth and division (proliferation) and maturation (differentiation) of cells within hair follicles . These cell processes ... LIPH , LPAR6 , or DSG4 gene result in the production of abnormal proteins that cannot aid in the ...

  20. Familial megacalyces with autosomal recessive inheritance

    International Nuclear Information System (INIS)

    Lam, A.H.

    1988-01-01

    Three children with bilateral congenital megacalyces from a consanguinous marriage are reported. No renal abnormality was detected in the parents. Our observation supports the genetic nature of the disease. The ultrasonographic features of congenital megacalyces are described. (orig.)

  1. Autosomal-dominant osteopetrosis: An incidental finding

    Directory of Open Access Journals (Sweden)

    Rajathi Maria

    2010-01-01

    Full Text Available Osteopetrosis is a descriptive term that refers to a group of rare, heritable disorders of the skeleton. Osteopetrotic conditions vary greatly in their presentation and severity, from just as an incidental finding on radiographs to causing life-threatening complications such as bone marrow suppression. It is caused by failure of osteoclast development and function. Osteopetrosis can be inherited as autosomal-recessive, autosomal-dominant or as X-linked traits, with the most severe forms being the autosomal-recessive ones. The severity of the disease is mild to moderate in the autosomal-dominant forms, with normal life expectancy. Diagnosis is largely based on clinical and radiographic evaluation. The present paper reports a case of autosomal-dominant osteopetrosis complicated by osteomyelitis with a short review of the condition.

  2. Clinical Pregenetic Screening for Stroke Monogenic Diseases: Results From Lombardia GENS Registry.

    Science.gov (United States)

    Bersano, Anna; Markus, Hugh Stephen; Quaglini, Silvana; Arbustini, Eloisa; Lanfranconi, Silvia; Micieli, Giuseppe; Boncoraglio, Giorgio B; Taroni, Franco; Gellera, Cinzia; Baratta, Silvia; Penco, Silvana; Mosca, Lorena; Grasso, Maurizia; Carrera, Paola; Ferrari, Maurizio; Cereda, Cristina; Grieco, Gaetano; Corti, Stefania; Ronchi, Dario; Bassi, Maria Teresa; Obici, Laura; Parati, Eugenio A; Pezzini, Alessando; De Lodovici, Maria Luisa; Verrengia, Elena P; Bono, Giorgio; Mazucchelli, Francesca; Zarcone, Davide; Calloni, Maria Vittoria; Perrone, Patrizia; Bordo, Bianca Maria; Colombo, Antonio; Padovani, Alessandro; Cavallini, Anna; Beretta, Simone; Ferrarese, Carlo; Motto, Cristina; Agostoni, Elio; Molini, Graziella; Sasanelli, Francesco; Corato, Manuel; Marcheselli, Simona; Sessa, Maria; Comi, Giancarlo; Checcarelli, Nicoletta; Guidotti, Mario; Uccellini, Davide; Capitani, Erminio; Tancredi, Lucia; Arnaboldi, Marco; Incorvaia, Barbara; Tadeo, Carlo Sebastiano; Fusi, Laura; Grampa, Giampiero; Merlini, Giampaolo; Trobia, Nadia; Comi, Giacomo Pietro; Braga, Massimiliano; Vitali, Paolo; Baron, Pierluigi; Grond-Ginsbach, Caspar; Candelise, Livia

    2016-07-01

    Lombardia GENS is a multicentre prospective study aimed at diagnosing 5 single-gene disorders associated with stroke (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, Fabry disease, MELAS [mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes], hereditary cerebral amyloid angiopathy, and Marfan syndrome) by applying diagnostic algorithms specific for each clinically suspected disease We enrolled a consecutive series of patients with ischemic or hemorrhagic stroke or transient ischemic attack admitted in stroke units in the Lombardia region participating in the project. Patients were defined as probable when presenting with stroke or transient ischemic attack of unknown etiopathogenic causes, or in the presence of young age at onset, or positive familial history or of specific clinical features. Patients fulfilling diagnostic algorithms specific for each monogenic disease (suspected) were referred for genetic analysis. In 209 patients (57.4±14.7 years), the application of the disease-specific algorithm identified 227 patients with possible monogenic disease. Genetic testing identified pathogenic mutations in 7% of these cases. Familial history of stroke was the only significant specific feature that distinguished mutated patients from nonmutated ones. The presence of cerebrovascular risk factors did not exclude a genetic disease. In patients prescreened using a clinical algorithm for monogenic disorders, we identified monogenic causes of events in 7% of patients in comparison to the 1% to 5% prevalence reported in previous series. © 2016 American Heart Association, Inc.

  3. Monogenic autoimmune diseases of the endocrine system.

    Science.gov (United States)

    Johnson, Matthew B; Hattersley, Andrew T; Flanagan, Sarah E

    2016-10-01

    The most common endocrine diseases, type 1 diabetes, hyperthyroidism, and hypothyroidism, are the result of autoimmunity. Clustering of autoimmune endocrinopathies can result from polygenic predisposition, or more rarely, may present as part of a wider syndrome due to a mutation within one of seven genes. These monogenic autoimmune diseases show highly variable phenotypes both within and between families with the same mutations. The average age of onset of the monogenic forms of autoimmune endocrine disease is younger than that of the common polygenic forms, and this feature combined with the manifestation of other autoimmune diseases, specific hallmark features, or both, can inform clinicians as to the relevance of genetic testing. A genetic diagnosis can guide medical management, give an insight into prognosis, inform families of recurrence risk, and facilitate prenatal diagnoses. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Molekylaer patogenese ved monogen og polygen fedme

    DEFF Research Database (Denmark)

    Larsen, Philip J; Echwald, Søren Morgenthaler; Sørensen, Thorkild I A

    2006-01-01

    During the last few years, studies of the molecular pathogenesis of obesity both in mouse models and in the rare cases of monogenic obesity in humans have added significantly to our understanding of the key role of the hypothalamus in mediating hunger and satiety. These insights have brought us c...... closer to the development of rational therapies of obesity, the epidemic of which is continuing in the post-industrial society, which is characterised by sedentary behaviour patterns....

  5. Case Report: Whole exome sequencing reveals a novel frameshift deletion mutation p.G2254fs in COL7A1 associated with autosomal recessive dystrophic epidermolysis bullosa [version 2; referees: 2 approved, 1 approved with reservations

    Directory of Open Access Journals (Sweden)

    Shamsudheen Karuthedath Vellarikkal

    2016-07-01

    Full Text Available Dystrophic epidermolysis bullosa simplex (DEB is a phenotypically diverse inherited skin fragility disorder. It is majorly manifested by appearance of epidermal bullae upon friction caused either by physical or environmental trauma. The phenotypic manifestations also include appearance of milia, scarring all over the body and nail dystrophy. DEB can be inherited in a recessive or dominant form and the recessive form of DEB (RDEB is more severe. In the present study, we identify a novel p.G2254fs mutation in COL7A1 gene causing a sporadic case of RDEB by whole exome sequencing (WES. Apart from adding a novel frameshift Collagen VII mutation to the repertoire of known mutations reported in the disease, to the best of our knowledge, this is the first report of a genetically characterized case of DEB from India.

  6. Case Report: Whole exome sequencing reveals a novel frameshift deletion mutation p.G2254fs in COL7A1 associated with autosomal recessive dystrophic epidermolysis bullosa [version 1; referees: 2 approved, 1 approved with reservations

    Directory of Open Access Journals (Sweden)

    Shamsudheen Karuthedath Vellarikkal

    2016-05-01

    Full Text Available Dystrophic epidermolysis bullosa simplex (DEB is a phenotypically diverse inherited skin fragility disorder. It is majorly manifested by appearance of epidermal bullae upon friction caused either by physical or environmental trauma. The phenotypic manifestations also include appearance of milia, scarring all over the body and nail dystrophy. DEB can be inherited in a recessive or dominant form and the recessive form of DEB (RDEB is more severe. In the present study, we identify a novel p.G2254fs mutation in COL7A1 gene causing a sporadic case of RDEB by whole exome sequencing (WES. Apart from adding a novel frameshift Collagen VII mutation to the repertoire of known mutations reported in the disease, to the best of our knowledge, this is the first report of a genetically characterized case of DEB from India.

  7. Genetics of recessive cognitive disorders

    OpenAIRE

    Musante, Luciana; Ropers, H. Hilger

    2014-01-01

    Most severe forms of intellectual disability (ID) have specific genetic causes. Numerous X chromosome gene defects and disease-causing copy-number variants have been linked to ID and related disorders, and recent studies have revealed that sporadic cases are often due to dominant de novo mutations with low recurrence risk. For autosomal recessive ID (ARID) the recurrence risk is high and, in populations with frequent parental consanguinity, ARID is the most common form of ID. Even so, its elu...

  8. Exome Sequencing in Suspected Monogenic Dyslipidemias

    Science.gov (United States)

    Stitziel, Nathan O.; Peloso, Gina M.; Abifadel, Marianne; Cefalu, Angelo B.; Fouchier, Sigrid; Motazacker, M. Mahdi; Tada, Hayato; Larach, Daniel B.; Awan, Zuhier; Haller, Jorge F.; Pullinger, Clive R.; Varret, Mathilde; Rabès, Jean-Pierre; Noto, Davide; Tarugi, Patrizia; Kawashiri, Masa-aki; Nohara, Atsushi; Yamagishi, Masakazu; Risman, Marjorie; Deo, Rahul; Ruel, Isabelle; Shendure, Jay; Nickerson, Deborah A.; Wilson, James G.; Rich, Stephen S.; Gupta, Namrata; Farlow, Deborah N.; Neale, Benjamin M.; Daly, Mark J.; Kane, John P.; Freeman, Mason W.; Genest, Jacques; Rader, Daniel J.; Mabuchi, Hiroshi; Kastelein, John J.P.; Hovingh, G. Kees; Averna, Maurizio R.; Gabriel, Stacey; Boileau, Catherine; Kathiresan, Sekar

    2015-01-01

    Background Exome sequencing is a promising tool for gene mapping in Mendelian disorders. We utilized this technique in an attempt to identify novel genes underlying monogenic dyslipidemias. Methods and Results We performed exome sequencing on 213 selected family members from 41 kindreds with suspected Mendelian inheritance of extreme levels of low-density lipoprotein (LDL) cholesterol (after candidate gene sequencing excluded known genetic causes for high LDL cholesterol families) or high-density lipoprotein (HDL) cholesterol. We used standard analytic approaches to identify candidate variants and also assigned a polygenic score to each individual in order to account for their burden of common genetic variants known to influence lipid levels. In nine families, we identified likely pathogenic variants in known lipid genes (ABCA1, APOB, APOE, LDLR, LIPA, and PCSK9); however, we were unable to identify obvious genetic etiologies in the remaining 32 families despite follow-up analyses. We identified three factors that limited novel gene discovery: (1) imperfect sequencing coverage across the exome hid potentially causal variants; (2) large numbers of shared rare alleles within families obfuscated causal variant identification; and (3) individuals from 15% of families carried a significant burden of common lipid-related alleles, suggesting complex inheritance can masquerade as monogenic disease. Conclusions We identified the genetic basis of disease in nine of 41 families; however, none of these represented novel gene discoveries. Our results highlight the promise and limitations of exome sequencing as a discovery technique in suspected monogenic dyslipidemias. Considering the confounders identified may inform the design of future exome sequencing studies. PMID:25632026

  9. Monogenic Forms of Diabetes: Neonatal Diabetes Mellitus and Maturity-Onset Diabetes of the Young

    Science.gov (United States)

    ... After Your Baby is Born Monogenic Diabetes Monogenic Diabetes (Neonatal Diabetes Mellitus & MODY) The most common forms of diabetes, ... from each parent. What are monogenic forms of diabetes? Some rare forms of diabetes result from mutations ...

  10. Recessive Epidermolysis Bullosa simplex- A case report

    African Journals Online (AJOL)

    Ademu

    Abstract: Background:Epidermolysis bullosa simplex (EBS) is characterized by intraepidermal blister formation, most commonly appearing in early infancy. Many variants of EBS exist; the four most common variants are inherited in an autosomal dominant fashion. The recessive forms are rare and less reported in our ...

  11. Genetic counseling in monogenic diabetes GCK MODY.

    Science.gov (United States)

    Skała-Zamorowska, Eliza; Deja, Grażyna; Borowiec, Maciej; Fendler, Wojciech; Małachowska, Beata; Kamińska, Halla; Młynarski, Wojciech; Jarosz-Chobot, Przemysława

    2016-01-01

    Genetic testing in families with monogenic GCK MODY has predictive, diagnostic, and preventive utility. Predictive tests relate to people who have no features of the disorder themselves at the time of testing. Diagnostic tests relate to family members who have been previously diagnosed with diabetes mellitus or glucose metabolism disturbances. The preventive value of genetic testing for families is to raise awareness of the circumstances leading to glucose metabolism disorders. The detection of mutation carriers among family members of patients with GCK MODY and the determination of the clinical significance of the genetic test result. The study group included 27 families of adolescent patients with GCK MODY (39 (75%) of parents and 19 (73.08%) of siblings) monitored in the Department of Pediatrics, Endocrinology and Diabetes and in the Diabetes Clinic of John Paul II Upper Silesian Child Health Centre in Katowice in the years 2007-2012. Subjects underwent a blood sample drawing for genetic and biochemical testing. Through the genetic diagnostics we diagnosed GCK MODY in 14 (63.64%) mothers, 6 (35.29%) fathers and in 7 (36,84%) siblings. Genetic testing has contributed to the detection of 7 (26.92%) asymptomatic carriers of GCK gene mutation among parents and 3 (15,79%) asymptomatic carriers among siblings declaring no carbohydrate metabolism disturbances (before genetic testing there were no indications suggesting carbohydrate metabolism disturbances; OGTT were performed after positive genetic testing). Each case of mutation detection, which is the cause of monogenic diabetes in a patient, justifies the genetic testing in other members of his/her family. Awareness of the genetic status may allow sick family member to confirm the diagnosis, while asymptomatic mutation carriers could benefit from an early clinical observation. Consequently, in each case it gives an opportunity to take diagnostic and therapeutic measures in accordance with the current state of

  12. [Monogenic and syndromic symptoms of morbid obesity. Rare but important].

    Science.gov (United States)

    Wiegand, S; Krude, H

    2015-02-01

    Monogenic and syndromic obesity are rare diseases with variable manifestation. Therefore diagnosis is difficult and often delayed. The purpose of this work was to develop a clinical diagnostic algorithm for earlier diagnosis. Available publications for clinical symptoms and molecular defects of monogenic and syndromic obesity cases were evaluated. Monogenic and syndromic obesity can be expected in cases with early manifestation before the age of 5 years and a BMI above 40 or above the 99th percentile. Syndromic cases are mostly associated with a low IQ and dwarfism. Monogenic cases are associated with additional endocrine defects. Measurement of serum leptin proves the treatable leptin deficiency. Sequencing of the melanocortin-4 receptor gene (MC4R) allows diagnosis of the most frequent monogenic form of obesity. Treatment with a melanocyte-stimulating hormone (MSH) analog can be expected in the future. Early treatment of children with Prader-Willi syndrome can prevent severe obesity. Because in some cases treatment is available, monogenic and syndromic obesity should be diagnosed early. Based on the disease symptoms, serum leptin, and MC4R sequencing, a diagnostic algorithm is proposed, which can be used to diagnose cases of morbid obesity.

  13. Live births after simultaneous avoidance of monogenic diseases and chromosome abnormality by next-generation sequencing with linkage analyses.

    Science.gov (United States)

    Yan, Liying; Huang, Lei; Xu, Liya; Huang, Jin; Ma, Fei; Zhu, Xiaohui; Tang, Yaqiong; Liu, Mingshan; Lian, Ying; Liu, Ping; Li, Rong; Lu, Sijia; Tang, Fuchou; Qiao, Jie; Xie, X Sunney

    2015-12-29

    In vitro fertilization (IVF), preimplantation genetic diagnosis (PGD), and preimplantation genetic screening (PGS) help patients to select embryos free of monogenic diseases and aneuploidy (chromosome abnormality). Next-generation sequencing (NGS) methods, while experiencing a rapid cost reduction, have improved the precision of PGD/PGS. However, the precision of PGD has been limited by the false-positive and false-negative single-nucleotide variations (SNVs), which are not acceptable in IVF and can be circumvented by linkage analyses, such as short tandem repeats or karyomapping. It is noteworthy that existing methods of detecting SNV/copy number variation (CNV) and linkage analysis often require separate procedures for the same embryo. Here we report an NGS-based PGD/PGS procedure that can simultaneously detect a single-gene disorder and aneuploidy and is capable of linkage analysis in a cost-effective way. This method, called "mutated allele revealed by sequencing with aneuploidy and linkage analyses" (MARSALA), involves multiple annealing and looping-based amplification cycles (MALBAC) for single-cell whole-genome amplification. Aneuploidy is determined by CNVs, whereas SNVs associated with the monogenic diseases are detected by PCR amplification of the MALBAC product. The false-positive and -negative SNVs are avoided by an NGS-based linkage analysis. Two healthy babies, free of the monogenic diseases of their parents, were born after such embryo selection. The monogenic diseases originated from a single base mutation on the autosome and the X-chromosome of the disease-carrying father and mother, respectively.

  14. Clinical spectrum of early onset cerebellar ataxia with retained tendon reflexes: an autosomal recessive ataxia not to be missed Espectro clínico da ataxia cerebelar de início precoce com reflexos mantidos: uma ataxia autossômica recessiva para não ser esquecida

    Directory of Open Access Journals (Sweden)

    José Luiz Pedroso

    2013-06-01

    Full Text Available Autosomal recessive cerebellar ataxias are a heterogeneous group of neurological disorders. In 1981, a neurological entity comprised by early onset progressive cerebellar ataxia, dysarthria, pyramidal weakness of the limbs and retained or increased upper limb reflexes and knee jerks was described. This disorder is known as early onset cerebellar ataxia with retained tendon reflexes. In this article, we aimed to call attention for the diagnosis of early onset cerebellar ataxia with retained tendon reflexes as the second most common cause of autosomal recessive cerebellar ataxias, after Friedreich ataxia, and also to perform a clinical spectrum study of this syndrome. In this data, 12 patients from different families met all clinical features for early onset cerebellar ataxia with retained tendon reflexes. Dysarthria and cerebellar atrophy were the most common features in our sample. It is uncertain, however, whether early onset cerebellar ataxia with retained tendon reflexes is a homogeneous disease or a group of phenotypically similar syndromes represented by different genetic entities. Further molecular studies are required to provide definitive answers to the questions that remain regarding early onset cerebellar ataxia with retained tendon reflexes.As ataxias cerebelares autossômicas recessivas são um grupo heterogêneo de doenças neurológicas. Em 1981, foi descrita uma entidade neurológica incluindo ataxia cerebelar progressiva de início precoce, disartria, liberação piramidal e manutenção ou aumento dos reflexos tendíneos nos membros superiores e inferiores. Essa síndrome é conhecida como ataxia cerebelar de início precoce com reflexos mantidos. Neste artigo, o objetivo foi chamar a atenção para o diagnóstico de ataxia cerebelar de início precoce com reflexos mantidos como a segunda causa mais comum de ataxia cerebelar autossômica recessiva, após a ataxia de Friedreich, e também realizar um estudo do espectro cl

  15. Looking the Cow in the Eye: Deletion in the NID1 Gene Is Associated with Recessive Inherited Cataract in Romagnola Cattle

    Science.gov (United States)

    Murgiano, Leonardo; Jagannathan, Vidhya; Calderoni, Valerio; Joechler, Monika; Gentile, Arcangelo; Drögemüller, Cord

    2014-01-01

    Cataract is a known condition leading to opacification of the eye lens causing partial or total blindness. Mutations are known to cause autosomal dominant or recessive inherited forms of cataracts in humans, mice, rats, guinea pigs and dogs. The use of large-sized animal models instead of those using mice for the study of this condition has been discussed due to the small size of rodent lenses. Four juvenile-onset cases of bilateral incomplete immature nuclear cataract were recently observed in Romagnola cattle. Pedigree analysis suggested a monogenic autosomal recessive inheritance. In addition to the cataract, one of the cases displayed abnormal head movements. Genome-wide association and homozygosity mapping and subsequent whole genome sequencing of a single case identified two perfectly associated sequence variants in a critical interval of 7.2 Mb on cattle chromosome 28: a missense point mutation located in an uncharacterized locus and an 855 bp deletion across the exon 19/intron 19 border of the bovine nidogen 1 (NID1) gene (c.3579_3604+829del). RT-PCR showed that NID1 is expressed in bovine lenses while the transcript of the second locus was absent. The NID1 deletion leads to the skipping of exon 19 during transcription and is therefore predicted to cause a frameshift and premature stop codon (p.1164fs27X). The truncated protein lacks a C-terminal domain essential for binding with matrix assembly complexes. Nidogen 1 deficient mice show neurological abnormalities and highly irregular crystal lens alterations. This study adds NID1 to the list of candidate genes for inherited cataract in humans and is the first report of a naturally occurring mutation leading to non-syndromic catarct in cattle provides a potential large animal model for human cataract. PMID:25347398

  16. Looking the cow in the eye: deletion in the NID1 gene is associated with recessive inherited cataract in Romagnola cattle.

    Science.gov (United States)

    Murgiano, Leonardo; Jagannathan, Vidhya; Calderoni, Valerio; Joechler, Monika; Gentile, Arcangelo; Drögemüller, Cord

    2014-01-01

    Cataract is a known condition leading to opacification of the eye lens causing partial or total blindness. Mutations are known to cause autosomal dominant or recessive inherited forms of cataracts in humans, mice, rats, guinea pigs and dogs. The use of large-sized animal models instead of those using mice for the study of this condition has been discussed due to the small size of rodent lenses. Four juvenile-onset cases of bilateral incomplete immature nuclear cataract were recently observed in Romagnola cattle. Pedigree analysis suggested a monogenic autosomal recessive inheritance. In addition to the cataract, one of the cases displayed abnormal head movements. Genome-wide association and homozygosity mapping and subsequent whole genome sequencing of a single case identified two perfectly associated sequence variants in a critical interval of 7.2 Mb on cattle chromosome 28: a missense point mutation located in an uncharacterized locus and an 855 bp deletion across the exon 19/intron 19 border of the bovine nidogen 1 (NID1) gene (c.3579_3604+829del). RT-PCR showed that NID1 is expressed in bovine lenses while the transcript of the second locus was absent. The NID1 deletion leads to the skipping of exon 19 during transcription and is therefore predicted to cause a frameshift and premature stop codon (p.1164fs27X). The truncated protein lacks a C-terminal domain essential for binding with matrix assembly complexes. Nidogen 1 deficient mice show neurological abnormalities and highly irregular crystal lens alterations. This study adds NID1 to the list of candidate genes for inherited cataract in humans and is the first report of a naturally occurring mutation leading to non-syndromic catarct in cattle provides a potential large animal model for human cataract.

  17. The Genetics of Monogenic Frontotemporal Dementia

    Directory of Open Access Journals (Sweden)

    Leonel T. Takada

    Full Text Available ABSTRACTAround 10-15% of patients diagnosed with frontotemporal dementia (FTD have a positive family history for FTD with an autosomal dominant pattern of inheritance. Since the identification of mutations in MAPT(microtubuleassociated protein tau gene in 1998, over 10 other genes have been associated with FTD spectrum disorders, discussed in this review. Along with MAPT, mutations in GRN(progranulin and C9orf72(chromosome 9 open reading frame 72 are the most commonly identified in FTD cohorts. The association of FTD and motor neuron disease (MND can be caused by mutations in C9orf72and other genes, such as TARDBP(TAR DNA-binding protein, FUS(fused in sarcoma, UBQLN2(ubiquilin 2. Multisystem proteinopathy is a complex phenotype that includes FTD, Paget disease of the bone, inclusion body myopathy and MND, and can be due to mutations in VCP(valosing containing protein and other recently identified genes.

  18. A Multi-Model Stereo Similarity Function Based on Monogenic Signal Analysis in Poisson Scale Space

    Directory of Open Access Journals (Sweden)

    Jinjun Li

    2011-01-01

    Full Text Available A stereo similarity function based on local multi-model monogenic image feature descriptors (LMFD is proposed to match interest points and estimate disparity map for stereo images. Local multi-model monogenic image features include local orientation and instantaneous phase of the gray monogenic signal, local color phase of the color monogenic signal, and local mean colors in the multiscale color monogenic signal framework. The gray monogenic signal, which is the extension of analytic signal to gray level image using Dirac operator and Laplace equation, consists of local amplitude, local orientation, and instantaneous phase of 2D image signal. The color monogenic signal is the extension of monogenic signal to color image based on Clifford algebras. The local color phase can be estimated by computing geometric product between the color monogenic signal and a unit reference vector in RGB color space. Experiment results on the synthetic and natural stereo images show the performance of the proposed approach.

  19. Autosomal recessive inheritance of GLUT1 deficiency syndrome.

    NARCIS (Netherlands)

    Klepper, J.; Scheffer, H.; Elsaid, M.F.; Kamsteeg, E.J.; Leferink, M.; Ben-Omran, T.

    2009-01-01

    GLUT1 deficiency syndrome (GLUT1DS) is understood as a monogenetic disease caused by heterozygous SLC2A1 gene mutations with autosomaldominant and sporadic transmission. We report on a six-year-old girl from an inbred Arab family with moderate global developmental delay, epilepsy, ataxia, hypotonia,

  20. Genetics Home Reference: autosomal recessive hyper-IgE syndrome

    Science.gov (United States)

    ... is a disorder of the immune system. A hallmark feature of the condition is recurrent infections that ... have a greater-than-average risk of developing cancer, particularly cancers of the blood or skin. Related ...

  1. Genetics Home Reference: autosomal recessive cerebellar ataxia type 1

    Science.gov (United States)

    ... Canada, but it has since been found in populations worldwide. Related Information What information about a genetic ... are involved in chemical signaling between nerve cells ( neurons ). SYNE1 gene mutations that cause ARCA1 result in ...

  2. Genetics Home Reference: autosomal recessive axonal neuropathy with neuromyotonia

    Science.gov (United States)

    ... intolerance) and can lead to an unusual walking style (gait), frequent falls, and joint deformities (contractures) in ... pediatrneurol.2013.08.028. Epub 2013 Oct 13. Citation on PubMed Zhao H, Race V, Matthijs G, ...

  3. Autosomal recessive ichthyosis with limb reduction defect: A simple ...

    African Journals Online (AJOL)

    Rabah M. Shawky

    2015-10-01

    Oct 1, 2015 ... Our patient is a 13 year old girl, the first in birth order of first cousin parents, (Fig. 1). She was born at term by cesarean sec- tion of uncomplicated pregnancy. The patient was born in a yellow, tight and shiny sheath that started to desquamate after two to three weeks and replaced by rounded dark scaly ...

  4. Novel ITGB6 mutation in autosomal recessive amelogenesis imperfecta.

    Science.gov (United States)

    Seymen, F; Lee, K-E; Koruyucu, M; Gencay, K; Bayram, M; Tuna, E B; Lee, Z H; Kim, J-W

    2015-05-01

    Hereditary defects in tooth enamel formation, amelogenesis imperfecta (AI), can be non-syndromic or syndromic phenotype. Integrins are signaling proteins that mediate cell-cell and cell-extracellular matrix communication, and their involvement in tooth development is well known. The purposes of this study were to identify genetic cause of an AI family and molecular pathogenesis underlying defective enamel formation. We recruited a Turkish family with isolated AI and performed mutational analyses to clarify the underlying molecular genetic etiology. Autozygosity mapping and exome sequencing identified a novel homozygous ITGB6 transversion mutation in exon 4 (c.517G>C, p.Gly173Arg). The glycine at this position in the middle of the βI-domain is conserved among a wide range of vertebrate orthologs and human paralogs. Clinically, the enamel was generally thin and pitted with pigmentation. Thicker enamel was noted at the cervical area of the molars. In this study, we identified a novel homozygous ITGB6 mutation causing isolated AI, and this advances the understanding of normal and pathologic enamel development. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Subtotal amelia in a child with autosomal recessive hypohidrotic ...

    African Journals Online (AJOL)

    We report an inbred Tunisian family, in which the proband manifested signs of hypohidrotic ectodermal dysplasia, subtotal amelia, scoliosis and left renal agenesis. Two other family members had the full clinical criteria of hypohidrotic ectodermal dysplasia, characterized by deficient sweat glands, hypodontia, hypoplasia of ...

  6. Identification and molecular modelling of a mutation in the motor head domain of myosin VIIA in a family with autosomal dominant hearing impairment (DFNA11)

    NARCIS (Netherlands)

    Luijendijk, M.W.J.; Wijk, E. van; Bischoff, A.M.L.C.; Krieger, E.; Huygen, P.L.M.; Pennings, R.J.E.; Brunner, H.G.; Cremers, C.W.R.J.; Cremers, F.P.M.; Kremer, J.M.J.

    2004-01-01

    Myosin VIIA is an unconventional myosin that has been implicated in Usher syndrome type 1B, atypical Usher syndrome, non-syndromic autosomal recessive hearing impairment (DFNB2) and autosomal dominant hearing impairment (DFNA11). Here, we present a family with non-syndromic autosomal dominant

  7. Identification and molecular modelling of a mutation in the motor head domain of myosin VIIA in a family with autosomal dominant hearing impairment (DFNA11).

    NARCIS (Netherlands)

    Luijendijk, M.W.J.; Wijk, E. van; Bischoff, A.M.L.C.; Krieger, E.; Huygen, P.L.M.; Pennings, R.J.E.; Brunner, H.G.; Cremers, C.W.R.J.; Cremers, F.P.M.; Kremer, J.M.J.

    2004-01-01

    Myosin VIIA is an unconventional myosin that has been implicated in Usher syndrome type 1B, atypical Usher syndrome, non-syndromic autosomal recessive hearing impairment (DFNB2) and autosomal dominant hearing impairment (DFNA11). Here, we present a family with non-syndromic autosomal dominant

  8. A Boundary Value Problem for Hermitian Monogenic Functions

    Directory of Open Access Journals (Sweden)

    Ricardo Abreu Blaya

    2008-02-01

    Full Text Available We study the problem of finding a Hermitian monogenic function with a given jump on a given hypersurface in ℝm, m=2n. Necessary and sufficient conditions for the solvability of this problem are obtained.

  9. Sensitive Monogenic Noninvasive Prenatal Diagnosis by Targeted Haplotyping

    NARCIS (Netherlands)

    Vermeulen, Carlo; Geeven, Geert; de Wit, Elzo; Verstegen, Marjon J A M; Jansen, Rumo P.M.; van Kranenburg, Melissa; de Bruijn, Ewart; Pulit, Sara L.; Kruisselbrink, Evelien; Shahsavari, Zahra; Omrani, Davood; Zeinali, Fatemeh; Najmabadi, Hossein; Katsila, Theodora; Vrettou, Christina; Patrinos, George P.; Traeger-Synodinos, Joanne; Splinter, Erik; Beekman, Jeffrey M.; Kheradmand Kia, Sima; Te Meerman, Gerard J; Ploos van Amstel, Hans Kristian; de Laat, Wouter

    2017-01-01

    During pregnancy, cell-free DNA (cfDNA) in maternal blood encompasses a small percentage of cell-free fetal DNA (cffDNA), an easily accessible source for determination of fetal disease status in risk families through non-invasive procedures. In case of monogenic heritable disease, background

  10. Genetics of recessive cognitive disorders.

    Science.gov (United States)

    Musante, Luciana; Ropers, H Hilger

    2014-01-01

    Most severe forms of intellectual disability (ID) have specific genetic causes. Numerous X chromosome gene defects and disease-causing copy-number variants have been linked to ID and related disorders, and recent studies have revealed that sporadic cases are often due to dominant de novo mutations with low recurrence risk. For autosomal recessive ID (ARID) the recurrence risk is high and, in populations with frequent parental consanguinity, ARID is the most common form of ID. Even so, its elucidation has lagged behind. Here we review recent progress in this field, show that ARID is not rare even in outbred Western populations, and discuss the prospects for improving its diagnosis and prevention. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. Combined Occurrence of Autosomal Dominant Aniridia and Autosomal Recessive Albinism in Several Members of a Family.

    Science.gov (United States)

    Yahalom, Claudia; Sharon, Dror; Dalia, Eli; Simhon, Shiran Ben; Shemesh, Efrat; Blumenfeld, Anat

    2015-06-01

    To characterize clinical and genetic aspects of a family with a unique combination of two hereditary blinding eye diseases. Comprehensive eye examination of proband and family members. Molecular analyses of the TYR and PAX6 genes. A young couple, both legally blind, requested genetic counselling regarding their ocular condition. The female was previously diagnosed with oculocutaneous albinism (OCA1A) and her spouse was diagnosed with Peters anomaly. A comprehensive clinical examination revealed that the female had OCA1A combined with signs of another ocular disease, showing some similarity to aniridia. A complete ocular examination of her family members revealed that her brother also suffered from the same combined phenotype, her father had typical OCA1A signs, and her mother and sister had aniridia-like phenotype, without clinical diagnosis until the time of presentation. Molecular analysis identified two compound heterozygous TYR mutations known to cause OCAIA and cosegregate with oculocutaneous albinism. In addition, we identified a novel heterozygous PAX6 mutation confirming the atypical aniridia phenotype. We report here a unique and rare clinical phenotype that is explained by the segregation of two severe inherited eye diseases. The clinical and genetic analysis in this family allowed them to receive accurate genetic counseling.

  12. Forecasting US Recessions

    DEFF Research Database (Denmark)

    Christiansen, Charlotte; Eriksen, Jonas Nygaard; Møller, Stig Vinther

    2014-01-01

    We study the role of sentiment variables as predictors for US recessions. We combine sentiment variables with either classical recession predictors or common factors based on a large panel of macroeconomic and financial variables. Sentiment variables hold vast predictive power for US recessions...

  13. DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome

    DEFF Research Database (Denmark)

    White, Janson; Mazzeu, Juliana F; Hoischen, Alexander

    2015-01-01

    Robinow syndrome is a genetically heterogeneous disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features and for which both autosomal-recessive and autosomal-dominant inheritance patterns have been described. Causative variants in the non-canonical ...

  14. Monogenic diabetes associated with PAX4 gene mutations (MODY9: first description in Russia

    Directory of Open Access Journals (Sweden)

    Natalya A. Zubkova

    2017-12-01

    Full Text Available Maturity-onset diabetes of the young (MODY is a heterogeneous group of disorders characterised by autosomal dominant type of inheritance and caused by genetic defects leading to dysfunction of pancreatic beta-cells. To date, at least 13 subtypes of MODY have been described in the literature, the most frequent of which are MODY types 1–3. MODY2 and MODY3 are the most prevalent subtypes, and were previously described in our country, Russia. Several cases of rare MODY subtypes were subsequently described in the Russian literature. The current report is the first in the Russian literature to present clinical and molecular genetic characteristics of two cases of another rare MODY subtype—MODY9. This type of MODY is associated with mutations in the PAX4 gene, which encodes transcription factor PAX4, one of the factors essential for pancreatic beta-cell differentiation. Molecular genetic analysis was performed using next-generation sequencing, a new method recently applied to verify monogenic diseases and, in particular, MODY. This study reports a novel mutation in the PAX4 gene in MODY patients.

  15. Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically.

    Science.gov (United States)

    Wang, Jian; Dron, Jacqueline S; Ban, Matthew R; Robinson, John F; McIntyre, Adam D; Alazzam, Maher; Zhao, Pei Jun; Dilliott, Allison A; Cao, Henian; Huff, Murray W; Rhainds, David; Low-Kam, Cécile; Dubé, Marie-Pierre; Lettre, Guillaume; Tardif, Jean-Claude; Hegele, Robert A

    2016-12-01

    Next-generation sequencing technology is transforming our understanding of heterozygous familial hypercholesterolemia, including revision of prevalence estimates and attribution of polygenic effects. Here, we examined the contributions of monogenic and polygenic factors in patients with severe hypercholesterolemia referred to a specialty clinic. We applied targeted next-generation sequencing with custom annotation, coupled with evaluation of large-scale copy number variation and polygenic scores for raised low-density lipoprotein cholesterol in a cohort of 313 individuals with severe hypercholesterolemia, defined as low-density lipoprotein cholesterol >5.0 mmol/L (>194 mg/dL). We found that (1) monogenic familial hypercholesterolemia-causing mutations detected by targeted next-generation sequencing were present in 47.3% of individuals; (2) the percentage of individuals with monogenic mutations increased to 53.7% when copy number variations were included; (3) the percentage further increased to 67.1% when individuals with extreme polygenic scores were included; and (4) the percentage of individuals with an identified genetic component increased from 57.0% to 92.0% as low-density lipoprotein cholesterol level increased from 5.0 to >8.0 mmol/L (194 to >310 mg/dL). In a clinically ascertained sample with severe hypercholesterolemia, we found that most patients had a discrete genetic basis detected using a comprehensive screening approach that includes targeted next-generation sequencing, an assay for copy number variations, and polygenic trait scores. © 2016 American Heart Association, Inc.

  16. Dominant versus recessive traits conveyed by allelic mutations - to what extent is nonsense-mediated decay involved?

    NARCIS (Netherlands)

    Ben-Shachar, S.; Khajavi, M.; Withers, M.A.; Shaw, C.A.; Bokhoven, J.H.L.M. van; Brunner, H.G.; Lupski, J.R.

    2009-01-01

    Mutations in ROR2, encoding a receptor tyrosine kinase, can cause autosomal recessive Robinow syndrome (RRS), a severe skeletal dysplasia with limb shortening, brachydactyly, and a dysmorphic facial appearance. Other mutations in ROR2 result in the autosomal dominant disease, brachydactyly type B

  17. [Autosomal dominant polycystic kidney].

    Science.gov (United States)

    Jorge Adad, S; Estevão Barbosa, M; Fácio Luíz, J M; Furlan Rodrigues, M C; Iwamoto, S

    1996-01-01

    A 48-year-old male had autosomic dominant polycystic kidneys with dimensions, to the best of our knowledge, never previously reported; the right kidney weighed 15,100 g and measured 53 x 33 x 9cm and the left one 10.200 g and 46 x 21 x 7cm, with cysts measuring up to 14cm in diameter. Nephrectomy was done to control persistent hematuria and to relief disconfort caused by the large kidneys. The renal function is stable four years after transplantation.

  18. The population genetics of X-autosome synthetic lethals and steriles.

    Science.gov (United States)

    Lachance, Joseph; Johnson, Norman A; True, John R

    2011-11-01

    Epistatic interactions are widespread, and many of these interactions involve combinations of alleles at different loci that are deleterious when present in the same individual. The average genetic environment of sex-linked genes differs from that of autosomal genes, suggesting that the population genetics of interacting X-linked and autosomal alleles may be complex. Using both analytical theory and computer simulations, we analyzed the evolutionary trajectories and mutation-selection balance conditions for X-autosome synthetic lethals and steriles. Allele frequencies follow a set of fundamental trajectories, and incompatible alleles are able to segregate at much higher frequencies than single-locus expectations. Equilibria exist, and they can involve fixation of either autosomal or X-linked alleles. The exact equilibrium depends on whether synthetic alleles are dominant or recessive and whether fitness effects are seen in males, females, or both sexes. When single-locus fitness effects and synthetic incompatibilities are both present, population dynamics depend on the dominance of alleles and historical contingency (i.e., whether X-linked or autosomal mutations occur first). Recessive synthetic lethality can result in high-frequency X-linked alleles, and dominant synthetic lethality can result in high-frequency autosomal alleles. Many X-autosome incompatibilities in natural populations may be cryptic, appearing to be single-locus effects because one locus is fixed. We also discuss the implications of these findings with respect to standing genetic variation and the origins of Haldane's rule.

  19. Targeted next-generation sequencing in monogenic dyslipidemias.

    Science.gov (United States)

    Hegele, Robert A; Ban, Matthew R; Cao, Henian; McIntyre, Adam D; Robinson, John F; Wang, Jian

    2015-04-01

    To evaluate the potential clinical translation of high-throughput next-generation sequencing (NGS) methods in diagnosis and management of dyslipidemia. Recent NGS experiments indicate that most causative genes for monogenic dyslipidemias are already known. Thus, monogenic dyslipidemias can now be diagnosed using targeted NGS. Targeting of dyslipidemia genes can be achieved by either: designing custom reagents for a dyslipidemia-specific NGS panel; or performing genome-wide NGS and focusing on genes of interest. Advantages of the former approach are lower cost and limited potential to detect incidental pathogenic variants unrelated to dyslipidemia. However, the latter approach is more flexible because masking criteria can be altered as knowledge advances, with no need for re-design of reagents or follow-up sequencing runs. Also, the cost of genome-wide analysis is decreasing and ethical concerns can likely be mitigated. DNA-based diagnosis is already part of the clinical diagnostic algorithms for familial hypercholesterolemia. Furthermore, DNA-based diagnosis is supplanting traditional biochemical methods to diagnose chylomicronemia caused by deficiency of lipoprotein lipase or its co-factors. The increasing availability and decreasing cost of clinical NGS for dyslipidemia means that its potential benefits can now be evaluated on a larger scale.

  20. Extension problem for generalized multi-monogenic functions in Clifford analysis

    International Nuclear Information System (INIS)

    Tran Quyet Thang.

    1992-10-01

    The main purpose of this paper is to extend some properties of multi-monogenic functions, which is a generalization of monogenic functions in higher dimensions, for a class of functions satisfying Vekua-type generalized Cauchy-Riemann equations in Clifford Analysis. It is proved that the Hartogs theorem is valid for these functions. (author). 7 refs

  1. The Recession Squeezes Training.

    Science.gov (United States)

    Geber, Beverly

    1991-01-01

    Recession is having an impact on training departments. Besides a slowdown, it provides managers with a chance to reevaluate programs to ensure they are attuned to the specific goals of the company. (JOW)

  2. Enamelin/ameloblastin gene polymorphisms in autosomal amelogenesis imperfecta among Syrian families.

    Science.gov (United States)

    Dashash, Mayssoon; Bazrafshani, Mohamed Riza; Poulton, Kay; Jaber, Saaed; Naeem, Emad; Blinkhorn, Anthony Stevenson

    2011-02-01

      This study was undertaken to investigate whether a single G deletion within a series of seven G residues (codon 196) at the exon 9-intron 9 boundary of the enamelin gene ENAM and a tri-nucleotide deletion at codon 180 in exon 7 (GGA vs deletion) of ameloblastin gene AMBN could have a role in autosomal amelogenesis imperfecta among affected Syrian families.   A new technique - size-dependent, deletion screening - was developed to detect nucleotide deletion in ENAM and AMBN genes. Twelve Syrian families with autosomal-dominant or -recessive amelogenesis imperfecta were included.   A homozygous/heterozygous mutation in the ENAM gene (152/152, 152/153) was identified in affected members of three families with autosomal-dominant amelogenesis imperfecta and one family with autosomal-recessive amelogenesis imperfecta. A heterozygous mutation (222/225) in the AMBN gene was identified. However, no disease causing mutations was found. The present findings provide useful information for the implication of ENAM gene polymorphism in autosomal-dominant/-recessive amelogenesis imperfecta.   Further investigations are required to identify other genes responsible for the various clinical phenotypes. © 2010 Blackwell Publishing Asia Pty Ltd.

  3. Pathogenesis of the Metabolic Syndrome: Insights from Monogenic Disorders

    Directory of Open Access Journals (Sweden)

    Rinki Murphy

    2013-01-01

    Full Text Available Identifying rare human metabolic disorders that result from a single-gene defect has not only enabled improved diagnostic and clinical management of such patients, but also has resulted in key biological insights into the pathophysiology of the increasingly prevalent metabolic syndrome. Insulin resistance and type 2 diabetes are linked to obesity and driven by excess caloric intake and reduced physical activity. However, key events in the causation of the metabolic syndrome are difficult to disentangle from compensatory effects and epiphenomena. This review provides an overview of three types of human monogenic disorders that result in (1 severe, non-syndromic obesity, (2 pancreatic beta cell forms of early-onset diabetes, and (3 severe insulin resistance. In these patients with single-gene defects causing their exaggerated metabolic disorder, the primary defect is known. The lessons they provide for current understanding of the molecular pathogenesis of the common metabolic syndrome are highlighted.

  4. Management of suspected monogenic lung fibrosis in a specialised centre

    Directory of Open Access Journals (Sweden)

    Raphael Borie

    2017-04-01

    Full Text Available At least 10% of patients with interstitial lung disease present monogenic lung fibrosis suspected on familial aggregation of pulmonary fibrosis, specific syndromes or early age of diagnosis. Approximately 25% of families have an identified mutation in genes mostly involved in telomere homeostasis, and more rarely in surfactant homeostasis. Beyond pathophysiological knowledge, detection of these mutations has practical consequence for patients. For instance, mutations involved in telomere homeostasis are associated with haematological complications after lung transplantation and may require adapted immunosuppression. Moreover, relatives may benefit from a clinical and genetic evaluation that should be specifically managed. The field of genetics of pulmonary fibrosis has made great progress in the last 10 years, raising specific problems that should be addressed by a specialised team.

  5. A dichotomy for upper domination in monogenic classes

    KAUST Repository

    AbouEisha, Hassan M.

    2014-01-01

    An upper dominating set in a graph is a minimal (with respect to set inclusion) dominating set of maximum cardinality. The problem of finding an upper dominating set is NP-hard for general graphs and in many restricted graph families. In the present paper, we study the computational complexity of this problem in monogenic classes of graphs (i.e. classes defined by a single forbidden induced subgraph) and show that the problem admits a dichotomy in this family. In particular, we prove that if the only forbidden induced subgraph is a P4 or a 2K2 (or any induced subgraph of these graphs), then the problem can be solved in polynomial time. Otherwise, it is NP-hard.

  6. Evidence for autosomal dominant inheritance of ablepharon-macrostomia syndrome.

    Science.gov (United States)

    Rohena, Luis; Kuehn, Devon; Marchegiani, Shannon; Higginson, Jason D

    2011-04-01

    Ablepharon-macrostomia syndrome (AMS) is characterized by absent or short eyelids, macrostomia, ear anomalies, absent lanugo and hair, redundant skin, abnormal genitalia, and developmental delay in two-thirds of the reported patients. Additional anomalies include dry skin, growth retardation, hearing loss, camptodactyly, hypertelorism, absent zygomatic arches, and umbilical abnormalities. We present the second familial case of ablepharon-macrostomia syndrome in a newborn female and her 22-year-old father making autosomal dominant inheritance more likely than the previously proposed autosomal recessive transmission for this disorder. These cases likely represent the 16th and 17th reported cases of AMS and the first case suspected on prenatal ultrasound. Additionally, the child shows more prominent features of the disorder when compared to her father documenting variable expression and possible anticipation. This article is a US Government work and, as such, is in the public domain in the United States of America. Published 2011 Wiley-Liss, Inc.

  7. Gene therapy in animal models of autosomal dominant retinitis pigmentosa

    Science.gov (United States)

    Rossmiller, Brian; Mao, Haoyu

    2012-01-01

    Gene therapy for dominantly inherited genetic disease is more difficult than gene-based therapy for recessive disorders, which can be treated with gene supplementation. Treatment of dominant disease may require gene supplementation partnered with suppression of the expression of the mutant gene either at the DNA level, by gene repair, or at the RNA level by RNA interference or transcriptional repression. In this review, we examine some of the gene delivery approaches used to treat animal models of autosomal dominant retinitis pigmentosa, focusing on those models associated with mutations in the gene for rhodopsin. We conclude that combinatorial approaches have the greatest promise for success. PMID:23077406

  8. Gingival Recessions and Biomechanics

    DEFF Research Database (Denmark)

    Laursen, Morten Godtfredsen

    Gingival recessions and biomechanics “Tissue is the issue, but bone sets the tone.“ A tooth outside the cortical plate can result in loss of bone and development of a gingival recession. The presentation aims to show biomechanical considerations in relation to movement of teeth with gingival...... by moving the root back in the alveolus. The tooth movement is accompanied by bone gain and thus increase the success rate for soft tissue augmentation. The choice of biomechanical system influences the treatment outcome. If a standard straight wire appliance is used, a biomechanical dilemma can arise...

  9. Genomics of Systemic Lupus Erythematosus: Insights Gained by Studying Monogenic Young-Onset Systemic Lupus Erythematosus.

    Science.gov (United States)

    Hiraki, Linda T; Silverman, Earl D

    2017-08-01

    Systemic lupus erythematosus (SLE) is a systemic, autoimmune, multisystem disease with a heterogeneous clinical phenotype. Genome-wide association studies have identified multiple susceptibility loci, but these explain a fraction of the estimated heritability. This is partly because within the broad spectrum of SLE are monogenic diseases that tend to cluster in patients with young age of onset, and in families. This article highlights insights into the pathogenesis of SLE provided by these monogenic diseases. It examines genetic causes of complement deficiency, abnormal interferon production, and abnormalities of tolerance, resulting in monogenic SLE with overlapping clinical features, autoantibodies, and shared inflammatory pathways. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Clinical Considerations of Preimplantation Genetic Diagnosis for Monogenic Diseases.

    Directory of Open Access Journals (Sweden)

    Xiaokun Hu

    Full Text Available The aim of this study was to explore factors contribute to the success of PGD cycles for monogenic diseases.During a 3-year period (January 2009 to December 2012, 184 consecutive ICSI-PGD cycles for monogenic diseases reaching the ovum pick-up and fresh embryo-transfer stage performed at the Reproductive Medicine Center of The First Affiliated Hospital Of Sun Yat-sen University were evaluated.ICSI was performed on 2206 metaphase II oocytes, and normal fertilization and cleavage rates were 83.4% (1840/2206 and 96.2% (1770/1840, respectively. In the present study, 60.5% (181/299 of day 3 good-quality embryos developed into good-quality embryos on day 4 after biopsy. Collectively, 42.9% clinical pregnancy rate (79/184 and 28.5% implantation rate (111/389 were presented. In the adjusted linear regression model, the only two significant factors affecting the number of genetically unaffected embryos were the number of biopsied embryos (coefficient: 0.390, 95%CI 0.317-0.463, P = 0.000 and basal FSH level (coefficient: 0.198, 95%CI 0.031-0.365, P = 0.021. In the adjusted binary logistic regression model, the only two significant factors affecting pregnancy outcome were the number of genetically available transferable embryos after PGD (adjusted OR 1.345, 95% CI 1.148-1.575, P = 0.000 and number of oocyte retrieved (adjusted OR 0.934, 95% CI 0.877-0.994, P = 0.031.There should be at least four biopsied embryos to obtain at least one unaffected embryos in a PGD system for patients with single gene disorder and under the condition of basal FSH level smaller than 8.0mmol/L. Moreover, if only a low number (< 4 of biopsied embryos are available on day 3, the chance of unaffected embryos for transfer was small, with poor outcome.

  11. Autoimmunity/inflammation in a monogenic primary immunodeficiency cohort.

    Science.gov (United States)

    Rae, William; Ward, Daniel; Mattocks, Christopher J; Gao, Yifang; Pengelly, Reuben J; Patel, Sanjay V; Ennis, Sarah; Faust, Saul N; Williams, Anthony P

    2017-09-01

    Primary immunodeficiencies (PIDs) are rare inborn errors of immunity that have a heterogeneous phenotype that can include severe susceptibility to life-threatening infections from multiple pathogens, unique sensitivity to a single pathogen, autoimmune/inflammatory (AI/I) disease, allergies and/or malignancy. We present a diverse cohort of monogenic PID patients with and without AI/I diseases who underwent clinical, genetic and immunological phenotyping. Novel pathogenic variants were identified in IKBKG , CTLA4 , NFKB1 , GATA2 , CD40LG and TAZ as well as previously reported pathogenic variants in STAT3 , PIK3CD , STAT1 , NFKB2 and STXBP2 . AI/I manifestations were frequently encountered in PIDs, including at presentation. Autoimmunity/inflammation was multisystem in those effected, and regulatory T cell (Treg) percentages were significantly decreased compared with those without AI/I manifestations. Prednisolone was used as the first-line immunosuppressive agent in all cases, however steroid monotherapy failed long-term control of autoimmunity/inflammation in the majority of cases and additional immunosuppression was required. Patients with multisystem autoimmunity/inflammation should be investigated for an underlying PID, and in those with PID early assessment of Tregs may help to assess the risk of autoimmunity/inflammation.

  12. Spherical Dunkl-monogenics and a factorization of the Dunkl-Laplacian

    International Nuclear Information System (INIS)

    Fei Minggang; Cerejeiras, Paula; Kaehler, Uwe

    2010-01-01

    In this paper, we consider and study a factorization of the Dunkl-Laplacian in terms of spherical coordinates. This allows for the construction of a direct sum decomposition of spherical Dunkl-harmonics. By explicit representation in spherical coordinates of Dunkl-harmonics, one obtains explicit projection operators from Dunkl-harmonics to inner (resp. outer) Dunkl-monogenics. Concrete examples of spherical Dunkl-monogenics will be given at the end.

  13. Recessive mutations in PTHR1 cause contrasting skeletal dysplasias in Eiken and Blomstrand syndromes

    DEFF Research Database (Denmark)

    Duchatelet, Sabine; Ostergaard, Elsebet; Cortes, Dina

    2005-01-01

    Eiken syndrome is a rare autosomal recessive skeletal dysplasia. We identified a truncation mutation in the C-terminal cytoplasmic tail of the parathyroid hormone (PTH)/PTH-related peptide (PTHrP) type 1 receptor (PTHR1) gene as the cause of this syndrome. Eiken syndrome differs from Jansen...

  14. Statistical guidance for experimental design and data analysis of mutation detection in rare monogenic mendelian diseases by exome sequencing.

    Directory of Open Access Journals (Sweden)

    Degui Zhi

    Full Text Available Recently, whole-genome sequencing, especially exome sequencing, has successfully led to the identification of causal mutations for rare monogenic Mendelian diseases. However, it is unclear whether this approach can be generalized and effectively applied to other Mendelian diseases with high locus heterogeneity. Moreover, the current exome sequencing approach has limitations such as false positive and false negative rates of mutation detection due to sequencing errors and other artifacts, but the impact of these limitations on experimental design has not been systematically analyzed. To address these questions, we present a statistical modeling framework to calculate the power, the probability of identifying truly disease-causing genes, under various inheritance models and experimental conditions, providing guidance for both proper experimental design and data analysis. Based on our model, we found that the exome sequencing approach is well-powered for mutation detection in recessive, but not dominant, Mendelian diseases with high locus heterogeneity. A disease gene responsible for as low as 5% of the disease population can be readily identified by sequencing just 200 unrelated patients. Based on these results, for identifying rare Mendelian disease genes, we propose that a viable approach is to combine, sequence, and analyze patients with the same disease together, leveraging the statistical framework presented in this work.

  15. [Preimplantation genetic diagnosis and monogenic inherited eye diseases].

    Science.gov (United States)

    Hlavatá, L; Ďuďáková, Ľ; Trková, M; Soldátová, I; Skalická, P; Kousal, B; Lišková, P

    .Key words: preimplantation genetic diagnosis; monogenic eye diseases; in vitro fertilization.

  16. Autosomal dominant syndrome resembling Coffin-Siris syndrome.

    Science.gov (United States)

    Flynn, Maureen A; Milunsky, Jeff M

    2006-06-15

    Coffin-Siris syndrome is a multiple congenital anomaly/mental retardation syndrome with phenotypic variability [OMIM 135900]. The diagnosis is based solely on clinical findings, as there is currently no molecular, biochemical, or cytogenetic analysis available to confirm a diagnosis. Although typically described as an autosomal recessive disorder, autosomal dominant inheritance has also been infrequently reported. We describe a mother and her two daughters who all have features that resemble Coffin-Siris syndrome. However, this is not a completely convincing diagnosis given that hypertelorism is not a feature of Coffin-Siris syndrome and the family is relatively mildly affected. Yet, this family provides further evidence of an autosomal dominant mode of inheritance for a likely variant of Coffin-Siris syndrome (at least in some families). In addition, Sibling 1 had premature thelarche. She is the second reported individual within the spectrum of Coffin-Siris syndrome to have premature thelarche, indicating that it may be a rare clinical feature. Copyright 2006 Wiley-Liss, Inc.

  17. A novel approach identifying hybrid sterility QTL on the autosomes of Drosophila simulans and D. mauritiana.

    Science.gov (United States)

    Dickman, Christopher T D; Moehring, Amanda J

    2013-01-01

    When species interbreed, the hybrid offspring that are produced are often sterile. If only one hybrid sex is sterile, it is almost always the heterogametic (XY or ZW) sex. Taking this trend into account, the predominant model used to explain the genetic basis of F1 sterility involves a deleterious interaction between recessive sex-linked loci from one species and dominant autosomal loci from the other species. This model is difficult to evaluate, however, as only a handful of loci influencing interspecies hybrid sterility have been identified, and their autosomal genetic interactors have remained elusive. One hindrance to their identification has been the overwhelming effect of the sex chromosome in mapping studies, which could 'mask' the ability to accurately map autosomal factors. Here, we use a novel approach employing attached-X chromosomes to create reciprocal backcross interspecies hybrid males that have a non-recombinant sex chromosome and recombinant autosomes. The heritable variation in phenotype is thus solely caused by differences in the autosomes, thereby allowing us to accurately identify the number and location of autosomal sterility loci. In one direction of backcross, all males were sterile, indicating that sterility could be entirely induced by the sex chromosome complement in these males. In the other direction, we identified nine quantitative trait loci that account for a surprisingly large amount (56%) of the autosome-induced phenotypic variance in sterility, with a large contribution of autosome-autosome epistatic interactions. These loci are capable of acting dominantly, and thus could contribute to F1 hybrid sterility.

  18. A novel approach identifying hybrid sterility QTL on the autosomes of Drosophila simulans and D. mauritiana.

    Directory of Open Access Journals (Sweden)

    Christopher T D Dickman

    Full Text Available When species interbreed, the hybrid offspring that are produced are often sterile. If only one hybrid sex is sterile, it is almost always the heterogametic (XY or ZW sex. Taking this trend into account, the predominant model used to explain the genetic basis of F1 sterility involves a deleterious interaction between recessive sex-linked loci from one species and dominant autosomal loci from the other species. This model is difficult to evaluate, however, as only a handful of loci influencing interspecies hybrid sterility have been identified, and their autosomal genetic interactors have remained elusive. One hindrance to their identification has been the overwhelming effect of the sex chromosome in mapping studies, which could 'mask' the ability to accurately map autosomal factors. Here, we use a novel approach employing attached-X chromosomes to create reciprocal backcross interspecies hybrid males that have a non-recombinant sex chromosome and recombinant autosomes. The heritable variation in phenotype is thus solely caused by differences in the autosomes, thereby allowing us to accurately identify the number and location of autosomal sterility loci. In one direction of backcross, all males were sterile, indicating that sterility could be entirely induced by the sex chromosome complement in these males. In the other direction, we identified nine quantitative trait loci that account for a surprisingly large amount (56% of the autosome-induced phenotypic variance in sterility, with a large contribution of autosome-autosome epistatic interactions. These loci are capable of acting dominantly, and thus could contribute to F1 hybrid sterility.

  19. Autosomal Dominant Polycystic Kidney Disease

    Science.gov (United States)

    ... NIH Director Organization Budget History NIH Almanac Public Involvement Outreach & Education Visitor Information RePORT NIH Fact Sheets Home > Autosomal ... other than the observation that 50 percent of children born to an affected parent would develop the disease. Diagnosis of well-established ...

  20. Is Autosomal Dominant Polycystic Kidney Disease Becoming a Pediatric Disorder?

    Directory of Open Access Journals (Sweden)

    Stéphanie De Rechter

    2017-12-01

    Full Text Available Autosomal dominant polycystic kidney disease (ADPKD affects 1 in 400 to 1,000 live births, making it the most common monogenic cause of renal failure. Although no definite cure is available yet, it is important to affect disease progression by influencing modifiable factors such as hypertension and proteinuria. Besides this symptomatic management, the only drug currently recommended in Europe for selected adult patients with rapid disease progression, is the vasopressin receptor antagonist tolvaptan. However, the question remains whether these preventive interventions should be initiated before extensive renal damage has occurred. As renal cyst formation and expansion begins early in life, frequently in utero, ADPKD should no longer be considered an adult-onset disease. Moreover, the presence of hypertension and proteinuria in affected children has been reported to correlate well with disease severity. Until now, it is controversial whether children at-risk for ADPKD should be tested for the presence of the disease, and if so, how this should be done. Herein, we review the spectrum of pediatric ADPKD and discuss the pro and contra of testing at-risk children and the challenges and unmet needs in pediatric ADPKD care.

  1. Inheritance patterns of new genetic markers and occurrence of spontaneous mosaicism in the monogenic blowfly Chrysomya rufifacies (Diptera:Calliphoridae).

    Science.gov (United States)

    Ullerich, F H

    1996-11-27

    Four new genetic markers for Chrysomya rufifacies, a fly with maternal sex determination, were characterized. The markers include one body colour mutant, black body (bl), and three eye colour mutants, brown eye (br), apricot eye (ap), and red eye (wr). Two of the latter, br and wr, turn out to be sex linked, the others behave as autosomal genes belonging to different linkage groups. wr is a hypomorphic and w an apomorphic mutation of the white gene, w/w is epistatic to br/br and to ap/ap. A preliminary genetic linkage map with the sex realizer F'/f and the loci br and w residing in homomorphic sex chromosomes is established. Evidence is presented that crossing over is absent in the male sex. The possible causes of the spontaneous appearance of mosaics for eye colour observed among individuals heterozygous for recessive genes are discussed.

  2. Autosomal dominant epidermodysplasia verruciformis lacking a known EVER1 or EVER2 mutation

    OpenAIRE

    McDermott, David H.; Gammon, Bryan; Snijders, Peter J.; Mbata, Ihunanya; Phifer, Beth; Hartley, A. Howland; Lee, Chyi-Chia Richard; Murphy, Philip M.; Hwang, Sam T.

    2009-01-01

    Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by abnormal susceptibility to infection with specific human papillomavirus (HPV) serotypes. EV is a genetically heterogeneous disease, and autosomal recessive and X-linked inheritance patterns have been reported. Nonsense mutations in the genes EVER1 and EVER2 have been identified in over 75% of cases. We present EV in a father and son with typical histologic and clinical findings that occur in the absence of mutation...

  3. Barriers for recess physical activity

    DEFF Research Database (Denmark)

    Pawlowski, Charlotte Skau; Tjørnhøj-Thomsen, Tine; Schipperijn, Jasper

    2014-01-01

    BACKGROUND: Many children, in particular girls, do not reach the recommended amount of daily physical activity. School recess provides an opportunity for both boys and girls to be physically active, but barriers to recess physical activity are not well understood. This study explores gender...... differences in children's perceptions of barriers to recess physical activity. Based on the socio-ecological model four types of environmental barriers were distinguished: natural, social, physical and organizational environment. METHODS: Data were collected through 17 focus groups (at 17 different schools...... this study, we recommend promoting recess physical activity through a combination of actions, addressing barriers within the natural, social, physical and organizational environment....

  4. Evaluation of a target region capture sequencing platform using monogenic diabetes as a study-model

    DEFF Research Database (Denmark)

    Gao, Rui; Liu, Yanxia; Gjesing, Anette Marianne Prior

    2014-01-01

    Monogenic diabetes is a genetic disease often caused by mutations in genes involved in beta-cell function. Correct sub-categorization of the disease is a prerequisite for appropriate treatment and genetic counseling. Target-region capture sequencing is a combination of genomic region enrichment...... and next generation sequencing which might be used as an efficient way to diagnose various genetic disorders. We aimed to develop a target-region capture sequencing platform to screen 117 selected candidate genes involved in metabolism for mutations and to evaluate its performance using monogenic diabetes...

  5. Biological Treatments: New Weapons in the Management of Monogenic Autoinflammatory Disorders

    Directory of Open Access Journals (Sweden)

    Antonio Vitale

    2013-01-01

    Full Text Available Treatment of monogenic autoinflammatory disorders, an expanding group of hereditary diseases characterized by apparently unprovoked recurrent episodes of inflammation, without high-titre autoantibodies or antigen-specific T cells, has been revolutionized by the discovery that several of these conditions are caused by mutations in proteins involved in the mechanisms of innate immune response, including components of the inflammasome, cytokine receptors, receptor antagonists, and oversecretion of a network of proinflammatory molecules. Aim of this review is to synthesize the current experience and the most recent evidences about the therapeutic approach with biologic drugs in pediatric and adult patients with monogenic autoinflammatory disorders.

  6. Recessive omodysplasia: five new cases and review of the literature

    International Nuclear Information System (INIS)

    Elcioglu, Nursel H.; Gustavson, Karl H.; Wilkie, Andrew O.M.; Yueksel-Apak, Memune; Spranger, Juergen W.

    2004-01-01

    Autosomal recessive omodysplasia (MIM 258315) is a rare skeletal dysplasia characterized by severe congenital micromelia with shortening and distal tapering of the humeri and femora to give a club-like appearance. Fewer than 20 cases have been reported in the literature so far. The purpose of this study was to more clearly describe the clinical and radiographic phenotypes and their changes with age. Five new patients, including two sibs, with autosomal recessive omodysplasia are presented. Clinical features are rhizomelic dwarfism with limited extension of elbows and knees and a distinct face with a short nose, depressed nasal bridge, long philtrum, midline haemangiomas in infants and cryptorchidism in males. Radiological findings are distal hypoplasia of the short humerus and femur with characteristic radial dislocation and radioulnar diastasis. Based on a review of these and 16 previously reported patients, the regressive nature of the humerofemoral changes and the obvious male predominance are stressed. Phenotypic similarities with the atelosteogenesis group of disorders and with diastrophic dysplasia suggest common pathogenetic mechanisms. (orig.)

  7. Constitutional and acquired autosomal aneuploidy.

    Science.gov (United States)

    Jackson-Cook, Colleen

    2011-12-01

    Chromosomal imbalances can result from numerical or structural anomalies. Numerical chromosomal abnormalities are often referred to as aneuploid conditions. This article focuses on the occurrence of constitutional and acquired autosomal aneuploidy in humans. Topics covered include frequency, mosaicism, phenotypic findings, and etiology. The article concludes with a consideration of anticipated advances that might allow for the development of screening tests and/or lead to improvements in our understanding and management of the role that aneuploidy plays in the aging process and acquisition of age-related and constitutional conditions.

  8. Copper : recession and recovery

    International Nuclear Information System (INIS)

    Warwick-Ching, T.

    2002-01-01

    In 2002, the world output for copper will fall for the first time in nearly a decade because of financial pressure and voluntary constraints. Cutbacks at copper mines amount to 760,000 tonnes per year. These cutbacks have occurred mostly in the United States which holds the largest share of high cost mines. This paper discussed recent developments in both copper supply and demand. The United States is unique as both a large consumer and producer of copper. At 1.35 million tonnes, US mine output in 2001 was at its lowest since 1987. The cutbacks in mining in general were described in this paper with particular reference to the huge loss of mining and metallurgical activity in the United States during a prolonged period of low prices in the mid 1980s. The author noted that this period was followed by an exceptional decade when much of the industry rebounded. Only 8 mines closed outright in the United States and a handful in Canada since the recession of the 1980s, but that is partly because mines got bigger and there are fewer small mines in North America. There are only 4 electrolytic refineries and 3 smelters still active in the entire United States, of which 2 are operating at a fraction of capacity. It was noted that only the buoyancy of China prevented a much bigger decline in copper demand on a global scale

  9. Autosomal dominant adult neuronal ceroid lipofuscinosis

    NARCIS (Netherlands)

    Nijssen, Peter C.G.

    2011-01-01

    this thesis investigates a family with autosomal dominant neuronal ceroid lipofuscinosis, with chapters on clinical neurology, neuropathology, neurogenetics, neurophysiology, auditory and visual aspects.

  10. What Caused the Great Recession?

    OpenAIRE

    Homburg, Stefan

    2014-01-01

    This paper examines five possible explanations for the Great Recession of 2008 and 2009, using data for the United States and the eurozone. Of these five hypotheses, four are not supported by the data, while the fifth appears reasonable.

  11. Novel PMS2 Pseudogenes Can Conceal Recessive Mutations Causing a Distinctive Childhood Cancer Syndrome

    OpenAIRE

    De Vos, Michel; Hayward, Bruce E.; Picton, Susan; Sheridan, Eamonn; Bonthron, David T.

    2004-01-01

    We investigated a family with an autosomal recessive syndrome of café-au-lait patches and childhood malignancy, notably supratentorial primitive neuroectodermal tumor. There was no cancer predisposition in heterozygotes; nor was there bowel cancer in any individual. However, autozygosity mapping indicated linkage to a region of 7p22 surrounding the PMS2 mismatch-repair gene. Sequencing of genomic PCR products initially failed to identify a PMS2 mutation. Genome searches then revealed a previo...

  12. Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease

    Directory of Open Access Journals (Sweden)

    A.P. Bastos

    2011-07-01

    Full Text Available Autosomal dominant polycystic kidney disease (ADPKD is one of the most common human life-threatening monogenic disorders. The disease is characterized by bilateral, progressive renal cystogenesis and cyst and kidney enlargement, often leading to end-stage renal disease, and may include extrarenal manifestations. ADPKD is caused by mutation in one of two genes, PKD1 and PKD2, which encode polycystin-1 (PC1 and polycystin-2 (PC2, respectively. PC2 is a non-selective cation channel permeable to Ca2+, while PC1 is thought to function as a membrane receptor. The cyst cell phenotype includes increased proliferation and apoptosis, dedifferentiation, defective planar polarity, and a secretory pattern associated with extracellular matrix remodeling. The two-hit model for cyst formation has been recently extended by the demonstration that early gene inactivation leads to rapid and diffuse development of renal cysts, while inactivation in adult life is followed by focal and late cyst formation. Renal ischemia/reperfusion, however, can function as a third hit, triggering rapid cyst development in kidneys with Pkd1 inactivation induced in adult life. The PC1-PC2 complex behaves as a sensor in the primary cilium, mediating signal transduction via Ca2+ signaling. The intracellular Ca2+ homeostasis is impaired in ADPKD, being apparently responsible for the cAMP accumulation and abnormal cell proliferative response to cAMP. Activated mammalian target for rapamycin (mTOR and cell cycle dysregulation are also significant features of PKD. Based on the identification of pathways altered in PKD, a large number of preclinical studies have been performed and are underway, providing a basis for clinical trials in ADPKD and helping the design of future trials.

  13. The Great Recession was not so Great

    NARCIS (Netherlands)

    van Ours, J.C.

    2015-01-01

    The Great Recession is characterized by a GDP-decline that was unprecedented in the past decades. This paper discusses the implications of the Great Recession analyzing labor market data from 20 OECD countries. Comparing the Great Recession with the 1980s recession it is concluded that there is a

  14. A postnatal role for embryonic myosin revealed by MYH3 mutations that alter TGFbeta signaling and cause autosomal dominant spondylocarpotarsal synostosis

    NARCIS (Netherlands)

    Zieba, J.; Zhang, W.; Chong, J.X.; Forlenza, K.N.; Martin, J.H.; Heard, K.; Grange, D.K.; Butler, M.G.; Kleefstra, T.; Lachman, R.S.; Nickerson, D.; Regnier, M.; Cohn, D.H.; Bamshad, M.; Krakow, D.

    2017-01-01

    Spondylocarpotarsal synostosis (SCT) is a skeletal disorder characterized by progressive vertebral, carpal and tarsal fusions, and mild short stature. The majority of affected individuals have an autosomal recessive form of SCT and are homozygous or compound heterozygous for nonsense mutations in

  15. Recurrent De Novo Mutations Affecting Residue Arg1 38 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa

    NARCIS (Netherlands)

    Fischer-Zirnsak, Björn; Escande-Beillard, Nathalie; Ganesh, Jaya; Tan, Yu Xuan; Al Bughaili, Mohammed; Lin, Angela E.; Sahai, Inderneel; Bahena, Paulina; Reichert, Sara L.; Loh, Abigail; Wright, Graham D.; Liu, Jaron; Rahikkala, Elisa; Pivnick, Eniko K.; Choudhri, Asim F.; Krüger, Ulrike; Zemojtel, Tomasz; van Ravenswaaij-Arts, Conny; Mostafavi, Roya; Stolte-Dijkstra, Irene; Symoens, Sofie; Pajunen, Leila; Al-Gazali, Lihadh; Meierhofer, David; Robinson, Peter N.; Mundlos, Stefan; Villarroel, Camilo E.; Byers, Peter; Masri, Amira; Robertson, Stephen P.; Schwarze, Ulrike; Callewaert, Bert; Reversade, Bruno; Kornak, Uwe

    2015-01-01

    Progeroid disorders overlapping with De Barsy syndrome (DBS) are collectively denoted as autosomal-recessive cutis laxa type 3 (ARCL3). They are caused by biallelic mutations in PYCR1 or ALDH18A1, encoding pyrroline-5-carboxylate reductase 1 and pyrroline-5-carboxylate synthase (P5CS), respectively,

  16. Autosomal dominant hereditary ataxia in Sri Lanka

    OpenAIRE

    Sumathipala, Dulika S; Abeysekera, Gayan S; Jayasekara, Rohan W; Tallaksen, Chantal ME; Dissanayake, Vajira HW

    2013-01-01

    Background Spinocerebellar ataxias (SCA) are a group of hereditary neurodegenerative disorders. Prevalence of SCA subtypes differ worldwide. Autosomal dominant ataxias are the commonest types of inherited ataxias seen in Sri Lanka. The aim of the study is to determine the genetic etiology of patients with autosomal dominant ataxia in Sri Lanka and to describe the clinical features of each genetic subtype. Methods ...

  17. Associations of specific psychiatric disorders with isolated focal dystonia, and monogenic and idiopathic Parkinson's disease.

    Science.gov (United States)

    Steinlechner, Susanne; Hagenah, Johann; Rumpf, Hans-Jürgen; Meyer, Christian; John, Ulrich; Bäumer, Tobias; Brüggemann, Norbert; Kasten, Meike; Münchau, Alexander; Klein, Christine; Lencer, Rebekka

    2017-06-01

    Comorbidity of psychiatric disorders in patients with movement disorders is common. Often, psychiatric symptoms manifest before the onset of the movement disorder, thus not representing a mere reaction to its burden. How the disease mechanisms of psychiatric and movement disorders are related is still poorly understood. The aim of the present study was to compare prevalence rates of specific psychiatric disorders between different movement disorders including isolated focal dystonia (IFD, N = 91), monogenic Parkinson's disease (PD, N = 41), idiopathic PD (N = 45), and a sample from a Northern Germany general population (TACOS Study; N = 4075). Our results indicate an odds ratio (OR) of 2.6 [confidence interval (CI) 1.7-4.0] for general axis I disorders in IFD, an OR of 2.5 (CI 1.4-4.7) in monogenic PD, and an OR of 1.4 (CI 0.8-2.6) in idiopathic PD. More specifically, the monogenic PD group showed the highest ORs for affective disorders including depression (OR = 4.9), bipolar disorder (OR = 17.4), and hypomanic episodes (OR = 17.0), whereas IFD expressed the highest rates of anxiety disorders (OR = 3.3). Psychotic symptoms were only observed in the PD groups but not in IFD. Our findings underline the notion that psychiatric disorders are part of the phenotypic spectrum of movement disorders. Moreover, they suggest that IFD, monogenic PD, and idiopathic PD are associated with specific psychiatric disorders indicating disturbances in a different neural circuitry for sensorimotor control.

  18. Differential operators in a Clifford analysis associated to differential equations with anti-monogenic right-hand sides

    International Nuclear Information System (INIS)

    Nguyen Thanh Van

    2006-12-01

    This paper deals with the initial value problem of the type φw / φt = L (t, x, w, φw / φx i ) (1) w(0, x) = φ(x) (2) where t is the time, L is a linear first order operator in a Clifford Analysis and φ is a generalized monogenic function. We give sufficient conditions on the coefficients of operator L under which L is associated to differential equations with anti-monogenic right-hand sides. For such operator L the initial problem (1),(2) is solvable for an arbitrary generalized monogenic initial function φ and the solution is also generalized monogenic for each t. (author)

  19. LipidSeq: a next-generation clinical resequencing panel for monogenic dyslipidemias[S

    Science.gov (United States)

    Johansen, Christopher T.; Dubé, Joseph B.; Loyzer, Melissa N.; MacDonald, Austin; Carter, David E.; McIntyre, Adam D.; Cao, Henian; Wang, Jian; Robinson, John F.; Hegele, Robert A.

    2014-01-01

    We report the design of a targeted resequencing panel for monogenic dyslipidemias, LipidSeq, for the purpose of replacing Sanger sequencing in the clinical detection of dyslipidemia-causing variants. We also evaluate the performance of the LipidSeq approach versus Sanger sequencing in 84 patients with a range of phenotypes including extreme blood lipid concentrations as well as additional dyslipidemias and related metabolic disorders. The panel performs well, with high concordance (95.2%) in samples with known mutations based on Sanger sequencing and a high detection rate (57.9%) of mutations likely to be causative for disease in samples not previously sequenced. Clinical implementation of LipidSeq has the potential to aid in the molecular diagnosis of patients with monogenic dyslipidemias with a high degree of speed and accuracy and at lower cost than either Sanger sequencing or whole exome sequencing. Furthermore, LipidSeq will help to provide a more focused picture of monogenic and polygenic contributors that underlie dyslipidemia while excluding the discovery of incidental pathogenic clinically actionable variants in nonmetabolism-related genes, such as oncogenes, that would otherwise be identified by a whole exome approach, thus minimizing potential ethical issues. PMID:24503134

  20. Determining the sample size for co-dominant molecular marker-assisted linkage detection for a monogenic qualitative trait by controlling the type-I and type-II errors in a segregating F2 population.

    Science.gov (United States)

    Hühn, M; Piepho, H P

    2003-03-01

    Tests for linkage are usually performed using the lod score method. A critical question in linkage analyses is the choice of sample size. The appropriate sample size depends on the desired type-I error and power of the test. This paper investigates the exact type-I error and power of the lod score method in a segregating F(2) population with co-dominant markers and a qualitative monogenic dominant-recessive trait. For illustration, a disease-resistance trait is considered, where the susceptible allele is recessive. A procedure is suggested for finding the appropriate sample size. It is shown that recessive plants have about twice the information content of dominant plants, so the former should be preferred for linkage detection. In some cases the exact alpha-values for a given nominal alpha may be rather small due to the discrete nature of the sampling distribution in small samples. We show that a gain in power is possible by using exact methods.

  1. Autosomal recessive mutations in THOC6 cause intellectual disability: syndrome delineation requiring forward and reverse phenotyping.

    Science.gov (United States)

    Amos, J S; Huang, L; Thevenon, J; Kariminedjad, A; Beaulieu, C L; Masurel-Paulet, A; Najmabadi, H; Fattahi, Z; Beheshtian, M; Tonekaboni, S H; Tang, S; Helbig, K L; Alcaraz, W; Rivière, J-B; Faivre, L; Innes, A M; Lebel, R R; Boycott, K M

    2017-01-01

    THOC6 is a part of the THO complex, which is involved in coordinating mRNA processing with export. The THO complex interacts with additional components to form the larger TREX complex (transcription export complex). Previously, a homozygous missense mutation in THOC6 in the Hutterite population was reported in association with syndromic intellectual disability. Using exome sequencing, we identified three unrelated patients with bi-allelic mutations in THOC6 associated with intellectual disability and additional clinical features. Two of the patients were compound heterozygous for a stop and a missense mutation, and the third was homozygous for a missense mutation; the missense mutations were predicted to be pathogenic by in silico analysis and modeling. Clinical features of the three newly identified patients and those previously reported are reviewed; intellectual disability is moderate to severe, and malformations are variable including renal and heart defects, cleft palate, microcephaly, and corpus callosum dysgenesis. Facial features are variable and include tall forehead, short upslanting palpebral fissures +/- deep set eyes, and a long nose with overhanging columella. These subtle facial features render the diagnosis difficult to make in isolation with certainty. Our results expand the mutational and clinical spectrum of this rare disease, confirm that THOC6 is an intellectual disability causing gene, while providing insight into the importance of the THO complex in neurodevelopment. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Lymphangiectasia with persistent Müllerian derivatives: confirmation of autosomal recessive Urioste syndrome

    NARCIS (Netherlands)

    van Haelst, M. M.; Hoogeboom, J.; Galjaard, R. J.; Kleijer, W. J.; den Hollander, N. S.; de Krijger, R. R.; Hennekam, R. C.; Niermeijer, M. F.

    2001-01-01

    We report on a sibship with protein-losing enteropathy related to intestinal lymphangiectasia, a peculiar face, and genital anomalies. The parents are distantly related and from Dutch ancestry. The first patient was born with a protein-losing enteropathy, craniofacial anomalies, and renal defects.

  3. Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation

    NARCIS (Netherlands)

    Hennekam, R. C.; Geerdink, R. A.; Hamel, B. C.; Hennekam, F. A.; Kraus, P.; Rammeloo, J. A.; Tillemans, A. A.

    1989-01-01

    We report on two male and two female relatives with intestinal lymphangiectasia; severe lymphedema of limbs, genitalia, and face; facial anomalies; seizures; mild growth retardation; and moderate mental retardation. Main facial anomalies are a flat face, flat nasal bridge, hypertelorism, small

  4. A novel mutation in the EDAR gene causes severe autosomal recessive hypohidrotic ectodermal dysplasia.

    Science.gov (United States)

    Henningsen, Emil; Svendsen, Mathias Tiedemann; Lildballe, Dorte Launholt; Jensen, Peter Kjestrup Axel

    2014-08-01

    We report on a 2-year-old girl presenting with a severe form of hypohidrotic ectodermal dysplasia (HED). The patient presented with hypotrichosis, anodontia, hypohidrosis, frontal bossing, prominent lips and ears, dry, pale skin, and dermatitis. The patient had chronic rhinitis with malodorous nasal discharge. The girl was the second born child of first-cousin immigrants from Northern Iraq. A novel homozygous mutation (c.84delC) in the EDAR gene was identified. This mutation most likely causes a frameshift in the protein product (p.S29fs*74). This results in abolition of all ectodysplasin-mediated NF-kB signalling. This complete loss-of-function mutation likely accounts for the severe clinical abnormalities in ectodermal structures in the described patient. © 2014 Wiley Periodicals, Inc.

  5. A Novel Mutation in the EDAR Gene Causes Severe Autosomal Recessive Hypohidrotic Ectodermal Dysplasia

    DEFF Research Database (Denmark)

    Henningsen, Emil; Svendsen, Mathias Tiedemann; Lildballe, D. L.

    2014-01-01

    We report on a 2-year-old girl presenting with a severe form of hypohidrotic ectodermal dysplasia (HED). The patient presented with hypotrichosis, anodontia, hypohidrosis, frontal bossing, prominent lips and ears, dry, pale skin, and dermatitis. The patient had chronic rhinitis with malodorous......-mediated NF-kB signalling. This complete loss-of-function mutation likely accounts for the severe clinical abnormalities in ectodermal structures in the described patient. (C) 2014 Wiley Periodicals, Inc....

  6. Genetics Home Reference: cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy

    Science.gov (United States)

    ... Miyashita A, Yokoseki A, Kawata H, Koyama A, Arima K, Takahashi T, Ikeda M, Shiota H, Tamura ... Oide T, Nakayama H, Yanagawa S, Ito N, Ikeda S, Arima K. Extensive loss of arterial medial smooth muscle ...

  7. Mutations in c10orf11, a melanocyte-differentiation gene, cause autosomal-recessive albinism

    DEFF Research Database (Denmark)

    Grønskov, Karen; Dooley, Christopher M; Østergaard, Elsebet

    2013-01-01

    in an individual originating from Lithuania. Immunohistochemistry showed localization of C10orf11 in melanoblasts and melanocytes in human fetal tissue, but no localization was seen in retinal pigment epithelial cells. Knockdown of the zebrafish (Danio rerio) homolog with the use of morpholinos resulted...

  8. Spectrum of ABCA4 (ABCR) gene mutations in Spanish patients with autosomal recessive macular dystrophies.

    Science.gov (United States)

    Paloma, E; Martínez-Mir, A; Vilageliu, L; Gonzàlez-Duarte, R; Balcells, S

    2001-06-01

    The ABCA4 gene has been involved in several forms of inherited macular dystrophy. In order to further characterize the complex genotype-phenotype relationships involving this gene, we have performed a mutation analysis of ABCA4 in 14 Spanish patients comprising eight STGD (Stargardt), four FFM (fundus flavimaculatus), and two CRD (Cone-rod dystrophy) patients. SSCP (single-strand conformation polymorphism) analysis and DNA sequencing of the coding and 5' upstream regions of this gene allowed the identification of 16 putatively pathogenic alterations, nine of which are novel. Most of these were missense changes, and no patient was found to carry two null alleles. Overall, the new data agree with a working model relating the different pathogenic phenotypes to the severity of the mutations. When considering the information presented here together with that of previous reports, a picture of the geographic distribution of three particular mutations emerges. The R212C change has been found in French, Italian, Dutch, German, and Spanish but not in British patients. In the Spanish collection, R212C was found in a CRD patient, indicating that it may be a rather severe change. In contrast, c.2588G>C, a very common mild allele in the Dutch population, is rarely found in Southern Europe. Interestingly, the c.2588G>C mutation has been found in a double mutant allele together with the missense R1055W. Finally, the newly described L1940P was found in two unrelated Spanish patients, and may be a moderate to severe allele. Copyright 2001 Wiley-Liss, Inc.

  9. Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis (ARPKD/CHF)

    Energy Technology Data Exchange (ETDEWEB)

    Turkbey, Baris; Choyke, Peter L. [National Institutes of Health, Molecular Imaging Program, National Cancer Institute, Bethesda, MD (United States); Ocak, Iclal [National Institutes of Health, Molecular Imaging Program, National Cancer Institute, Bethesda, MD (United States); University of Pittsburgh Medical Center, Department of Radiology, Pittsburgh, PA (United States); Daryanani, Kailash [National Institutes of Health, Clinical Center, Department of Radiology, Bethesda, MD (United States); Font-Montgomery, Esperanza; Lukose, Linda; Bryant, Joy; Tuchman, Maya; Gahl, William A. [National Institutes of Health, National Human Genome Research Institute, Medical Genetics Branch, Bethesda, MD (United States); Mohan, Parvathi [George Washington University, Department of Pediatric Gastroenterology, Washington, DC (United States); Heller, Theo [National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD (United States); Gunay-Aygun, Meral [National Institutes of Health, National Human Genome Research Institute, Medical Genetics Branch, Bethesda, MD (United States); National Institutes of Health, Intramural Program, Office of Rare Diseases, Office of the Directors, Bethesda, MD (United States)

    2009-02-15

    ARPKD/CHF is an inherited disease characterized by non-obstructive fusiform dilatation of the renal collecting ducts leading to enlarged spongiform kidneys and ductal plate malformation of the liver resulting in congenital hepatic fibrosis. ARPKD/CHF has a broad spectrum of clinical presentations involving the kidney and liver. Imaging plays an important role in the diagnosis and follow-up of ARPKD/CHF. Combined use of conventional and high-resolution US with MR cholangiography in ARPKD/CHF patients allows detailed definition of the extent of kidney and hepatobiliary manifestations without requiring ionizing radiation and contrast agents. (orig.)

  10. Spectrum of mutations in the renin-angiotensin system genes in autosomal recessive renal tubular dysgenesis

    DEFF Research Database (Denmark)

    Gribouval, Olivier; Morinière, Vincent; Pawtowski, Audrey

    2012-01-01

    , pulmonary hypoplasia, and refractory arterial hypotension. The disease is linked to mutations in the genes encoding several components of the renin-angiotensin system (RAS): AGT (angiotensinogen), REN (renin), ACE (angiotensin-converting enzyme), and AGTR1 (angiotensin II receptor type 1). Here, we review...... the series of 54 distinct mutations identified in 48 unrelated families. Most of them are novel and ACE mutations are the most frequent, observed in two-thirds of families (64.6%). The severity of the clinical course was similar whatever the mutated gene, which underlines the importance of a functional RAS...

  11. Macrocephaly, epilepsy, autism, dysmorphic features, and mental retardation in two sisters: a new autosomal recessive syndrome?

    OpenAIRE

    Orstavik, K H; Strømme, P; Ek, J; Torvik, A; Skjeldal, O H

    1997-01-01

    We report two sisters with macrocephaly, epilepsy, and severe mental retardation. The first child was a 14 year old girl born at term after a normal pregnancy, with birth weight 3600 g and occipitofrontal circumference (OFC) 36 cm (75th centile). Her head size increased markedly during the first six months of life, and was later stable at 2-3 cm above the 97.5th centile. Her development was characterised by psychomotor delay, epilepsy, and autistic features. Her face appeared mildly dysmorphi...

  12. Apparent digenic inheritance of Waardenburg syndrome type 2 (WS2) and autosomal recessive ocular albinism (AROA).

    Science.gov (United States)

    Morell, R; Spritz, R A; Ho, L; Pierpont, J; Guo, W; Friedman, T B; Asher, J H

    1997-05-01

    Waardenburg syndrome (WS) is a clinically and genetically heterogeneous disease accounting for >2% of the congenitally deaf population. It is characterized by deafness in association with pigmentary anomalies and various defects of neural crest-derived tissues. At least four types are recognized (WS1, WS2, WS3 and WS4) on the basis of clinical and genetic criteria. Two previously described families seemed to delineate a new subtype characterized by WS2 in conjunction with ocular albinism (OA). Since mutations in the MITF gene are responsible for some instances of WS2, we screened for mutations in one of the WS2-OA families and discovered a 1 bp deletion in exon 8 of MITF. OA previously has been associated with compound heterozygosity for a mutant TYR allele and the TYR(R402Q) allele, a functionally significant polymorphism that is associated with moderately reduced tyrosinase catalytic activity. In this family, all of the individuals with the OA phenotype are either homozygous or heterozygous for TYR(R402Q), and heterozyous for the 1 bp deletion in MITF This suggests that the WS2-OA phenotype may result from digenic interaction between a gene for a transcription factor (MITF) and a gene that it regulates (TYR).

  13. CLPB Variants Associated with Autosomal-Recessive Mitochondrial Disorder with Cataract, Neutropenia, Epilepsy, and Methylglutaconic Aciduria

    DEFF Research Database (Denmark)

    Saunders, Carol; Smith, Laurie; Wibrand, Flemming

    2015-01-01

    of type IV 3-MGA-uria characterized by cataracts, severe psychomotor regression during febrile episodes, epilepsy, neutropenia with frequent infections, and death in early childhood. Four of the individuals were of Greenlandic descent, and one was North American, of Northern European and Asian descent...

  14. Missense variants in AIMP1 gene are implicated in autosomal recessive intellectual disability without neurodegeneration

    NARCIS (Netherlands)

    Iqbal, Z.; Puttmann, L.; Musante, L.; Razzaq, A.; Zahoor, M.Y.; Hu, H; Wienker, T.F.; Garshasbi, M.; Fattahi, Z.; Gilissen, C.; Vissers, L.E.; Brouwer, A.P. de; Veltman, J.A.; Pfundt, R.P.; Najmabadi, H.; Ropers, H.H.; Riazuddin, S.; Kahrizi, K.; Bokhoven, H. van

    2016-01-01

    AIMP1/p43 is a multifunctional non-catalytic component of the multisynthetase complex. The complex consists of nine catalytic and three non-catalytic proteins, which catalyze the ligation of amino acids to their cognate tRNA isoacceptors for use in protein translation. To date, two allelic variants

  15. KIF16B is a candidate gene for a novel autosomal-recessive intellectual disability syndrome.

    Science.gov (United States)

    Alsahli, Saud; Arold, Stefan T; Alfares, Ahmed; Alhaddad, Bader; Al Balwi, Mohammed; Kamsteeg, Erik-Jan; Al-Twaijri, Waleed; Alfadhel, Majid

    2018-05-07

    Intellectual disability (ID) and global developmental delay are closely related; the latter is reserved for children under the age of 5 years as it is challenging to reliably assess clinical severity in this population. ID is a common condition, with up to 1%-3% of the population being affected and leading to a huge social and economic impact. ID is attributed to genetic abnormalities most of the time; however, the exact role of genetic involvement in ID is yet to be determined. Whole exome sequencing (WES) has gained popularity in the workup for ID, and multiple studies have been published examining the diagnostic yield in identification of the disease-causing variant (16%-55%), with the genetic involvement increasing as intelligence quotient decreases. WES has also accelerated novel disease gene discovery in this field. We identified a novel biallelic variant in the KIF16B gene (NM_024704.4:c.3611T > G) in two brothers that may be the cause of their phenotype. © 2018 Wiley Periodicals, Inc.

  16. Autosomal recessive congenital cataract in captive-bred vervet monkeys (Chlorocebus aethiops).

    Science.gov (United States)

    Magwebu, Zandisiwe E; Abdul-Rasool, Sahar; Seier, Jürgen V; Chauke, Chesa G

    2018-04-01

    The aim of the study was to evaluate the genetic predisposition of congenital cataract in a colony of captive-bred vervet monkeys. Four congenital cataract genes: glucosaminyl (N-acetyl) transferase 2 (GCNT2), heat shock transcription factor 4 (HSF4), crystallin alpha A (CRYAA) and lens intrinsic membrane protein-2 (LIM2) were screened, sequenced and analysed for possible genetic variants in 36 monkeys. Gene expression was also evaluated in these genes. Fifteen sequence variants were identified in the coding regions of three genes (GCNT2, HSF4 and CRYAA). Of these variations, only three were missense mutations (M258V, V16I and S24N) and identified in the GCNT2 transcripts A, B and C, respectively, which resulted in a downregulated gene expression. Although the three missense mutations in GCNT2 have a benign effect, a possibility exists that the candidate genes (GCNT2, HSF4 and CRYAA) might harbour mutations that are responsible for total congenital cataract. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. Mutations in SNX14 cause a distinctive autosomal-recessive cerebellar ataxia and intellectual disability syndrome

    NARCIS (Netherlands)

    Thomas, Anna C.; Williams, Hywel; Setó-Salvia, Núria; Bacchelli, Chiara; Jenkins, Dagan; O'Sullivan, Mary; Mengrelis, Konstantinos; Ishida, Miho; Ocaka, Louise; Chanudet, Estelle; James, Chela; Lescai, Francesco; Anderson, Glenn; Morrogh, Deborah; Ryten, Mina; Duncan, Andrew J.; Pai, Yun Jin; Saraiva, Jorge M.; Ramos, Fabiana; Farren, Bernadette; Saunders, Dawn; Vernay, Bertrand; Gissen, Paul; Straatmaan-Iwanowska, Anna; Baas, Frank; Wood, Nicholas W.; Hersheson, Joshua; Houlden, Henry; Hurst, Jane; Scott, Richard; Bitner-Glindzicz, Maria; Moore, Gudrun E.; Sousa, Sérgio B.; Stanier, Philip

    2014-01-01

    Intellectual disability and cerebellar atrophy occur together in a large number of genetic conditions and are frequently associated with microcephaly and/or epilepsy. Here we report the identification of causal mutations in Sorting Nexin 14 (SNX14) found in seven affected individuals from three

  18. ITGB6 loss-of-function mutations cause autosomal recessive amelogenesis imperfecta.

    Science.gov (United States)

    Wang, Shih-Kai; Choi, Murim; Richardson, Amelia S; Reid, Bryan M; Lin, Brent P; Wang, Susan J; Kim, Jung-Wook; Simmer, James P; Hu, Jan C-C

    2014-04-15

    Integrins are cell-surface adhesion receptors that bind to extracellular matrices (ECM) and mediate cell-ECM interactions. Some integrins are known to play critical roles in dental enamel formation. We recruited two Hispanic families with generalized hypoplastic amelogenesis imperfecta (AI). Analysis of whole-exome sequences identified three integrin beta 6 (ITGB6) mutations responsible for their enamel malformations. The female proband of Family 1 was a compound heterozygote with an ITGB6 transition mutation in Exon 4 (g.4545G > A c.427G > A p.Ala143Thr) and an ITGB6 transversion mutation in Exon 6 (g.27415T > A c.825T > A p.His275Gln). The male proband of Family 2 was homozygous for an ITGB6 transition mutation in Exon 11 (g.73664C > T c.1846C > T p.Arg616*) and hemizygous for a transition mutation in Exon 6 of Nance-Horan Syndrome (NHS Xp22.13; g.355444T > C c.1697T > C p.Met566Thr). These are the first disease-causing ITGB6 mutations to be reported. Immunohistochemistry of mouse mandibular incisors localized ITGB6 to the distal membrane of differentiating ameloblasts and pre-ameloblasts, and then ITGB6 appeared to be internalized by secretory stage ameloblasts. ITGB6 expression was strongest in the maturation stage and its localization was associated with ameloblast modulation. Our findings demonstrate that early and late amelogenesis depend upon cell-matrix interactions. Our approach (from knockout mouse phenotype to human disease) demonstrates the power of mouse reverse genetics in mutational analysis of human genetic disorders and attests to the need for a careful dental phenotyping in large-scale knockout mouse projects.

  19. Hematologically important mutations: The autosomal recessive forms of chronic granulomatous disease (second update)

    NARCIS (Netherlands)

    Roos, Dirk; Kuhns, Douglas B.; Maddalena, Anne; Bustamante, Jacinta; Kannengiesser, Caroline; de Boer, Martin; van Leeuwen, Karin; Köker, M. Yavuz; Wolach, Baruch; Roesler, Joachim; Malech, Harry L.; Holland, Steven M.; Gallin, John I.; Stasia, Marie-José

    2010-01-01

    Chronic granulomatous Disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. The disease is caused by mutations in the genes encoding the components of the leukocyte NADPH oxidase. This enzyme produces superoxide, which is essential in the process of intracellular

  20. The impact of genome editing on the introduction of monogenic traits in livestock.

    Science.gov (United States)

    Bastiaansen, John W M; Bovenhuis, Henk; Groenen, Martien A M; Megens, Hendrik-Jan; Mulder, Han A

    2018-04-16

    Genome editing technologies provide new tools for genetic improvement and have the potential to become the next game changer in animal and plant breeding. The aim of this study was to investigate how genome editing in combination with genomic selection can accelerate the introduction of a monogenic trait in a livestock population as compared to genomic selection alone. A breeding population was simulated under genomic selection for a polygenic trait. After reaching Bulmer equilibrium, the selection objective was to increase the allele frequency of a monogenic trait, with or without genome editing, in addition to improving the polygenic trait. Scenarios were compared for time to fixation of the desired allele, selection response for the polygenic trait, and level of inbreeding. The costs, in terms of number of editing procedures, were compared to the benefits of having more animals with the desired phenotype of the monogenic trait. Effects of reduced editing efficiency were investigated. In a population of 20,000 selection candidates per generation, the total number of edited zygotes needed to reach fixation of the desired allele was 22,118, 7072, or 3912 with, no, moderate, or high selection emphasis on the monogenic trait, respectively. Genome editing resulted in up to four-fold faster fixation of the desired allele when efficiency was 100%, while the loss in long-term selection response for the polygenic trait was up to seven-fold less compared to genomic selection alone. With moderate selection emphasis on the monogenic trait, introduction of genome editing led to a four-fold reduction in the total number of animals showing the undesired phenotype before fixation. However, with a currently realistic editing efficiency of 4%, the number of required editing procedures increased by 72% and loss in selection response increased eight-fold compared to 100% efficiency. With low efficiency, loss in selection response was 29% more compared to genomic selection alone

  1. The Great Recession: a comparison of recession magnitudes in Europe, USA and Japan

    OpenAIRE

    Mazurek, Jiří

    2013-01-01

    In this article recession magnitudes in Europe, the USA and Japan during the Great Recession are compared. The strongest recessions (of severe category) occurred in Latvia, Lithuania and Estonia, while recessions in Japan and the USA were significantly weaker. Even the strongest recession (in Latvia) was found smaller in its magnitude than the Great Depression 1929-1933 in the USA. Hence, comparisons of the Great Recession to the Great Depression in the literature are somewhat exaggerated.

  2. EDAR mutation in autosomal dominant hypohidrotic ectodermal dysplasia in two Swedish families

    Directory of Open Access Journals (Sweden)

    Schmitt-Egenolf Marcus

    2006-11-01

    Full Text Available Abstract Background Hypohidrotic ectodermal dysplasia (HED is a genetic disorder characterized by defective development of teeth, hair, nails and eccrine sweat glands. Both autosomal dominant and autosomal recessive forms of HED have previously been linked to mutations in the ectodysplasin 1 anhidrotic receptor (EDAR protein that plays an important role during embryogenesis. Methods The coding DNA sequence of the EDAR gene was analyzed in two large Swedish three-generational families with autosomal dominant HED. Results A non-sense C to T mutation in exon 12 was identified in both families. This disease-specific mutation changes an arginine amino acid in position 358 of the EDAR protein into a stop codon (p.Arg358X, thereby truncating the protein. In addition to the causative mutation two polymorphisms, not associated with the HED disorder, were also found in the EDAR gene. Conclusion The finding of the p.Arg358X mutation in the Swedish families is the first corroboration of a previously described observation in an American family. Thus, our study strengthens the role of this particular mutation in the aetiology of autosomal dominant HED and confirms the importance of EDAR for the development of HED.

  3. [Clinical and molecular study in a family with autosomal dominant hypohidrotic ectodermal dysplasia].

    Science.gov (United States)

    Callea, Michele; Cammarata-Scalisi, Francisco; Willoughby, Colin E; Giglio, Sabrina R; Sani, Ilaria; Bargiacchi, Sara; Traficante, Giovanna; Bellacchio, Emanuele; Tadini, Gianluca; Yavuz, Izzet; Galeotti, Angela; Clarich, Gabriella

    2017-02-01

    Hypohidrotic ectodermal dysplasia (HED) is a rare disease characterized by deficiency in development of structure derived from the ectoderm and is caused by mutations in the genes EDA, EDAR, or EDARADD. Phenotypes caused by mutations in these three may exhibit similar clinical features, explained by a common signaling pathway. Mutations in EDA gene cause X linked HED, which is the most common form. Mutations in EDAR and EDARADD genes cause autosomal dominant and recessive form of HED. The most striking clinical findings in HED are hypodontia, hypotrichosis and hypohidrosis that can lead to episodes of hyperthermia. We report on clinical findings in a child with HED with autosomal dominant inheritance pattern with a heterozygous mutation c.1072C>T (p.Arg358X) in the EDAR gene. A review of the literature with regard to other cases presenting the same mutation has been carried out and discussed. Sociedad Argentina de Pediatría.

  4. Autosomal male determination in a spinosad-resistant housefly strain from Denmark

    DEFF Research Database (Denmark)

    Højland, Dorte H; Scott, Jeffrey G; Vagn Jensen, Karl-Martin

    2014-01-01

    males in this strain. The factor responsible for spinosad resistance in the strain is unknown, but previous studies suggest a role of cytochrome P450s for detoxification of spinosad. Sex determination in the housefly is controlled by a male-determining factor (M), either located on the Y chromosome......BACKGROUND The housefly, Musca domestica L., is a global pest and has developed resistance to most insecticides applied for its control. The insecticide spinosad plays an important role in housefly control. Females of the Danish housefly strain 791spin are threefold more resistant to spinosad than...... of resistance to spinosad. Sex determination in 791spin is due to a male factor on autosome 3. CONCLUSIONS The most likely explanation for the differentiation of spinosad resistance between males and females is a recessive spinosad resistance factor on autosome III. © 2013 Society of Chemical Industry...

  5. Autosomal-dominant Leber Congenital Amaurosis Caused by a Heterozygous CRX Mutation in a Father and Son.

    Science.gov (United States)

    Arcot Sadagopan, Karthikeyan; Battista, Robert; Keep, Rosanne B; Capasso, Jenina E; Levin, Alex V

    2015-06-01

    Leber congenital amaurosis (LCA) is most often an autosomal recessive disorder. We report a father and son with autosomal dominant LCA due to a mutation in the CRX gene. DNA screening using an allele specific assay of 90 of the most common LCA-causing variations in the coding sequences of AIPL1, CEP290, CRB1, CRX, GUCY2D, RDH12 and RPE65 was performed on the father. Automated DNA sequencing of his son examining exon 3 of the CRX gene was subsequently performed. Both father and son have a heterozygous single base pair deletion of an adenine at codon 153 in the coding sequence of the CRX gene resulting in a frameshift mutation. Mutations involving the CRX gene may demonstrate an autosomal dominant inheritance pattern for LCA.

  6. Analysis of the predetermining effect of a sex realizer by ovary transplantations in the monogenic flyChrysomya rufifacies.

    Science.gov (United States)

    Ullerich, Fritz-Helmut

    1980-02-01

    In the heterozygousF'/f female-producing females of the strictly monogenic blowflyChrysomya rufifacies the gene product of the dominant or epistatic female sex realizerF' which causes sexpredetermination is thought to be synthesized either by cells of the germ line (oocytes, nurse cells or oogonia) or by somatic cells and then transferred into the oocytes. To determine the possible site of synthesis, reciprocal transplantations were made of prepupal ovaries between female-producing (thelygenic; t) and male-producing (arrhenogenic; a) females ofChrysomya rufifacies. In another series of experiments prepupal host females of the wild t-type and a-type were each provided with one additional ovary either from a0type (f/f) or a t-type (F'/f) prepupa (neither were distinguishable by their phenotypes). In all these experiments the donor females were marked by the recessive sex-linked mutation 'white' (w/w); white eyes, white Malpighian tubules). In a considerable number of cases the implanted ovaries were in contact with the host's own oviduct and grew normally, but the rate of hatched adults was somewhat reduced. Crosses between such host females andw/w males (f/f) produced female or male offspring with white eyes from the eggs of the implantedw/w ovary, as well as flies with wild-type eyes (+/w) which had developed in the host's own ovaries. In all cases so far examined, the genetically thelygenic (or arrhenogenic) host females with an additional ovary implanted from an arrhenogenic (thelygenic) donor, produced progeny of both sexes: sons (daughters) from the eggs of the donor's ovary and daugthers (sons) from the eggs of the host's own gonads.These results demonstrate that the ovaries of the t-females ofChrysomya rufifacies at least from the early prepupal stage, are autonomous for the product of theF' gene. Transplantations of the premordial germ cells (pole cells) are planned to find out whether the predeterminingF' gene product is synthesized before the prepupal

  7. Algebra, Home Mortgages, and Recessions

    Science.gov (United States)

    Mariner, Jean A. Miller; Miller, Richard A.

    2009-01-01

    The current financial crisis and recession in the United States present an opportunity to discuss relevant applications of some topics in typical first-and second-year algebra and precalculus courses. Real-world applications of percent change, exponential functions, and sums of finite geometric sequences can help students understand the problems…

  8. Autosomal dominant inheritance of Weaver syndrome.

    OpenAIRE

    Fryer, A; Smith, C; Rosenbloom, L; Cole, T

    1997-01-01

    Most report of Weaver syndrome have been sporadic cases and the genetic basis of the syndrome is uncertain. This report of an affected father and daughter provides evidence for autosomal dominant inheritance.

  9. Genetics Home Reference: autosomal dominant hypocalcemia

    Science.gov (United States)

    ... individuals have features of a kidney disorder called Bartter syndrome in addition to hypocalcemia. These features can include ... sometimes referred to as autosomal dominant hypocalcemia with Bartter syndrome or Bartter syndrome type V. There are two ...

  10. Missense Mutations in CRYAB Are Liable for Recessive Congenital Cataracts.

    Directory of Open Access Journals (Sweden)

    Xiaodong Jiao

    Full Text Available This study was initiated to identify causal mutations responsible for autosomal recessive congenital cataracts in consanguineous familial cases.Affected individuals underwent a detailed ophthalmological and clinical examination, and slit-lamp photographs were ascertained for affected individuals who have not yet been operated for the removal of the cataractous lens. Blood samples were obtained, and genomic DNA was extracted from white blood cells. A genome-wide scan was completed with short tandem repeat (STR markers, and the logarithm of odds (LOD scores were calculated. Protein coding exons of CRYAB were sequenced, bi-directionally. Evolutionary conservation was investigated by aligning CRYAB orthologues, and the expression of Cryab in embryonic and postnatal mice lens was investigated with TaqMan probe.The clinical and ophthalmological examinations suggested that all affected individuals had nuclear cataracts. Genome-wide linkage analysis suggested a potential region on chromosome 11q23 harboring CRYAB. DNA sequencing identified a missense variation: c.34C>T (p.R12C in CRYAB that segregated with the disease phenotype in the family. Subsequent interrogation of our entire cohort of familial cases identified a second familial case localized to chromosome 11q23 harboring a c.31C>T (p.R11C mutation. In silico analyses suggested that the mutations identified in familial cases, p.R11C and p.R12C will not be tolerated by the three-dimensional structure of CRYAB. Real-time PCR analysis identified the expression of Cryab in mouse lens as early as embryonic day 15 (E15 that increased significantly until postnatal day 6 (P6 with steady level of expression thereafter.Here, we report two novel missense mutations, p.R11C and p.R12C, in CRYAB associated with autosomal recessive congenital nuclear cataracts.

  11. Recessed floating pier caps for highway bridges.

    Science.gov (United States)

    1973-01-01

    Presented are alternate designs for two existing bridges in Virginia - one with steel beams and the other with prestressed concrete beams - whereby the pier caps are recessed within the depth of the longitudinal beams. The purpose of this recession i...

  12. Assessing the putative roles of X-autosome and X-Y interactions in hybrid male sterility of the Drosophila bipectinata species complex.

    Science.gov (United States)

    Mishra, Paras Kumar; Singh, Bashisth Narayan

    2007-07-01

    Interspecific F1 hybrid males of the Drosophila bipectinata species complex are sterile, while females are fertile, following Haldane's rule. A backcross scheme involving a single recessive visible marker on the X chromosome has been used to assess the putative roles of X-autosome and X-Y interactions in hybrid male sterility in the D. bipectinata species complex. The results suggest that X-Y interactions are playing the major role in hybrid male sterility in the crosses D. bipectinata x D. parabipectinata and D. bipectinata x D. pseudoananassae, while X-autosome interactions are largely involved in hybrid male sterility in the crosses D. malerkotliana x D. bipectinata and D. malerkotliana x D. parabipectinata. However, by using this single marker it is not possible to rule out the involvement of autosome-autosome interactions in hybrid male sterility. These findings also lend further support to the phylogenetic relationships among 4 species of the D. bipectinata complex.

  13. Differences in Physical Activity during School Recess

    Science.gov (United States)

    Ridgers, Nicola D.; Saint-Maurice, Pedro F.; Welk, Gregory J.; Siahpush, Mohammad; Huberty, Jennifer

    2011-01-01

    Background: School recess provides a daily opportunity for physical activity engagement. The purpose of this study was to examine physical activity levels during recess by gender, ethnicity, and grade, and establish the contribution of recess to daily school physical activity levels. Methods: Two hundred and ten children (45% boys) from grades 3…

  14. Monogenic diabetes in children and young adults: Challenges for researcher, clinician and patient

    Science.gov (United States)

    2006-01-01

    Monogenic diabetes results from one or more mutations in a single gene which might hence be rare but has great impact leading to diabetes at a very young age. It has resulted in great challenges for researchers elucidating the aetiology of diabetes and related features in other organ systems, for clinicians specifying a diagnosis that leads to improved genetic counselling, predicting of clinical course and changes in treatment, and for patients to altered treatment that has lead to coming off insulin and injections with no alternative (Glucokinase mutations), insulin injections being replaced by tablets (e.g. low dose in HNFα or high dose in potassium channel defects -Kir6.2 and SUR1) or with tablets in addition to insulin (e.g. metformin in insulin resistant syndromes). Genetic testing requires guidance to test for what gene especially given limited resources. Monogenic diabetes should be considered in any diabetic patient who has features inconsistent with their current diagnosis (unspecified neonatal diabetes, type 1 or type 2 diabetes) and clinical features of a specific subtype of monogenic diabetes (neonatal diabetes, familial diabetes, mild hyperglycaemia, syndromes). Guidance is given by clinical and physiological features in patient and family and the likelihood of the proposed mutation altering clinical care. In this article, I aimed to provide insight in the genes and mutations involved in insulin synthesis, secretion, and resistance, and to provide guidance for genetic testing by showing the clinical and physiological features and tests for each specified diagnosis as well as the opportunities for treatment. PMID:17186387

  15. What Is the Best NGS Enrichment Method for the Molecular Diagnosis of Monogenic Diabetes and Obesity?

    Directory of Open Access Journals (Sweden)

    Julien Philippe

    Full Text Available Molecular diagnosis of monogenic diabetes and obesity is of paramount importance for both the patient and society, as it can result in personalized medicine associated with a better life and it eventually saves health care spending. Genetic clinical laboratories are currently switching from Sanger sequencing to next-generation sequencing (NGS approaches but choosing the optimal protocols is not easy. Here, we compared the sequencing coverage of 43 genes involved in monogenic forms of diabetes and obesity, and variant detection rates, resulting from four enrichment methods based on the sonication of DNA (Agilent SureSelect, RainDance technologies, or using enzymes for DNA fragmentation (Illumina Nextera, Agilent HaloPlex. We analyzed coding exons and untranslated regions of the 43 genes involved in monogenic diabetes and obesity. We found that none of the methods achieves yet full sequencing of the gene targets. Nonetheless, the RainDance, SureSelect and HaloPlex enrichment methods led to the best sequencing coverage of the targets; while the Nextera method resulted in the poorest sequencing coverage. Although the sequencing coverage was high, we unexpectedly found that the HaloPlex method missed 20% of variants detected by the three other methods and Nextera missed 10%. The question of which NGS technique for genetic diagnosis yields the highest diagnosis rate is frequently discussed in the literature and the response is still unclear. Here, we showed that the RainDance enrichment method as well as SureSelect, which are both based on the sonication of DNA, resulted in a good sequencing quality and variant detection, while the use of enzymes to fragment DNA (HaloPlex or Nextera might not be the best strategy to get an accurate sequencing.

  16. Monogenic Diabetes: What It Teaches Us on the Common Forms of Type 1 and Type 2 Diabetes

    Science.gov (United States)

    2016-01-01

    To date, more than 30 genes have been linked to monogenic diabetes. Candidate gene and genome-wide association studies have identified > 50 susceptibility loci for common type 1 diabetes (T1D) and approximately 100 susceptibility loci for type 2 diabetes (T2D). About 1–5% of all cases of diabetes result from single-gene mutations and are called monogenic diabetes. Here, we review the pathophysiological basis of the role of monogenic diabetes genes that have also been found to be associated with common T1D and/or T2D. Variants of approximately one-third of monogenic diabetes genes are associated with T2D, but not T1D. Two of the T2D-associated monogenic diabetes genes—potassium inward-rectifying channel, subfamily J, member 11 (KCNJ11), which controls glucose-stimulated insulin secretion in the β-cell; and peroxisome proliferator-activated receptor γ (PPARG), which impacts multiple tissue targets in relation to inflammation and insulin sensitivity—have been developed as major antidiabetic drug targets. Another monogenic diabetes gene, the preproinsulin gene (INS), is unique in that INS mutations can cause hyperinsulinemia, hyperproinsulinemia, neonatal diabetes mellitus, one type of maturity-onset diabetes of the young (MODY10), and autoantibody-negative T1D. Dominant heterozygous INS mutations are the second most common cause of permanent neonatal diabetes. Moreover, INS gene variants are strongly associated with common T1D (type 1a), but inconsistently with T2D. Variants of the monogenic diabetes gene Gli-similar 3 (GLIS3) are associated with both T1D and T2D. GLIS3 is a key transcription factor in insulin production and β-cell differentiation during embryonic development, which perturbation forms the basis of monogenic diabetes as well as its association with T1D. GLIS3 is also required for compensatory β-cell proliferation in adults; impairment of this function predisposes to T2D. Thus, monogenic forms of diabetes are invaluable “human models” that

  17. A Comparison of Selective Pressures in Plant X-Linked and Autosomal Genes.

    Science.gov (United States)

    Krasovec, Marc; Nevado, Bruno; Filatov, Dmitry A

    2018-05-03

    Selection is expected to work differently in autosomal and X-linked genes because of their ploidy difference and the exposure of recessive X-linked mutations to haploid selection in males. However, it is not clear whether these expectations apply to recently evolved sex chromosomes, where many genes retain functional X- and Y-linked gametologs. We took advantage of the recently evolved sex chromosomes in the plant Silene latifolia and its closely related species to compare the selective pressures between hemizygous and non-hemizygous X-linked genes as well as between X-linked genes and autosomal genes. Our analysis, based on over 1000 genes, demonstrated that, similar to animals, X-linked genes in Silene evolve significantly faster than autosomal genes—the so-called faster-X effect. Contrary to expectations, faster-X divergence was detectable only for non-hemizygous X-linked genes. Our phylogeny-based analyses of selection revealed no evidence for faster adaptation in X-linked genes compared to autosomal genes. On the other hand, partial relaxation of purifying selection was apparent on the X-chromosome compared to the autosomes, consistent with a smaller genetic diversity in S. latifolia X-linked genes (π x = 0.016; π aut = 0.023). Thus, the faster-X divergence in S. latifolia appears to be a consequence of the smaller effective population size rather than of a faster adaptive evolution on the X-chromosome. We argue that this may be a general feature of “young” sex chromosomes, where the majority of X-linked genes are not hemizygous, preventing haploid selection in heterogametic sex.

  18. Intrusion detection on oil pipeline right of way using monogenic signal representation

    Science.gov (United States)

    Nair, Binu M.; Santhaseelan, Varun; Cui, Chen; Asari, Vijayan K.

    2013-05-01

    We present an object detection algorithm to automatically detect and identify possible intrusions such as construction vehicles and equipment on the regions designated as the pipeline right-of-way (ROW) from high resolution aerial imagery. The pipeline industry has buried millions of miles of oil pipelines throughout the country and these regions are under constant threat of unauthorized construction activities. We propose a multi-stage framework which uses a pyramidal template matching scheme in the local phase domain by taking a single high resolution training image to classify a construction vehicle. The proposed detection algorithm makes use of the monogenic signal representation to extract the local phase information. Computing the monogenic signal from a two dimensional object region enables us to separate out the local phase information (structural details) from the local energy (contrast) thereby achieving illumination invariance. The first stage involves the local phase based template matching using only a single high resolution training image in a local region at multiple scales. Then, using the local phase histogram matching, the orientation of the detected region is determined and a voting scheme gives a certain weightage to the resulting clusters. The final stage involves the selection of clusters based on the number of votes attained and using the histogram of oriented phase feature descriptor, the object is located at the correct orientation and scale. The algorithm is successfully tested on four different datasets containing imagery with varying image resolution and object orientation.

  19. Severe infectious diseases of childhood as monogenic inborn errors of immunity

    Science.gov (United States)

    Casanova, Jean-Laurent

    2015-01-01

    This paper reviews the developments that have occurred in the field of human genetics of infectious diseases from the second half of the 20th century onward. In particular, it stresses and explains the importance of the recently described monogenic inborn errors of immunity underlying resistance or susceptibility to specific infections. The monogenic component of the genetic theory provides a plausible explanation for the occurrence of severe infectious diseases during primary infection. Over the last 20 y, increasing numbers of life-threatening infectious diseases striking otherwise healthy children, adolescents, and even young adults have been attributed to single-gene inborn errors of immunity. These studies were inspired by seminal but neglected findings in plant and animal infections. Infectious diseases typically manifest as sporadic traits because human genotypes often display incomplete penetrance (most genetically predisposed individuals remain healthy) and variable expressivity (different infections can be allelic at the same locus). Infectious diseases of childhood, once thought to be archetypal environmental diseases, actually may be among the most genetically determined conditions of mankind. This nascent and testable notion has interesting medical and biological implications. PMID:26621750

  20. Severe infectious diseases of childhood as monogenic inborn errors of immunity.

    Science.gov (United States)

    Casanova, Jean-Laurent

    2015-12-22

    This paper reviews the developments that have occurred in the field of human genetics of infectious diseases from the second half of the 20th century onward. In particular, it stresses and explains the importance of the recently described monogenic inborn errors of immunity underlying resistance or susceptibility to specific infections. The monogenic component of the genetic theory provides a plausible explanation for the occurrence of severe infectious diseases during primary infection. Over the last 20 y, increasing numbers of life-threatening infectious diseases striking otherwise healthy children, adolescents, and even young adults have been attributed to single-gene inborn errors of immunity. These studies were inspired by seminal but neglected findings in plant and animal infections. Infectious diseases typically manifest as sporadic traits because human genotypes often display incomplete penetrance (most genetically predisposed individuals remain healthy) and variable expressivity (different infections can be allelic at the same locus). Infectious diseases of childhood, once thought to be archetypal environmental diseases, actually may be among the most genetically determined conditions of mankind. This nascent and testable notion has interesting medical and biological implications.

  1. Cleft lip with or without cleft palate in Shanghai, China: Evidence for an autosomal major locus

    Energy Technology Data Exchange (ETDEWEB)

    Marazita, M.L. (Virginia Commonwealth Univ., Richmond, VA (United States)); Hu, Dan-Ning; Liu, You-E. (Zhabei Eye Institute, Shanghai (China)); Spence, A. (Univ. of California, Los Angeles, CA (United States)); Melnick, M. (Univ. of Southern California, Los Angeles, CA (United States))

    1992-09-01

    Orientals are at higher risk for cleft lip with our without cleft palate (CL[+-] P) than Caucasians or blacks. The authors collected demographic and family data to study factors contributing to the etiology of CL[+-]P in Shanghai. The birth incidence of nonsyndromic CL[+-]P (SHanghai 1980-87) was 1.11/1,000, with a male/female ratio of 1.42. Almost 2,000 nonsyndromic CL[+-]P probands were ascertained from individuals operated on during the years 1956-83 at surgical hospitals in Shanghai. Detailed family histories and medical examinations were obtained for the probands and all available family members. Genetic analysis of the probands' families were performed under the mixed model with major locus (ML) and multifactorial (MFT) components. The hypothesis of no familial transmission and of MFT alone could be rejected. Of the ML models, the autosomal recessive was significantly most likely and was assumed for testing three complex hypothesis: (1) ML and sporadics; (2) ML and MFT; (3) ML, MFT, and sporadics. None of the complex models were more likely than the ML alone model. In conclusion, the best-fitting, most parsimonious model for CL[+-]P in Shanghai was that of an autosomal recessive major locus. 37 refs., 1 tab.

  2. Common recessive limb girdle muscular dystrophies differential diagnosis: why and how?

    Directory of Open Access Journals (Sweden)

    Ana Cotta

    2014-09-01

    Full Text Available Limb girdle muscular dystrophies are heterogeneous autosomal hereditary neuromuscular disorders. They produce dystrophic changes on muscle biopsy and they are associated with mutations in several genes involved in muscular structure and function. Detailed clinical, laboratorial, imaging, diagnostic flowchart, photographs, tables, and illustrated diagrams are presented for the differential diagnosis of common autosomal recessive limb girdle muscular dystrophy subtypes diagnosed nowadays at one reference center in Brazil. Preoperative image studies guide muscle biopsy site selection. Muscle involvement image pattern differs depending on the limb girdle muscular dystrophy subtype. Muscle involvement is conspicuous at the posterior thigh in calpainopathy and fukutin-related proteinopathy; anterior thigh in sarcoglycanopathy; whole thigh in dysferlinopathy, and telethoninopathy. The precise differential diagnosis of limb girdle muscular dystrophies is important for genetic counseling, prognostic orientation, cardiac and respiratory management. Besides that, it may probably, in the future, provide specific genetic therapies for each subtype.

  3. The trauma of a recession.

    LENUS (Irish Health Repository)

    Murphy, S M

    2011-09-01

    Employment in construction in Ireland fell by 10% from nearly 282,000 in the second quarter of 2007 to 255,000 in the same period of 2008. Our study looks at the differences in soft tissue upper limb trauma dynamics of a pre- and post-recession Ireland. Construction accounted for 330 patients (27%) of all hand injuries in 2006, but only 18 (3%) in 2009. Our data shows a significant drop in hand injuries related to the construction industry, and more home\\/DIY cases and deliberate self-harm presenting in their stead.

  4. The trauma of a recession.

    Science.gov (United States)

    Murphy, S M; Kieran, I; Shaughnessy, M O

    2011-09-01

    Employment in construction in Ireland fell by 10% from nearly 282,000 in the second quarter of 2007 to 255,000 in the same period of 2008. Our study looks at the differences in soft tissue upper limb trauma dynamics of a pre- and post-recession Ireland. Construction accounted for 330 patients (27%) of all hand injuries in 2006, but only 18 (3%) in 2009. Our data shows a significant drop in hand injuries related to the construction industry, and more home/DIY cases and deliberate self-harm presenting in their stead.

  5. Chromosomal deletion unmasking a recessive disease: 22q13 deletion syndrome and metachromatic leukodystrophy

    DEFF Research Database (Denmark)

    Bisgaard, A-M; Kirchhoff, M; Nielsen, J E

    2008-01-01

    A deletion on one chromosome and a mutant allele on the other may cause an autosomal recessive disease. We report on two patients with mental retardation, dysmorphic features and low catalytic activity of arylsulfatase A. One patient had a pathogenic mutation in the arylsulfatase A gene (ARSA......) and succumbed to metachromatic leukodystrophy (MLD). The other patient had a pseudoallele, which does not lead to MLD. The presenting clinical features and low arylsulfatase A activity were explained, in each patients, by a deletion of 22q13 and, thereby, of one allele of ARSA....

  6. Strategies to Advance Drug Discovery in Rare Monogenic Intellectual Disability Syndromes

    Science.gov (United States)

    Hettige, Nuwan C; Manzano-Vargas, Karla; Jefri, Malvin; Ernst, Carl

    2018-01-01

    Abstract Some intellectual disability syndromes are caused by a mutation in a single gene and have been the focus of therapeutic intervention attempts, such as Fragile X and Rett Syndrome, albeit with limited success. The rate at which new drugs are discovered and tested in humans for intellectual disability is progressing at a relatively slow pace. This is particularly true for rare diseases where so few patients make high-quality clinical trials challenging. We discuss how new advances in human stem cell reprogramming and gene editing can facilitate preclinical study design and we propose new workflows for how the preclinical to clinical trajectory might proceed given the small number of subjects available in rare monogenic intellectual disability syndromes. PMID:29040584

  7. Depression and quality of life in monogenic compared to idiopathic, early-onset Parkinson's disease

    DEFF Research Database (Denmark)

    Kasten, Meike; Kertelge, Lena; Tadic, Vera

    2012-01-01

    , and 44% of manifesting carriers of mutations in PD genes, but was rare in the nonmanifesting carriers (7%) and healthy controls (5%). Subjects with Parkinson-associated depression reported fewer feelings of guilt or self-doubt than treated controls, but the occurrence of suicidal ideation was associated......Quality of life (QoL) is decreased in PD and is linked with depression and anxiety. However, little is known about QoL in monogenic PD. Subjects with mutations in PD genes were recruited from ongoing family and genetic studies (manifesting carriers, n = 23; nonmanifesting carriers, n = 19......). For comparison purposes, we included patients with idiopathic PD (IPD; n = 128; early onset, n = 38; late onset, n = 90), healthy controls (n = 127), and data on depressive symptoms of 144 patients with major depression (treated controls). Depression affected 31% of early-onset PD cases, 21% of late-onset cases...

  8. The Effect of Recessions on Firms’ Boundaries

    DEFF Research Database (Denmark)

    Knudsen, Eirik Sjåholm; Foss, Kirsten

    2014-01-01

    The economic theory of the firm offers conflicting predictions of how the two major effects of recessions, changes in demand and access to credit, affect firm boundaries. Using data on Norwegian firms in the recent recession, we find support for both increased and reduced vertical integration...... explanation for the conflicting theoretical predictions regarding vertical integration in response to demand and credit shocks....

  9. CT evaluation of the anterior epitympanic recess

    International Nuclear Information System (INIS)

    Yamasoba, Tatsuya; Kikuchi, Shigeru; Takeuchi, Naonobu; Harada, Takehiko; Nomura, Yasuya

    1991-01-01

    The structures of the anterior epitympanic recess and its surrounding tissues were examined among non-inflammatory ear, chronic otitis media with central perforation and cholesteatoma, using axial scans of high resolution computed tomography. The length and width of the recess, as well as the number of the slices where the cog was determined, had no significant differences among them. Thus, the bony structure of the recess was considered to be seldom influenced by inflammatory processes. In the non-inflammatory ear, the degree of pneumatization around the recess was similar to that of the petrous apex cells and lower than that of the mastoid cells. In the chronic otitis media with central perforation and cholesteatoma, the pneumatization of the whole temporal bones was suppressed and the tendency was also found that the cells around the recess were less pneumatized than the mastoid cells. When cholesteatoma invaded into the anterior epitympanic recess, the destruction of the bony protrusion of the lateral wall between the recess and the epitympanum was recognized, as well as the disappearance of the cog. The bony protrusion was considered to be an inferior extention of the cog toward the anterior tympanic spine. (author)

  10. Hereditary sensory and autosomal peripheral neuropathy-type IV: case series and review of literature.

    Science.gov (United States)

    Ashwin, D P; Chandan, G D; Jasleen, Handa Kaur; Rajkumar, G C; Rudresh, K B; Prashanth, R

    2015-06-01

    Hereditary sensory and autonomic neuropathy (HSAN) IV is a rare autosomal recessive disorder which is characterized by a decrease in the number of myelinated and non-myelinated nerve fibers of peripheral nerves which causes diminished or absent pain sensation leading to increase in self-mutilative habits. A retrospective study of eight cases ranging from age group of 4 to 17 years for oral and digital signs and symptoms is presented. All the patients showed congenital insensitivity to pain and anhidrosis. Oral self-mutilations, such as autoextraction of teeth and severe bite injuries (with resultant scarring) of the finger tips and oral soft tissues (tongue, lip, and buccal mucosa) were found in most patients. Our study suggests that early diagnosis and specific treatment plan are important for prevention of characteristic of the oral as well as digital trauma associated with this disorder.

  11. Cardiovascular risk assessment of dyslipidemic children: analysis of biomarkers to identify monogenic dyslipidemia[S

    Science.gov (United States)

    Medeiros, Ana Margarida; Alves, Ana Catarina; Aguiar, Pedro; Bourbon, Mafalda

    2014-01-01

    The distinction between a monogenic dyslipidemia and a polygenic/environmental dyslipidemia is important for the cardiovascular risk assessment, counseling, and treatment of these patients. The present work aims to perform the cardiovascular risk assessment of dyslipidemic children to identify useful biomarkers for clinical criteria improvement in clinical settings. Main cardiovascular risk factors were analyzed in a cohort of 237 unrelated children with clinical diagnosis of familial hypercholesterolemia (FH). About 40% carried at least two cardiovascular risk factors and 37.6% had FH, presenting mutations in LDLR and APOB. FH children showed significant elevated atherogenic markers and lower concentration of antiatherogenic particles. Children without a molecular diagnosis of FH had higher levels of TGs, apoC2, apoC3, and higher frequency of BMI and overweight/obesity, suggesting that environmental factors can be the underlying cause of their hypercholesterolem≥ia. An apoB/apoA1 ratio ≥0.68 was identified as the best biomarker (area under the curve = 0.835) to differentiate FH from other dyslipidemias. The inclusion in clinical criteria of a higher cut-off point for LDL cholesterol or an apoB/apoA1 ratio ≥0.68 optimized the criteria sensitivity and specificity. The correct identification, at an early age, of all children at-risk is of great importance so that specific interventions can be implemented. apoB/apoA1 can improve the identification of FH patients. PMID:24627126

  12. Interpolation problem for the solutions of linear elasticity equations based on monogenic functions

    Science.gov (United States)

    Grigor'ev, Yuri; Gürlebeck, Klaus; Legatiuk, Dmitrii

    2017-11-01

    Interpolation is an important tool for many practical applications, and very often it is beneficial to interpolate not only with a simple basis system, but rather with solutions of a certain differential equation, e.g. elasticity equation. A typical example for such type of interpolation are collocation methods widely used in practice. It is known, that interpolation theory is fully developed in the framework of the classical complex analysis. However, in quaternionic analysis, which shows a lot of analogies to complex analysis, the situation is more complicated due to the non-commutative multiplication. Thus, a fundamental theorem of algebra is not available, and standard tools from linear algebra cannot be applied in the usual way. To overcome these problems, a special system of monogenic polynomials the so-called Pseudo Complex Polynomials, sharing some properties of complex powers, is used. In this paper, we present an approach to deal with the interpolation problem, where solutions of elasticity equations in three dimensions are used as an interpolation basis.

  13. GCK-MODY in the US National Monogenic Diabetes Registry: frequently misdiagnosed and unnecessarily treated.

    Science.gov (United States)

    Carmody, David; Naylor, Rochelle N; Bell, Charles D; Berry, Shivani; Montgomery, Jazzmyne T; Tadie, Elizabeth C; Hwang, Jessica L; Greeley, Siri Atma W; Philipson, Louis H

    2016-10-01

    GCK-MODY leads to mildly elevated blood glucose typically not requiring therapy. It has been described in all ethnicities, but mainly in Caucasian Europeans. Here we describe our US cohort of GCK-MODY. We examined the rates of detection of heterozygous mutations in the GCK gene in individuals referred to the US Monogenic Diabetes Registry with a phenotype consistent with GCK-MODY. We also assessed referral patterns, treatment and demography, including ethnicity, of the cohort. Deleterious heterozygous GCK mutations were found in 54.7 % of Registry probands selected for GCK sequencing for this study. Forty-nine percent were previously unnecessarily treated with glucose-lowering agents, causing hypoglycemia and other adverse effects in some of the subjects. The proportion of probands found to have a GCK mutation through research-based testing was similar across each ethnic group. However, together African-American, Latino and Asian subjects represented only 20.5 % of screened probands and 17.2 % of those with GCK-MODY, despite higher overall diabetes prevalence in these groups. Our data show that a high detection rate of GCK-MODY is possible based on clinical phenotype and that prior to genetic diagnosis, a large percentage are inappropriately treated with glucose-lowering therapies. We also find low minority representation in our Registry, which may be due to disparities in diagnostic diabetes genetic testing and is an area needing further investigation.

  14. Newcomers in paediatric GI pathology: childhood enteropathies including very early onset monogenic IBD.

    Science.gov (United States)

    Ensari, Arzu; Kelsen, Judith; Russo, Pierre

    2018-01-01

    Childhood enteropathies are a group of diseases causing severe chronic (>2-3 weeks) diarrhoea often starting in the first week of life with the potential for fatal complications for the affected infant. Early identification and accurate classification of childhood enteropathies are, therefore, crucial for making treatment decisions to prevent life-threatening complications. Childhood enteropathies are classified into four groups based on the underlying pathology: (i) conditions related to defective digestion, absorption and transport of nutrients and electrolytes; (ii) disorders related to enterocyte differentiation and polarization; (iii) defects of enteroendocrine cell differentiation; and (iv) disorders associated with defective modulation of intestinal immune response. While the intestinal mucosa is usually normal in enteropathies related to congenital transport or enzyme deficiencies, the intestinal biopsy in other disorders may reveal a wide range of abnormalities varying from normal villous architecture to villous atrophy and/or inflammation, or features specific to the underlying disorder including epithelial abnormalities, lipid vacuolization in the enterocytes, absence of plasma cells, lymphangiectasia, microorganisms, and mucosal eosinophilic or histiocytic infiltration. This review intends to provide an update on small intestinal biopsy findings in childhood enteropathies, the "newcomers", including very early onset monogenic inflammatory bowel disease (IBD), in particular, for the practicing pathologist.

  15. Implementing Non-Invasive Prenatal Diagnosis (NIPD) in a National Health Service Laboratory; From Dominant to Recessive Disorders.

    Science.gov (United States)

    Drury, Suzanne; Mason, Sarah; McKay, Fiona; Lo, Kitty; Boustred, Christopher; Jenkins, Lucy; Chitty, Lyn S

    2016-01-01

    Our UK National Health Service regional genetics laboratory offers NIPD for autosomal dominant and de novo conditions (achondroplasia, thanataphoric dysplasia, Apert syndrome), paternal mutation exclusion for cystic fibrosis and a range of bespoke tests. NIPD avoids the risks associated with invasive testing, making prenatal diagnosis more accessible to families at high genetic risk. However, the challenge remains in offering definitive diagnosis for autosomal recessive diseases, which is complicated by the predominance of the maternal mutant allele in the cell-free DNA sample and thus requires a variety of different approaches. Validation and diagnostic implementation for NIPD of congenital adrenal hyperplasia (CAH) is further complicated by presence of a pseudogene that requires a different approach. We have used an assay targeting approximately 6700 heterozygous SNPs around the CAH gene (CYP21A2) to construct the high-risk parental haplotypes and tested this approach in five cases, showing that inheritance of the parental alleles can be correctly identified using NIPD. We are evaluating various measures of the fetal fraction to help determine inheritance of parental mutations. We are currently exploring the utility of an NIPD multi-disorder panel for autosomal recessive disease, to make testing more widely applicable to families with a variety of serious genetic conditions.

  16. Early childhood BMI trajectories in monogenic obesity due to leptin, leptin receptor, and melanocortin 4 receptor deficiency.

    Science.gov (United States)

    Kohlsdorf, Katja; Nunziata, Adriana; Funcke, Jan-Bernd; Brandt, Stephanie; von Schnurbein, Julia; Vollbach, Heike; Lennerz, Belinda; Fritsch, Maria; Greber-Platzer, Susanne; Fröhlich-Reiterer, Elke; Luedeke, Manuel; Borck, Guntram; Debatin, Klaus-Michael; Fischer-Posovszky, Pamela; Wabitsch, Martin

    2018-02-27

    To evaluate whether early childhood body mass index (BMI) is an appropriate indicator for monogenic obesity. A cohort of n = 21 children living in Germany or Austria with monogenic obesity due to congenital leptin deficiency (group LEP, n = 6), leptin receptor deficiency (group LEPR, n = 6) and primarily heterozygous MC4 receptor deficiency (group MC4R, n = 9) was analyzed. A control group (CTRL) was defined that consisted of n = 22 obese adolescents with no mutation in the above mentioned genes. Early childhood (0-5 years) BMI trajectories were compared between the groups at selected time points. The LEP and LEPR group showed a tremendous increase in BMI during the first 2 years of life with all patients displaying a BMI >27 kg/m 2 (27.2-38.4 kg/m 2 ) and %BMI P95 (percentage of the 95th percentile BMI for age and sex) >140% (144.8-198.6%) at the age of 2 years and a BMI > 33 kg/m 2 (33.3-45.9 kg/m 2 ) and %BMI P95  > 184% (184.1-212.6%) at the age of 5 years. The MC4R and CTRL groups had a later onset of obesity with significantly lower BMI values at both time points (p BMI trajectories in this pediatric cohort with monogenic obesity we suggest that BMI values >27.0 kg/m 2 or %BMI P95  > 140% at the age of 2 years and BMI values >33.0 kg/m 2 or %BMI P95  > 184% at the age of 5 years may be useful cut points to identify children who should undergo genetic screening for monogenic obesity due to functionally relevant mutations in the leptin gene or leptin receptor gene.

  17. Hospital Capital Investment During the Great Recession.

    Science.gov (United States)

    Choi, Sung

    2017-01-01

    Hospital capital investment is important for acquiring and maintaining technology and equipment needed to provide health care. Reduction in capital investment by a hospital has negative implications for patient outcomes. Most hospitals rely on debt and internal cash flow to fund capital investment. The great recession may have made it difficult for hospitals to borrow, thus reducing their capital investment. I investigated the impact of the great recession on capital investment made by California hospitals. Modeling how hospital capital investment may have been liquidity constrained during the recession is a novel contribution to the literature. I estimated the model with California Office of Statewide Health Planning and Development data and system generalized method of moments. Findings suggest that not-for-profit and public hospitals were liquidity constrained during the recession. Comparing the changes in hospital capital investment between 2006 and 2009 showed that hospitals used cash flow to increase capital investment by $2.45 million, other things equal.

  18. The Great Recession and confidence in homeownership

    OpenAIRE

    Anat Bracha; Julian Jamison

    2013-01-01

    Confidence in homeownership shifts for those who personally experienced real estate loss during the Great Recession. Older Americans are confident in the value of homeownership. Younger Americans are less confident.

  19. Bond return predictability in expansions and recessions

    DEFF Research Database (Denmark)

    Engsted, Tom; Møller, Stig Vinther; Jensen, Magnus David Sander

    We document that over the period 1953-2011 US bond returns are predictable in expansionary periods but unpredictable during recessions. This result holds in both in-sample and out-of-sample analyses and using both univariate regressions and combination forecasting techniques. A simulation study...... but negative in recessions. The results are also consistent with tests showing that the expectations hypothesis of the term structure holds in recessions but not in expansions. However, the results for bonds are in sharp contrast to results for stocks showing that stock returns are predictable in recessions...... but not in expansions. Thus, our results indicate that there is not a common predictive pattern of stock and bond returns associated with the state of the economy....

  20. The Great Recession and Workers' Health Benefits.

    Science.gov (United States)

    Koh, Kanghyock

    2018-03-01

    During a recession, cost-sharing of employer-sponsored health benefits could increase to reduce labor costs in the U.S. Using a variation in the severity of recession shocks across industries, I find evidence that the enrollment rate of high deductible health plans (HDHPs) among workers covered by employer-sponsored health benefits increased more among firms in industries that experienced severe recession shocks. As potential mechanisms, I study employer-side and worker-side mechanisms. I find that employers changed health benefit offerings to force or incentivize workers to enroll in HDHPs. But I find little evidence of an increase in workers' demand for HDHPs due to a reduction in income. These results suggest that the HDHP enrollment rate increased during the Great Recession, as employers tried to save costs of offering health benefits. Copyright © 2018 Elsevier B.V. All rights reserved.

  1. Recessive Dystrophic Epidermolysis Bullosa and Pregnancy.

    Science.gov (United States)

    Boria, F; Maseda, R; Martín-Cameán, M; De la Calle, M; de Lucas, R

    2017-12-01

    Dystrophic epidermolysis bullosa is a rare inherited disease caused by mutations in the COL7A1 gene. Its recessive variant (recessive dystrophic epidermolysis bullosa) is characterized by the absence or considerably reduced expression of type VII collagen, which leads to marked fragility of the skin and mucous membranes and subsequent blister formation, whether spontaneously or following minimal injury. There have been very few reports of this disease in pregnant women. We present 2 cases of pregnant women with recessive dystrophic epidermolysis bullosa managed in our High-Risk Pregnancy Unit at Hospital Universitario La Paz, Madrid, Spain. Both patients underwent full-term cesarean delivery, with no further complications for mother or child. Although recessive dystrophic epidermolysis bullosa increases the risk of maternal complications, a patient is not advised against pregnancy. With adequate monitoring, these patients can fulfil their desire to become mothers. Copyright © 2017 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

  2. Hospital Capital Investment During the Great Recession

    Science.gov (United States)

    Choi, Sung

    2017-01-01

    Hospital capital investment is important for acquiring and maintaining technology and equipment needed to provide health care. Reduction in capital investment by a hospital has negative implications for patient outcomes. Most hospitals rely on debt and internal cash flow to fund capital investment. The great recession may have made it difficult for hospitals to borrow, thus reducing their capital investment. I investigated the impact of the great recession on capital investment made by California hospitals. Modeling how hospital capital investment may have been liquidity constrained during the recession is a novel contribution to the literature. I estimated the model with California Office of Statewide Health Planning and Development data and system generalized method of moments. Findings suggest that not-for-profit and public hospitals were liquidity constrained during the recession. Comparing the changes in hospital capital investment between 2006 and 2009 showed that hospitals used cash flow to increase capital investment by $2.45 million, other things equal. PMID:28617202

  3. Autosomal dominant craniometaphyseal dysplasia with atypical features.

    Science.gov (United States)

    McKay, D R; Fialkov, J A

    2002-03-01

    Craniometaphyseal dysplasia (CMD) is a rare genetic disorder of bone modelling characterised by hyperostosis and sclerosis of the craniofacial bones, and abnormal modelling of the metaphyses. Clinically, autosomal dominant (AD) CMD is characterised by facial distortion and cranial-nerve compression. The goals of surgical treatment for AD CMD are cosmetic recontouring of the sclerotic craniofacial bones, correction of nasal obstruction and correction or prevention of neurological manifestations. We describe the successful correction of AD CMD craniofacial manifestations in an individual with atypical findings, and outline an approach for correcting the craniofacial deformities associated with this rare disorder. Copyright 2002 The British Association of Plastic Surgeons.

  4. Clinical neurogenetics: autosomal dominant spinocerebellar ataxia.

    Science.gov (United States)

    Shakkottai, Vikram G; Fogel, Brent L

    2013-11-01

    The autosomal dominant spinocerebellar ataxias are a diverse and clinically heterogeneous group of disorders characterized by degeneration and dysfunction of the cerebellum and its associated pathways. Clinical and diagnostic evaluation can be challenging because of phenotypic overlap among causes, and a stratified and systematic approach is essential. Recent advances include the identification of additional genes causing dominant genetic ataxia, a better understanding of cellular pathogenesis in several disorders, the generation of new disease models that may stimulate development of new therapies, and the use of new DNA sequencing technologies, including whole-exome sequencing, to improve diagnosis. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. The diverse impacts of the great recession

    OpenAIRE

    Makoto Nakajima

    2013-01-01

    The Great Recession had a large negative impact on the U.S. economy. Asset prices, most notably stock and house prices, declined substantially, resulting in a loss in wealth for many American households. In this article, Makoto Nakajima documents how diverse households were affected in a variety of dimensions during the Great Recession, in particular between 2007 and 2009, using newly available data from the 2007-2009 Survey of Consumer Finances. He discusses why it is important to look at th...

  6. Academic Performance and the Great Recession

    OpenAIRE

    Adamopoulou, Effrosyni; Tanzi, Giulia M.

    2014-01-01

    In this paper we study how the Great Recession affected university students in terms of performance, with a special focus on the dropout probability. To do so, we use individual-level data on a representative sample of university students in Italy in 2007 and 2011. We measure the severity of the recession in terms of increases in adult and youth unemployment rate and we exploit geographical variation to achieve identification. On the one hand, an increase in adult male unemployment rate deter...

  7. HYDRORECESSION: A toolbox for streamflow recession analysis

    Science.gov (United States)

    Arciniega, S.

    2015-12-01

    Streamflow recession curves are hydrological signatures allowing to study the relationship between groundwater storage and baseflow and/or low flows at the catchment scale. Recent studies have showed that streamflow recession analysis can be quite sensitive to the combination of different models, extraction techniques and parameter estimation methods. In order to better characterize streamflow recession curves, new methodologies combining multiple approaches have been recommended. The HYDRORECESSION toolbox, presented here, is a Matlab graphical user interface developed to analyse streamflow recession time series with the support of different tools allowing to parameterize linear and nonlinear storage-outflow relationships through four of the most useful recession models (Maillet, Boussinesq, Coutagne and Wittenberg). The toolbox includes four parameter-fitting techniques (linear regression, lower envelope, data binning and mean squared error) and three different methods to extract hydrograph recessions segments (Vogel, Brutsaert and Aksoy). In addition, the toolbox has a module that separates the baseflow component from the observed hydrograph using the inverse reservoir algorithm. Potential applications provided by HYDRORECESSION include model parameter analysis, hydrological regionalization and classification, baseflow index estimates, catchment-scale recharge and low-flows modelling, among others. HYDRORECESSION is freely available for non-commercial and academic purposes.

  8. Novel Presenting Phenotype in a Child With Autosomal Dominant Best's Vitelliform Macular Dystrophy.

    Science.gov (United States)

    Abdalla, Yasmine F; De Salvo, Gabriella; Elsahn, Ahmad; Self, James E

    2017-07-01

    Best's macular dystrophy (BMD) usually manifests with visual failure in the first or second decade of life; however, there is a large variability in expressivity of the disease, and some patients have no manifestation other than a pathological electro-oculogram (EOG). Autosomal dominant Best's vitelliform macular dystrophy (AD-BVMD) has a very specific phenotype that varies with the stage of the disease. In recent years, the authors have seen description of another clinical entity known as autosomal recessive BMD. Herein, the authors describe a 5-year-old girl referred from a peripheral hospital for investigation with a positive family history of BMD. Clinical findings included best-corrected visual acuity of 0.325 and 0.300 in the right and left eyes, respectively, by Sonksen logMar test, full color vision, normal orthoptic examination, and a small degree of hyperopia consistent with age. Macular optical coherence tomography (OCT) showed intraretinal fluid cysts and EOG showed reduced Arden ratio. Genetic testing was done for the proband and her father, who were found to be heterozygous for c.37C>T p. (Arg13Cys). The proband's younger sister will be reviewed and followed up once of age. The authors identified a new phenotype of AD-BVMD; although this is a single patient, more young children with BMD can now be scanned with the availability of hand-held OCT with better knowledge of the phenotype. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:580-585.]. Copyright 2017, SLACK Incorporated.

  9. Modeling Monogenic Human Nephrotic Syndrome in the Drosophila Garland Cell Nephrocyte.

    Science.gov (United States)

    Hermle, Tobias; Braun, Daniela A; Helmstädter, Martin; Huber, Tobias B; Hildebrandt, Friedhelm

    2017-05-01

    Steroid-resistant nephrotic syndrome is characterized by podocyte dysfunction. Drosophila garland cell nephrocytes are podocyte-like cells and thus provide a potential in vivo model in which to study the pathogenesis of nephrotic syndrome. However, relevant pathomechanisms of nephrotic syndrome have not been studied in nephrocytes. Here, we discovered that two Drosophila slit diaphragm proteins, orthologs of the human genes encoding nephrin and nephrin-like protein 1, colocalize within a fingerprint-like staining pattern that correlates with ultrastructural morphology. Using RNAi and conditional CRISPR/Cas9 in nephrocytes, we found this pattern depends on the expression of both orthologs. Tracer endocytosis by nephrocytes required Cubilin and reflected size selectivity analogous to that of glomerular function. Using RNAi and tracer endocytosis as a functional read-out, we screened Drosophila orthologs of human monogenic causes of nephrotic syndrome and observed conservation of the central pathogenetic alterations. We focused on the coenzyme Q 10 (CoQ 10 ) biosynthesis gene Coq2 , the silencing of which disrupted slit diaphragm morphology. Restoration of CoQ 10 synthesis by vanillic acid partially rescued the phenotypic and functional alterations induced by Coq2 -RNAi. Notably, Coq2 colocalized with mitochondria, and Coq2 silencing increased the formation of reactive oxygen species (ROS). Silencing of ND75 , a subunit of the mitochondrial respiratory chain that controls ROS formation independently of CoQ 10 , phenocopied the effect of Coq2 -RNAi. Moreover, the ROS scavenger glutathione partially rescued the effects of Coq2 -RNAi. In conclusion, Drosophila garland cell nephrocytes provide a model with which to study the pathogenesis of nephrotic syndrome, and ROS formation may be a pathomechanism of COQ2 -nephropathy. Copyright © 2017 by the American Society of Nephrology.

  10. Prevalence of monogenic diabetes amongst Polish children after a nationwide genetic screening campaign.

    Science.gov (United States)

    Fendler, W; Borowiec, M; Baranowska-Jazwiecka, A; Szadkowska, A; Skala-Zamorowska, E; Deja, G; Jarosz-Chobot, P; Techmanska, I; Bautembach-Minkowska, J; Mysliwiec, M; Zmyslowska, A; Pietrzak, I; Malecki, M T; Mlynarski, W

    2012-10-01

    The aim of this study was to study dynamic changes in the prevalence of different types of diabetes in paediatric populations in Poland, with a specific focus on monogenic diabetes (MD). Using epidemiologic data (PolPeDiab Collaboration) and nationwide genetic test results (TEAM Programme), we compared the prevalence of type 1, type 2 and cystic fibrosis-related diabetes (CFRD) and MD. Genetically confirmed MD included MODY, neonatal diabetes and Wolfram and Alström syndromes. The study covered all children aged 0-18 years treated for diabetes between 2005 and 2011 in three regions, inhabited by 23.7% (1,989,988) of Polish children, with a low prevalence of childhood obesity (type 1 diabetes showed a continuous increase, from 96 to 138/100,000 children. The prevalence of type 2 diabetes and CFRD also increased, from 0.3 to 1.01/100,000 children and from 0.1 to 0.95/100,000 children, respectively. The prevalence of MD was stable at between 4.2 and 4.6/100,000 children, accounting for 3.1-4.2% of children with diabetes, with glucokinase (GCK)-MODY being the most frequent type, amounting to 83% of patients with MD. The percentage of positive test results decreased with the number of referrals, suggesting that children with the highest probability of MD were referred initially, followed by those with a less clear-cut phenotype. The prevalence of neonatal diabetes equalled 1 in 300,000 children. The prevalence of MD in a paediatric population with a low prevalence of obesity remains stable and is nearly fivefold higher than that of type 2 diabetes and CFRD, justifying a need for increased access to genetic diagnostic procedures in diabetic children.

  11. Bacillus thuringiensis monogenic strains: screening and interactions with insecticides used against rice pests

    Science.gov (United States)

    Pinto, Laura M.N.; Dörr, Natália C.; Ribeiro, Ana Paula A.; de Salles, Silvia M.; de Oliveira, Jaime V.; Menezes, Valmir G.; Fiuza, Lidia M.

    2012-01-01

    The screening of Bacillus thuringiensis (Bt) Cry proteins with high potential to control insect pests has been the goal of numerous research groups. In this study, we evaluated six monogenic Bt strains (Bt dendrolimus HD-37, Bt kurstaki HD-1, Bt kurstaki HD-73, Bt thuringiensis 4412, Bt kurstaki NRD-12 and Bt entomocidus 60.5, which codify the cry1Aa, cry1Ab, cry1Ac, cry1Ba, cry1C, cry2A genes respectively) as potential insecticides for the most important insect pests of irrigated rice: Spodoptera frugiperda, Diatraea saccharalis, Oryzophagus oryzae, Oebalus poecilus and Tibraca limbativentris. We also analyzed their compatibility with chemical insecticides (thiamethoxam, labdacyhalothrin, malathion and fipronil), which are extensively used in rice crops. The bioassay results showed that Bt thuringiensis 4412 and Bt entomocidus 60.5 were the most toxic for the lepidopterans, with a 93% and 82% mortality rate for S. frugiperda and D. saccharalis, respectively. For O. oryzae, the Bt kurstaki NRD-12 (64%) and Bt dendrolimus HD-37 (62%) strains were the most toxic. The Bt dendrolimus HD-37 strain also caused high mortality (82%) to O. poecilus, however the strains assessed to T. limbativentris caused a maximum rate of 5%. The assays for the Bt strains interaction with insecticides revealed the compatibility of the six strains with the four insecticides tested. The results from this study showed the high potential of cry1Aa and cry1Ba genes for genetic engineering of rice plants or the strains to biopesticide formulations. PMID:24031872

  12. Aeroacoustical Study of the Tgv Pantograph Recess

    Science.gov (United States)

    NOGER, C.; PATRAT, J. C.; PEUBE, J.; PEUBE, J. L.

    2000-03-01

    The general focus of this aerodynamic noise research, induced by turbulent incompressible flow, is to improve our knowledge of acoustic production mechanisms in the TGV pantograph recess in order to be able to reduce the radiated noise. This work is performed under contract with SNCF as a part of the German-French Cooperation DEUFRAKO K2, and is supported by French Ministries for Transport and Research. Previous studies on TGV noise source locations (DEUFRAKO K) have identified the pantograph recess as one of the important aerodynamic noise sources, for speeds higher than 300 km/h, due to flow separation. The pantograph recess is a very complex rectangular cavity, located both on the power car and the first coach roofs of the TGV, and has not been studied before due to the complex shapes. Its aeroacoustic features are investigated experimentally in a low-subsonic wind tunnel, on a realistic 1/7th scale mock-up both with and without pantographs. Flow velocities, estimated with hot-wire anemometry, and parietal visualizations show the flow to reattach on the recess bottom wall and to separate again at the downstream face. Wall pressure fluctuations and “acoustic” measurements using 14 and 12 in microphones respectively are also measured to qualify the flow: no aerodynamic or acoustic oscillations are observed. The study indicates that the pantograph recess has a different behaviour compared to the usual cavity grazing flows.

  13. Autosomal dominant cortical tremor, myoclonus and epilepsy.

    Science.gov (United States)

    Striano, Pasquale; Zara, Federico

    2016-09-01

    The term 'cortical tremor' was first introduced by Ikeda and colleagues to indicate a postural and action-induced shivering movement of the hands which mimics essential tremor, but presents with the electrophysiological findings of cortical reflex myoclonus. The association between autosomal dominant cortical tremor, myoclonus and epilepsy (ADCME) was first recognized in Japanese families and is now increasingly reported worldwide, although it is described using different acronyms (BAFME, FAME, FEME, FCTE and others). The disease usually takes a benign course, although drug-resistant focal seizures or slight intellectual disability occur in some cases. Moreover, a worsening of cortical tremor and myoclonus is common in advanced age. Although not yet recognized by the International League Against Epilepsy (ILAE), this is a well-delineated epilepsy syndrome with remarkable features that clearly distinguishes it from other myoclonus epilepsies. Moreover, genetic studies of these families show heterogeneity and different susceptible chromosomal loci have been identified.

  14. MRI of autosomal dominant pure spastic paraplegia

    DEFF Research Database (Denmark)

    Krabbe, K.; Nielsen, J.E.; Fallentin, E.

    1997-01-01

    We examined 16 patients with autosomal dominant pure spastic paraplegia (HSP) and 15 normal controls matched for age and sex using MRI of the brain and spinal cord. Images were assessed qualitatively by two independent radiologists, blinded to the clinical diagnosis. Areas of the brain and corpus...... callosum on one midsagittal slice and the area of the brain on one axial slice were measured and a "corpus-callosum index" expressing the size of the corpus callosum relative to that of the brain was calculated. Cross-sectional areas and anteroposterior and transverse diameters of the spinal cord...... at the levels of C 2, C 5, T 3, T 6, T 9 and T 11 were measured. No significant differences between patients and controls were found on qualitative evaluation of the images. The patients had a significantly smaller corpus callosum and "corpus-callosum index" than controls. This finding, not reported previously...

  15. Allele frequency distribution for 21 autosomal STR loci in Bhutan.

    Science.gov (United States)

    Kraaijenbrink, Thirsa; van Driem, George L; Tshering of Gaselô, Karma; de Knijff, Peter

    2007-07-20

    We studied the allele frequency distribution of 21 autosomal STR loci contained in the AmpFlSTR Identifiler (Applied Biosystems), the Powerplex 16 (Promega) and the FFFL (Promega) multiplex PCR kits among 936 individuals from the Royal Kingdom of Bhutan. As such these are the first published autosomal DNA results from this country.

  16. [Monogenic form of diabetes mellitus due to HNF4α mutation (MODY-1) - the first case in Hungary].

    Science.gov (United States)

    Jermendy, György; Balogh, István; Gaál, Zsolt

    2016-03-20

    The classification of diabetes mellitus in adolescents and young adults is often difficult. The diagnosis of the monogenic form of diabetes may have substantial influence on quality of life, prognosis and the choice of the appropriate treatment of affected patients. Among MODY (maturity-onset of diabetes in the young) MODY-1 is rarely detected, only 13 families were described in 2000, and 103 different mutations in 173 families were known in 2013 worldwide. The authors present the first Hungarian case of a monogenic form of diabetes due to HNF4α mutation (MODY-1). The diabetes of the index patient No. 1 (42-year-old woman with insulin treated diabetes) was diagnosed as gestational diabetes at age of 20 when she was treated with diet only. Later, insulin treatment has been initiated when marked hyperglycaemia was detected during an episode of acute pneumonia at age of 26. The diabetes of the index patient No. 2 (20-year-old daughter of the index patient No. 1, treated also with insulin) was diagnosed as type 2 diabetes at age of 13 and the patient was treated with diet only. Later the classification was modified to type 1 and insulin therapy was initiated at age of 14. The manifestation of diabetes, the familial occurrence and the low dose insulin requirement were suggestive for monogenic diabetes. Using molecular genetic method a mutation (c.869G>A, p.R290H) of HNF4α gene was found and MODY-1 was diagnosed in both cases. Insulin therapy was switched to treatment with low dose sulfanylurea and an excellent glycaemic control was achieved and sustained at follow-up of 1-year. No further positive cases were found during screening of other family members.

  17. Estimation of cardiac motion in cine-MRI sequences by correlation transform optical flow of monogenic features distance

    Science.gov (United States)

    Gao, Bin; Liu, Wanyu; Wang, Liang; Liu, Zhengjun; Croisille, Pierre; Delachartre, Philippe; Clarysse, Patrick

    2016-12-01

    Cine-MRI is widely used for the analysis of cardiac function in clinical routine, because of its high soft tissue contrast and relatively short acquisition time in comparison with other cardiac MRI techniques. The gray level distribution in cardiac cine-MRI is relatively homogenous within the myocardium, and can therefore make motion quantification difficult. To ensure that the motion estimation problem is well posed, more image features have to be considered. This work is inspired by a method previously developed for color image processing. The monogenic signal provides a framework to estimate the local phase, orientation, and amplitude, of an image, three features which locally characterize the 2D intensity profile. The independent monogenic features are combined into a 3D matrix for motion estimation. To improve motion estimation accuracy, we chose the zero-mean normalized cross-correlation as a matching measure, and implemented a bilateral filter for denoising and edge-preservation. The monogenic features distance is used in lieu of the color space distance in the bilateral filter. Results obtained from four realistic simulated sequences outperformed two other state of the art methods even in the presence of noise. The motion estimation errors (end point error) using our proposed method were reduced by about 20% in comparison with those obtained by the other tested methods. The new methodology was evaluated on four clinical sequences from patients presenting with cardiac motion dysfunctions and one healthy volunteer. The derived strain fields were analyzed favorably in their ability to identify myocardial regions with impaired motion.

  18. Evaluation of PCR-based preimplantation genetic diagnosis applied to monogenic diseases: a collaborative ESHRE PGD consortium study

    Science.gov (United States)

    Dreesen, Jos; Destouni, Aspasia; Kourlaba, Georgia; Degn, Birte; Mette, Wulf Christensen; Carvalho, Filipa; Moutou, Celine; Sengupta, Sioban; Dhanjal, Seema; Renwick, Pamela; Davies, Steven; Kanavakis, Emmanouel; Harton, Gary; Traeger-Synodinos, Joanne

    2014-01-01

    Preimplantation genetic diagnosis (PGD) for monogenic disorders currently involves polymerase chain reaction (PCR)-based methods, which must be robust, sensitive and highly accurate, precluding misdiagnosis. Twelve adverse misdiagnoses reported to the ESHRE PGD-Consortium are likely an underestimate. This retrospective study, involving six PGD centres, assessed the validity of PCR-based PGD through reanalysis of untransferred embryos from monogenic-PGD cycles. Data were collected on the genotype concordance at PGD and follow-up from 940 untransferred embryos, including details on the parameters of PGD cycles: category of monogenic disease, embryo morphology, embryo biopsy and genotype assay strategy. To determine the validity of PCR-based PGD, the sensitivity (Se), specificity (Sp) and diagnostic accuracy were calculated. Stratified analyses were also conducted to assess the influence of the parameters above on the validity of PCR-based PGD. The analysis of overall data showed that 93.7% of embryos had been correctly classified at the time of PGD, with Se of 99.2% and Sp of 80.9%. The stratified analyses found that diagnostic accuracy is statistically significantly higher when PGD is performed on two cells versus one cell (P=0.001). Se was significantly higher when multiplex protocols versus singleplex protocols were applied (P=0.005), as well as for PGD applied on cells from good compared with poor morphology embryos (P=0.032). Morphology, however, did not affect diagnostic accuracy. Multiplex PCR-based methods on one cell, are as robust as those on two cells regarding false negative rate, which is the most important criteria for clinical PGD applications. Overall, this study demonstrates the validity, robustness and high diagnostic value of PCR-based PGD. PMID:24301057

  19. Insights into cellular and molecular basis for urinary tract infection in autosomal-dominant polycystic kidney disease.

    Science.gov (United States)

    Gao, Chao; Zhang, Long; Zhang, Ye; Wallace, Darren P; Lopez-Soler, Reynold I; Higgins, Paul J; Zhang, Wenzheng

    2017-11-01

    Urinary tract infection (UTI) is a broad term referring to an infection of the kidneys, ureters, bladder, and/or urethra. Because of its prevalence, frequent recurrence, and rising resistance to antibiotics, UTI has become a challenge in clinical practice. Autosomal-dominant polycystic kidney disease (ADPKD) is the most common monogenic disorder of the kidney and is characterized by the growth of fluid-filled cysts in both kidneys. Progressive cystic enlargement, inflammation, and interstitial fibrosis result in nephron loss with subsequent decline in kidney function. ADPKD patients frequently develop UTI; however, the cellular and molecular mechanisms responsible for the high UTI incidence in ADPKD patients remain virtually unaddressed. Emerging evidence suggests that α-intercalated cells (α-ICs) of the collecting ducts function in the innate immune defense against UTI. α-ICs inhibit bacterial growth by acidifying urine and secreting neutrophil gelatinase-associated lipocalin (NGAL) that chelates siderophore-containing iron. It is necessary to determine, therefore, if ADPKD patients with recurrent UTI have a reduced number and/or impaired function of α-ICs. Identification of the underlying cellular and molecular mechanisms may lead to the development of novel strategies to reduce UTI in ADPKD. Copyright © 2017 the American Physiological Society.

  20. Recession-An issue for organizations

    Directory of Open Access Journals (Sweden)

    Daniel GEORGESCU

    2009-12-01

    Full Text Available The reality in all organization is that the directors and board are in the position of highest influence and their primary responsibility is leadership. As such, considering the consequences of a recession such as we currently face is not the time for directors to abdicate their responsibilities – it is time for governance leadership. The directors and the board must think and respond strategically. The article shows a matrix for positioning the general manager in recession that is similarly with BCG matrix and in the final a table with a set of essential questions for helping the board in new strategies building.

  1. Novel splice-site and missense mutations in the ALDH1A3 gene underlying autosomal recessive anophthalmia/microphthalmia.

    Science.gov (United States)

    Semerci, C Nur; Kalay, Ersan; Yıldırım, Cem; Dinçer, Tuba; Olmez, Akgün; Toraman, Bayram; Koçyiğit, Ali; Bulgu, Yunus; Okur, Volkan; Satıroğlu-Tufan, Lale; Akarsu, Nurten A

    2014-06-01

    This study aimed to identify the underlying genetic defect responsible for anophthalmia/microphthalmia. In total, two Turkish families with a total of nine affected individuals were included in the study. Affymetrix 250 K single nucleotide polymorphism genotyping and homozygosity mapping were used to identify the localisation of the genetic defect in question. Coding region of the ALDH1A3 gene was screened via direct sequencing. cDNA samples were generated from primary fibroblast cell cultures for expression analysis. Reverse transcriptase PCR (RT-PCR) analysis was performed using direct sequencing of the obtained fragments. The causative genetic defect was mapped to chromosome 15q26.3. A homozygous G>A substitution (c.666G>A) at the last nucleotide of exon 6 in the ALDH1A3 gene was identified in the first family. Further cDNA sequencing of ALDH1A3 showed that the c.666G>A mutation caused skipping of exon 6, which predicted in-frame loss of 43 amino acids (p.Trp180_Glu222del). A novel missense c.1398C>A mutation in exon 12 of ALDH1A3 that causes the substitution of a conserved asparagine by lysine at amino acid position 466 (p.Asn466Lys) was observed in the second family. No extraocular findings-except for nevus flammeus in one affected individual and a variant of Dandy-Walker malformation in another affected individual-were observed. Autistic-like behaviour and mental retardation were observed in three cases. In conclusion, novel ALDH1A3 mutations identified in the present study confirm the pivotal role of ALDH1A3 in human eye development. Autistic features, previously reported as an associated finding, were considered to be the result of social deprivation and inadequate parenting during early infancy in the presented families. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  2. A Novel Splicesite Mutation in the EDAR Gene Causes Severe Autosomal Recessive Hypohydrotic (Anhidrotic) Ectodermal Dysplasia in an Iranian Family.

    Science.gov (United States)

    Torkamandi, Shahram; Gholami, Milad; Mohammadi-Asl, Javad; Rezaie, Somaye; Zaimy, Mohammad Ali; Omrani, Mir Davood

    2016-01-01

    Hypohidrotic ectodermal dysplasia (HED) is a rare congenital disorder arising from deficient development of ectoderm-derived structures including skin, nails, glands and teeth. The phenotype of HED is associated with mutation in EDA, EDAR, EDARADD and NEMO genes, all of them disruptingNF-κB signaling cascade necessary for initiation, formation and differentiation in the embryo and adult. Here we describe a novel acceptor splice site mutation c.730-2 A>G(IVS 8-2 A>G) in EDAR gene in homozygous form in all affected members of a family,and in heterozygous form in carriers. Bioinformatics analysis showed that this mutation can create a new broken splicing site and lead to aberrant splicing.

  3. Adhalin, the 50 kD dystrophin associated protein, is not the locus for severe childhood autosomal recessive dystrophy (SCARMD)

    Energy Technology Data Exchange (ETDEWEB)

    McNally, E.M.; Selig, S.; Kunkel, L.M. [Children`s Hospital, Boston, MA (United States)

    1994-09-01

    Mutations in the carboxyl-terminus in dystrophin are normally sufficient to produce severely dystrophic muscle. This portion of dystrophin binds a complex of dystrophin-associated glycoproteins (DAGs). The genes encoding these DAGs are candidate genes for causing neuromuscular disease. Immunoreactivity for adhalin, the 50 kD DAG, is absent in muscle biopsies from patients with SCARMD, a form of dystrophy clinically similar Duchenne muscular dystrophy. Prior linkage analysis in SCARMD families revealed that the disease gene segregates with markers on chromosome 13. To determine the molecular role that adhalin may play in SCARMD, human cDNA and genomic sequences were isolated. Primers were designed based on predicted areas of conservation in rabbit adhalin and used in RT-PCR with human skeletal and cardiac muscle. RT-PCR products were confirmed by sequence as human adhalin and then used as probes for screening human cDNA and genomic libraries. Human and rabbit adhalin are 90% identical, and among the cDNAs, a novel splice form of adhalin was seen which may encode part of the 35 kD component of the dystrophin-glycoprotein complex. To our surprise, only human/rodent hybrids containing human chromosome 17 amplified adhalin sequences in a PCR analysis. FISH analysis with three overlapping genomic sequences confirmed the chromosome 17 location and further delineated the map position to 17q21. Therefore, adhalin is excluded as the gene causing SCARMD.

  4. A novel mutation in the sterol 27-hydroxylase gene of a woman with autosomal recessive cerebrotendinous xanthomatosis

    Directory of Open Access Journals (Sweden)

    Garuti Rita

    2010-10-01

    Full Text Available Article abstract Mutations of the gene encoding the mitochondrial enzyme sterol 27-hydroxylase (CYP27A1 gene cause defects in the cholesterol pathway to bile acids that lead to the storage of cholestanol and cholesterol in tendons, lenses and the central nervous system. This disorder is the cause of a clinical syndrome known as cerebrotendinous xanthomatosis (CTX. Since 1991 several mutations of the CYP27A1 gene have been reported. We diagnosed the clinical features of CTX in a caucasian woman. Serum levels of cholestanol and 7α-hydroxycholesterol were elevated and the concentration of 27-hydroxycholesterol was reduced. Bile alcohols in the urine and faeces were increased. The analysis of the CYP27A1 gene showed that the patient was a compound heterozygote carrying two mutations both located in exon 8. One mutation is a novel four nucleotide deletion (c.1330-1333delTTCC that results in a frameshift and the occurrence of a premature stop codon leading to the formation of a truncated protein of 448 amino acids. The other mutation, previously reported, is a C - > T transition (c. c.1381C > T that converts the glutamine codon at position 461 into a termination codon (p.Q461X. These truncated proteins are expected to have no biological function being devoid of the cysteine residue at position 476 of the normal enzyme that is crucial for heme binding and enzyme activity.

  5. A novel AP4M1 mutation in autosomal recessive cerebral palsy syndrome and clinical expansion of AP-4 deficiency

    OpenAIRE

    Jameel, Muhammad; Klar, Joakim; Tariq, Muhammad; Moawia, Abubakar; Altaf Malik, Naveed; Seema Waseem, Syeda; Abdullah, Uzma; Naeem Khan, Tahir; Raininko, Raili; Baig, Shahid Mahmood; Dahl, Niklas

    2014-01-01

    BACKGROUND: Cerebral palsy (CP) is a heterogeneous neurodevelopmental disorder associated with intellectual disability in one-third of cases. Recent findings support Mendelian inheritance in subgroups of patients with the disease. The purpose of this study was to identify a novel genetic cause of paraplegic CP with intellectual disability in a consanguineous Pakistani family. METHODS: We performed whole-exome sequencing (WES) in two brothers with CP and intellectual disability. Analysis of AP...

  6. Homozygous SLC6A17 Mutations Cause Autosomal-Recessive Intellectual Disability with Progressive Tremor, Speech Impairment, and Behavioral Problems

    NARCIS (Netherlands)

    Iqbal, Z.; Willemsen, M.H.; Papon, M.A.; Musante, L.; Benevento, M.; Hu, H; Venselaar, H.; Wissink-Lindhout, W.M.; Silfhout, A.T. van; Vissers, L.E.L.M.; Brouwer, A.P.M. de; Marouillat, S.; Wienker, T.F.; Ropers, H.H.; Kahrizi, K.; Nadif Kasri, N.; Najmabadi, H.; Laumonnier, F.; Kleefstra, T.; Bokhoven, H. van

    2015-01-01

    We report on Dutch and Iranian families with affected individuals who present with moderate to severe intellectual disability and additional phenotypes including progressive tremor, speech impairment, and behavioral problems in certain individuals. A combination of exome sequencing and homozygosity

  7. Homozygous SLC6A17 Mutations Cause Autosomal-Recessive Intellectual Disability with Progressive Tremor, Speech Impairment, and Behavioral Problems

    OpenAIRE

    Iqbal, Zafar; Willemsen, Marjolein H.; Papon, Marie-Amélie; Musante, Luciana; Benevento, Marco; Hu, Hao; Venselaar, Hanka; Wissink-Lindhout, Willemijn M.; Vulto-van Silfhout, Anneke T.; Vissers, Lisenka E.L.M.; de Brouwer, Arjan P.M.; Marouillat, Sylviane; Wienker, Thomas F.; Ropers, Hans Hilger; Kahrizi, Kimia

    2015-01-01

    We report on Dutch and Iranian families with affected individuals who present with moderate to severe intellectual disability and additional phenotypes including progressive tremor, speech impairment, and behavioral problems in certain individuals. A combination of exome sequencing and homozygosity mapping revealed homozygous mutations c.484G>A (p.Gly162Arg) and c.1898C>G (p.Pro633Arg) in SLC6A17. SLC6A17 is predominantly expressed in the brain, encodes a synaptic vesicular transporter of neu...

  8. Mutations in the histamine N-methyltransferase gene, HNMT, are associated with nonsyndromic autosomal recessive intellectual disability

    OpenAIRE

    Heidari, Abolfazl; Tongsook, Chanakan; Najafipour, Reza; Musante, Luciana; Vasli, Nasim; Garshasbi, Masoud; Hu, Hao; Mittal, Kirti; McNaughton, Amy J. M.; Sritharan, Kumudesh; Hudson, Melissa; Stehr, Henning; Talebi, Saeid; Moradi, Mohammad; Darvish, Hossein

    2015-01-01

    Histamine (HA) acts as a neurotransmitter in the brain, which participates in the regulation of many biological processes including inflammation, gastric acid secretion and neuromodulation. The enzyme histamine N-methyltransferase (HNMT) inactivates HA by transferring a methyl group from S-adenosyl-l-methionine to HA, and is the only well-known pathway for termination of neurotransmission actions of HA in mammalian central nervous system. We performed autozygosity mapping followed by targeted...

  9. A mutation in the FOXE3 gene causes congenital primary aphakia in an autosomal recessive consanguineous Pakistani family

    DEFF Research Database (Denmark)

    Anjum, Iram; Eiberg, Hans; Baig, Shahid Mahmood

    2010-01-01

    of the population in this region of Pakistan which has prevailed for many months. CONCLUSIONS: FOXE3 is responsible for the early developmental arrest of the lens placode, and the complete loss of a functional FOXE3 protein results in primary aphakia. It can also be deduced that this mutation is quite primitive...

  10. Pattern of Glacier Recession in Indian Himalaya

    Science.gov (United States)

    Singh, Ajay; Patwardhan, Anand

    All currently available climate models predict a near-surface warming trend under the influence of rising levels of greenhouse gases in the atmosphere. In addition to the direct effects on climate — for example, on the frequency of heat waves — this increase in surface temperatures has important consequences for the cryosphere subsequently hydrological cycle, particularly in regions where water supply is currently dominated by melting snow or ice. The Indian Himalayan region occupies a special place in the mountain ecosystems of the world. These geodynamically young mountains are not only important from the standpoint of climate and as a provider of life, giving water to a large part of the Indian subcontinent, but they also harbor a rich variety of flora, fauna, human communities and cultural diversity. Glaciers in this region are changing in area as well as in volume like those in other parts of the world. Studies have been carried out for recession in some of these glaciers using remote sensing as well as field observation techniques. Spatiotemporal pattern in the recession rate of the studied glaciers has been presented in this paper. Plausible causes for the recession have been also discussed. Finally, future scopes for observation and analysis in glaciers recession have been suggested.

  11. Nevada, the Great Recession, and Education

    Science.gov (United States)

    Verstegen, Deborah A.

    2013-01-01

    The impact of the Great Recession and its aftermath has been devastating in Nevada, especially for public education. This article discusses the budget shortfalls and the impact of the economic crisis in Nevada using case study methodology. It provides a review of documents, including Governor Gibbon's proposals for the public K-12 education system…

  12. The Labor Market and the Great Recession

    NARCIS (Netherlands)

    Hobijn, B.; Elsby, M.W.L.; Sahin, A.

    2010-01-01

    From the perspective of a wide range of labor market outcomes, the recession that began in 2007 represents the deepest downturn in the postwar era. Early on, the nature of labor market adjustment displayed a notable resemblance to that observed in past severe downturns. During the latter half of

  13. ECONOMIC RECESSION A CALL FOR COMPETITIVE INTELLIGENCE

    OpenAIRE

    Lucian Marius IVANOV

    2011-01-01

    Global recession brought about a significant growth in competition, stressing the need for relevant and reliable intelligence as a support for making efficient strategic decisions. The recent circumstances draw the attention far more earnestly this time on the need for an intelligence structure within companies to be ready for sustaining business management endeavours in line with increasing competitiveness, protection and promotion of their interests.

  14. Recess for Students with Visual Impairments

    Science.gov (United States)

    Lucas, Matthew D.

    2010-01-01

    During recess, the participation of a student with visual impairments in terms of movement can often be both challenging and rewarding for the student and general education teacher. This paper will address common characteristics of students with visual impairments and present basic solutions to improve the participation of these students in the…

  15. Results after gastrocnemius recession in 73 patients.

    Science.gov (United States)

    Molund, Marius; Paulsrud, Øyvind; Ellingsen Husebye, Elisabeth; Nilsen, Fredrik; Hvaal, Kjetil

    2014-12-01

    Very few studies describe the clinical results and complications following the surgical procedure of gastrocnemius recession. To survey the patient reported outcomes in patients operated with gastrocnemius recession as single procedure for various foot conditions. 93 patients operated with gastrocnemius recession as single procedure between 2006 and 2011 were detected in the database. 73 patients responded to the invitation for study participation. Questionnaires containing patient reported satisfaction, complications, plantar flexion power and visual analog pain score were used for evaluation of the postoperative result. 45/73 (62%) patients reported a good or excellent result. 8/73 (11%) patients reported a significant postoperative complication. 16/73 (22%) patients noted reduced or severely reduced plantar flexion power after surgery. VAS pain score significantly decreased from 7.0 before surgery to 1.8 (p=0.015) after surgery for patients with plantar fasciitis (n=18) and from 5.6 to 2.3 (p<0.01) for patients with metatarsalgia (n=28). Patients treated with gastrocnemius recession for plantar fasciitis demonstrated good clinical results. The complication rate was higher than reported by others. Copyright © 2014 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.

  16. Deducing the pathogenic contribution of recessive ABCA4 alleles in an outbred population.

    Science.gov (United States)

    Schindler, Emily I; Nylen, Erik L; Ko, Audrey C; Affatigato, Louisa M; Heggen, Andrew C; Wang, Kai; Sheffield, Val C; Stone, Edwin M

    2010-10-01

    Accurate prediction of the pathogenic effects of specific genotypes is important for the design and execution of clinical trials as well as for meaningful counseling of individual patients. However, for many autosomal recessive diseases, it can be difficult to deduce the relative pathogenic contribution of individual alleles because relatively few affected individuals share the same two disease-causing variations. In this study, we used multiple regression analysis to estimate the pathogenicity of specific alleles of ABCA4 in patients with retinal phenotypes ranging from Stargardt disease to retinitis pigmentosa. This analysis revealed quantitative allelic effects on two aspects of the visual phenotype, visual acuity (P disease and will also aid in the optimal selection of subjects for clinical trials of new therapies.

  17. Compound Heterozygosity of Dominant and Recessive COL7A Alleles in a Severely Affected Patient with a Family History of Dystrophic Epidermolysis Bullosa: Clinical Findings, Genetic Testing, and Treatment Implications.

    Science.gov (United States)

    Watson, Kendra D; Schoch, Jennifer J; Beek, Geoffrey J; Hand, Jennifer L

    2017-03-01

    An 8-year-old girl born to a family with more than three generations of dominant dystrophic epidermolysis bullosa (DDEB) presented with life-threatening confluent skin erosions, mitten hand deformity, and failure to thrive. Reassessment of her family history and genetic testing showed compound heterozygous COL7A mutations, one inherited from her DDEB-affected mother and one from her unaffected, healthy father. This family illustrates the risk of unexpected, severe, autosomal recessive epidermolysis bullosa (EB) in a family with milder, multigenerational autosomal dominant EB. Clinicians should recognize the clinical spectrum of dystrophic EB and recommend genetic consultation when the phenotype conflicts with family history. © 2017 Wiley Periodicals, Inc.

  18. MRI of autosomal dominant pure spastic paraplegia

    International Nuclear Information System (INIS)

    Krabbe, K.; Fallentin, E.; Herning, M.; Nielsen, J.E.; Fenger, K.

    1997-01-01

    We examined 16 patients with autosomal dominant pure spastic paraplegia (HSP) and 15 normal controls matched for age and sex using MRI of the brain and spinal cord. Images were assessed qualitatively by two independent radiologists, blinded to the clinical diagnosis. Areas of the brain and corpus callosum on one midsagittal slice and the area of the brain on one axial slice were measured and a ''corpus-callosum index'' expressing the size of the corpus callosum relative to that of the brain was calculated. Cross-sectional areas and anteroposterior and transverse diameters of the spinal cord at the levels of C 2, C 5, T 3, T 6, T 9 and T 11 were measured. No significant differences between patients and controls were found on qualitative evaluation of the images. The patients had a significantly smaller corpus callosum and ''corpus-callosum index'' than controls. This finding, not reported previously, might indicate that the disease process in pure HSP is not confined to the spinal cord. The anteroposterior diameters of the spinal cord at T 3 and T 9 were significantly smaller in patients than in controls. This might correspond to the degeneration of the pyramidal tracts and the dorsal columns described at neuropathological examination. (orig.). With 1 fig., 3 tabs

  19. MRI of autosomal dominant pure spastic paraplegia

    Energy Technology Data Exchange (ETDEWEB)

    Krabbe, K.; Fallentin, E.; Herning, M. [Danish Research Center of Magnetic Resonance, Hvidovre Hospital, Kettegaard alle 30, DK-2650 Hvidovre (Denmark); Nielsen, J.E.; Fenger, K. [Institute of Medical Biochemistry and Genetics, Laboratory of Medical Genetics, Section of Neurogenetics, University of Copenhagen (Denmark)

    1997-10-01

    We examined 16 patients with autosomal dominant pure spastic paraplegia (HSP) and 15 normal controls matched for age and sex using MRI of the brain and spinal cord. Images were assessed qualitatively by two independent radiologists, blinded to the clinical diagnosis. Areas of the brain and corpus callosum on one midsagittal slice and the area of the brain on one axial slice were measured and a ``corpus-callosum index`` expressing the size of the corpus callosum relative to that of the brain was calculated. Cross-sectional areas and anteroposterior and transverse diameters of the spinal cord at the levels of C 2, C 5, T 3, T 6, T 9 and T 11 were measured. No significant differences between patients and controls were found on qualitative evaluation of the images. The patients had a significantly smaller corpus callosum and ``corpus-callosum index`` than controls. This finding, not reported previously, might indicate that the disease process in pure HSP is not confined to the spinal cord. The anteroposterior diameters of the spinal cord at T 3 and T 9 were significantly smaller in patients than in controls. This might correspond to the degeneration of the pyramidal tracts and the dorsal columns described at neuropathological examination. (orig.). With 1 fig., 3 tabs.

  20. Autosomal Dominant Growth Hormone Deficiency (Type II).

    Science.gov (United States)

    Alatzoglou, Kyriaki S; Kular, Dalvir; Dattani, Mehul T

    2015-06-01

    Isolated growth hormone deficiency (IGHD) is the commonest pituitary hormone deficiency resulting from congenital or acquired causes, although for most patients its etiology remains unknown. Among the known factors, heterozygous mutations in the growth hormone gene (GH1) lead to the autosomal dominant form of GHD, also known as type II GHD. In many cohorts this is the commonest form of congenital isolated GHD and is mainly caused by mutations that affect the correct splicing of GH-1. These mutations cause skipping of the third exon and lead to the production of a 17.5-kDa GH isoform that exerts a dominant negative effect on the secretion of the wild type GH. The identification of these mutations has clinical implications for the management of patients, as there is a well-documented correlation between the severity of the phenotype and the increased expression of the 17.5-kDa isoform. Patients with type II GHD have a variable height deficit and severity of GHD and may develop additional pituitary hormone defiencies over time, including ACTH, TSH and gonadotropin deficiencies. Therefore, their lifelong follow-up is recommended. Detailed studies on the effect of heterozygous GH1 mutations on the trafficking, secretion and action of growth hormone can elucidate their mechanism on a cellular level and may influence future treatment options for GHD type II.

  1. Recessive mutations in SPTBN2 implicate β-III spectrin in both cognitive and motor development.

    Directory of Open Access Journals (Sweden)

    Stefano Lise

    Full Text Available β-III spectrin is present in the brain and is known to be important in the function of the cerebellum. Heterozygous mutations in SPTBN2, the gene encoding β-III spectrin, cause Spinocerebellar Ataxia Type 5 (SCA5, an adult-onset, slowly progressive, autosomal-dominant pure cerebellar ataxia. SCA5 is sometimes known as "Lincoln ataxia," because the largest known family is descended from relatives of the United States President Abraham Lincoln. Using targeted capture and next-generation sequencing, we identified a homozygous stop codon in SPTBN2 in a consanguineous family in which childhood developmental ataxia co-segregates with cognitive impairment. The cognitive impairment could result from mutations in a second gene, but further analysis using whole-genome sequencing combined with SNP array analysis did not reveal any evidence of other mutations. We also examined a mouse knockout of β-III spectrin in which ataxia and progressive degeneration of cerebellar Purkinje cells has been previously reported and found morphological abnormalities in neurons from prefrontal cortex and deficits in object recognition tasks, consistent with the human cognitive phenotype. These data provide the first evidence that β-III spectrin plays an important role in cortical brain development and cognition, in addition to its function in the cerebellum; and we conclude that cognitive impairment is an integral part of this novel recessive ataxic syndrome, Spectrin-associated Autosomal Recessive Cerebellar Ataxia type 1 (SPARCA1. In addition, the identification of SPARCA1 and normal heterozygous carriers of the stop codon in SPTBN2 provides insights into the mechanism of molecular dominance in SCA5 and demonstrates that the cell-specific repertoire of spectrin subunits underlies a novel group of disorders, the neuronal spectrinopathies, which includes SCA5, SPARCA1, and a form of West syndrome.

  2. Molecular diagnosis of known recessive ataxias by homozygosity mapping with SNP arrays.

    Science.gov (United States)

    H'mida-Ben Brahim, D; M'zahem, A; Assoum, M; Bouhlal, Y; Fattori, F; Anheim, M; Ali-Pacha, L; Ferrat, F; Chaouch, M; Lagier-Tourenne, C; Drouot, N; Thibaut, C; Benhassine, T; Sifi, Y; Stoppa-Lyonnet, D; N'Guyen, K; Poujet, J; Hamri, A; Hentati, F; Amouri, R; Santorelli, F M; Tazir, M; Koenig, M

    2011-01-01

    The diagnosis of rare inherited diseases is becoming more and more complex as an increasing number of clinical conditions appear to be genetically heterogeneous. Multigenic inheritance also applies to the autosomal recessive progressive cerebellar ataxias (ARCAs), for which 14 genes have been identified and more are expected to be discovered. We used homozygosity mapping as a guide for identification of the defective locus in patients with ARCA born from consanguineous parents. Patients from 97 families were analyzed with GeneChip Mapping 10K or 50K SNP Affymetrix microarrays. We identified six families homozygous for regions containing the autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) gene, two families homozygous for the ataxia-telangiectasia gene (ATM), two families homozygous for the ataxia with oculomotor apraxia type 1 (AOA1) gene, and one family homozygous for the AOA type 2 (AOA2) gene. Upon direct gene testing, we were able to identify a disease-related mutation in all families but one of the two kindred homozygous at the ATM locus. Although linkage analyses pointed to a single locus on chromosome 11q22.1-q23.1 for this family, clinical features, normal levels of serum alpha-foetoprotein as well as absence of mutations in the ATM gene rather suggest the existence of an additional ARCA-related gene in that interval. While the use of homozygosity mapping was very effective at pointing to the correct gene, it also suggests that the majority of patients harbor mutations either in the genes of the rare forms of ARCA or in genes yet to be identified.

  3. Formulating the spring discharge-function for the recession period ...

    Indian Academy of Sciences (India)

    College of Agricultural Engineering & Post Harvest Technology (CAEPHT),. Central Agricultural ... during the recession period is the key to its proper management. The spring .... In equation (1), Q is the recession flow, t is time, and a, b are ...

  4. A novel missense mutation in the CLCN7 gene linked to benign autosomal dominant osteopetrosis: a case series

    Directory of Open Access Journals (Sweden)

    Rashid Ban Mousa

    2013-01-01

    Full Text Available Abstract Introduction Osteopetrosis is a rare inherited genetic disease characterized by sclerosis of the skeleton. The absence or malfunction of osteoclasts is found to be strongly associated with the disease evolution. Currently, four clinically distinct forms of the disease have been recognized: the infantile autosomal recessive osteopetrosis, the malignant and the intermediate forms, and autosomal dominant osteopetrosis, type I and type II forms. The autosomal recessive types are the most severe forms with symptoms in very early childhood, whereas the autosomal dominant classes exhibit a heterogeneous trait with milder symptoms, often at later childhood or adulthood. Case presentation Case 1 is the 12-year-old daughter (index patient of an Iraqi-Kurdish family who, at the age of eight years, was diagnosed clinically to have mild autosomal dominant osteopetrosis. Presently, at 12-years old, she has severe complications due to the disease progression. In addition, the same family previously experienced the death of a female child in her late childhood. The deceased child had been misdiagnosed, at that time, with thalassemia major. In this report, we extended our investigation to identify the type of the inheritance patterns of osteopetrosis using molecular techniques, because consanguineous marriages exist within the family history. We have detected one heterozygous mutation in exon 15 of the Chloride Channel 7 gene in the index patient (Case 1, whereas other mutations were not detected in the associated genes TCIRG1, OSTM1, RANK, and RANKL. The missense mutation (CGG>TGG located in exon 15 (c.1225C>T of the Chloride Channel 7 gene changed the amino acid position 409 from arginine to tryptophan (p.R409W, c.1225C>T. Case 2 is the 16-year-old son (brother of the index patient of the same family who was diagnosed clinically with mild autosomal dominant osteopetrosis. We have identified the same heterozygous mutation in exon 15 of the Chloride

  5. A novel missense mutation in the CLCN7 gene linked to benign autosomal dominant osteopetrosis: a case series.

    Science.gov (United States)

    Rashid, Ban Mousa; Rashid, Nawshirwan Gafoor; Schulz, Ansgar; Lahr, Georgia; Nore, Beston Faiek

    2013-01-09

    Osteopetrosis is a rare inherited genetic disease characterized by sclerosis of the skeleton. The absence or malfunction of osteoclasts is found to be strongly associated with the disease evolution. Currently, four clinically distinct forms of the disease have been recognized: the infantile autosomal recessive osteopetrosis, the malignant and the intermediate forms, and autosomal dominant osteopetrosis, type I and type II forms. The autosomal recessive types are the most severe forms with symptoms in very early childhood, whereas the autosomal dominant classes exhibit a heterogeneous trait with milder symptoms, often at later childhood or adulthood. Case 1 is the 12-year-old daughter (index patient) of an Iraqi-Kurdish family who, at the age of eight years, was diagnosed clinically to have mild autosomal dominant osteopetrosis. Presently, at 12-years old, she has severe complications due to the disease progression. In addition, the same family previously experienced the death of a female child in her late childhood. The deceased child had been misdiagnosed, at that time, with thalassemia major. In this report, we extended our investigation to identify the type of the inheritance patterns of osteopetrosis using molecular techniques, because consanguineous marriages exist within the family history. We have detected one heterozygous mutation in exon 15 of the Chloride Channel 7 gene in the index patient (Case 1), whereas other mutations were not detected in the associated genes TCIRG1, OSTM1, RANK, and RANKL. The missense mutation (CGG>TGG) located in exon 15 (c.1225C>T) of the Chloride Channel 7 gene changed the amino acid position 409 from arginine to tryptophan (p.R409W, c.1225C>T).Case 2 is the 16-year-old son (brother of the index patient) of the same family who was diagnosed clinically with mild autosomal dominant osteopetrosis. We have identified the same heterozygous mutation in exon 15 of the Chloride channel 7 gene in this patient (Case 2). The missense

  6. Genetics Home Reference: autosomal dominant leukodystrophy with autonomic disease

    Science.gov (United States)

    ... have muscle stiffness (spasticity) or weakness and involuntary rhythmic shaking, called intention tremor because it worsens during ... Hobson G, Brusco A, Brussino A, Padiath QS. Analysis of LMNB1 duplications in autosomal dominant leukodystrophy provides ...

  7. Genetics Home Reference: autosomal dominant congenital stationary night blindness

    Science.gov (United States)

    ... collapse boxes. Description Autosomal dominant congenital stationary night blindness is a disorder of the retina , which is the specialized tissue at the back of the eye that detects light and color. People with this condition typically have difficulty seeing ...

  8. Genetics Home Reference: autosomal dominant nocturnal frontal lobe epilepsy

    Science.gov (United States)

    ... with ADNFLE have experienced psychiatric disorders (such as schizophrenia), behavioral problems, or intellectual disability. It is unclear ... Epilepsy Society Citizens United for Research in Epilepsy (CURE) GeneReviews (1 link) Autosomal Dominant Nocturnal Frontal Lobe ...

  9. De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome.

    Science.gov (United States)

    Burrage, Lindsay C; Charng, Wu-Lin; Eldomery, Mohammad K; Willer, Jason R; Davis, Erica E; Lugtenberg, Dorien; Zhu, Wenmiao; Leduc, Magalie S; Akdemir, Zeynep C; Azamian, Mahshid; Zapata, Gladys; Hernandez, Patricia P; Schoots, Jeroen; de Munnik, Sonja A; Roepman, Ronald; Pearring, Jillian N; Jhangiani, Shalini; Katsanis, Nicholas; Vissers, Lisenka E L M; Brunner, Han G; Beaudet, Arthur L; Rosenfeld, Jill A; Muzny, Donna M; Gibbs, Richard A; Eng, Christine M; Xia, Fan; Lalani, Seema R; Lupski, James R; Bongers, Ernie M H F; Yang, Yaping

    2015-12-03

    Meier-Gorlin syndrome (MGS) is a genetically heterogeneous primordial dwarfism syndrome known to be caused by biallelic loss-of-function mutations in one of five genes encoding pre-replication complex proteins: ORC1, ORC4, ORC6, CDT1, and CDC6. Mutations in these genes cause disruption of the origin of DNA replication initiation. To date, only an autosomal-recessive inheritance pattern has been described in individuals with this disorder, with a molecular etiology established in about three-fourths of cases. Here, we report three subjects with MGS and de novo heterozygous mutations in the 5' end of GMNN, encoding the DNA replication inhibitor geminin. We identified two truncating mutations in exon 2 (the 1(st) coding exon), c.16A>T (p.Lys6(∗)) and c.35_38delTCAA (p.Ile12Lysfs(∗)4), and one missense mutation, c.50A>G (p.Lys17Arg), affecting the second-to-last nucleotide of exon 2 and possibly RNA splicing. Geminin is present during the S, G2, and M phases of the cell cycle and is degraded during the metaphase-anaphase transition by the anaphase-promoting complex (APC), which recognizes the destruction box sequence near the 5' end of the geminin protein. All three GMNN mutations identified alter sites 5' to residue Met28 of the protein, which is located within the destruction box. We present data supporting a gain-of-function mechanism, in which the GMNN mutations result in proteins lacking the destruction box and hence increased protein stability and prolonged inhibition of replication leading to autosomal-dominant MGS. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  10. Three novel GJB2 (connexin 26) variants associated with autosomal dominant syndromic and nonsyndromic hearing loss.

    Science.gov (United States)

    DeMille, Desiree; Carlston, Colleen M; Tam, Oliver H; Palumbos, Janice C; Stalker, Heather J; Mao, Rong; Zori, Roberto T; Viskochil, David H; Park, Albert H; Carey, John C

    2018-04-01

    Connexin 26 (Cx26), encoded by the GJB2 gene, is a key protein involved in the formation of gap junctions in epithelial organs including the inner ear and palmoplantar epidermis. Pathogenic variants in GJB2 are responsible for approximately 50% of inherited sensorineural deafness. The majority of these variants are associated with autosomal recessive inheritance; however, rare reports of dominantly co-segregating variants have been published. Since we began offering GJB2 testing in 2003, only about 2% of detected GJB2 variants from our laboratory have been classified as dominant. Here we report three novel dominant GJB2 variants (p.Thr55Ala, p.Gln57_Pro58delinsHisSer, and p.Trp44Gly); two associated with syndromic sensorineural hearing loss and one with nonsyndromic hearing loss. In the kindred with the p.Thr55Ala variant, the proband and his father present with only leukonychia as a cutaneous finding of their syndromic hearing loss. This phenotype has been previously documented in conjunction with palmoplantar hyperkeratosis, but isolated leukonychia is a novel finding likely associated with the unique threonine to alanine change at codon 55 (other variants at this codon have been reported in cases of nonsyndromic hearing loss). This report contributes to the short list of GJB2 variants associated with autosomal dominant hearing loss, highlights the variability of skin and nail findings associated with such cases, and illustrates the occurrence of both syndromic and nonsyndromic presentations with changes in the same gene. © 2018 Wiley Periodicals, Inc.

  11. Semiconductor structure and recess formation etch technique

    Energy Technology Data Exchange (ETDEWEB)

    Lu, Bin; Sun, Min; Palacios, Tomas Apostol

    2017-02-14

    A semiconductor structure has a first layer that includes a first semiconductor material and a second layer that includes a second semiconductor material. The first semiconductor material is selectively etchable over the second semiconductor material using a first etching process. The first layer is disposed over the second layer. A recess is disposed at least in the first layer. Also described is a method of forming a semiconductor structure that includes a recess. The method includes etching a region in a first layer using a first etching process. The first layer includes a first semiconductor material. The first etching process stops at a second layer beneath the first layer. The second layer includes a second semiconductor material.

  12. Diagnostic Impact and Cost-effectiveness of Whole-Exome Sequencing for Ambulant Children With Suspected Monogenic Conditions.

    Science.gov (United States)

    Tan, Tiong Yang; Dillon, Oliver James; Stark, Zornitza; Schofield, Deborah; Alam, Khurshid; Shrestha, Rupendra; Chong, Belinda; Phelan, Dean; Brett, Gemma R; Creed, Emma; Jarmolowicz, Anna; Yap, Patrick; Walsh, Maie; Downie, Lilian; Amor, David J; Savarirayan, Ravi; McGillivray, George; Yeung, Alison; Peters, Heidi; Robertson, Susan J; Robinson, Aaron J; Macciocca, Ivan; Sadedin, Simon; Bell, Katrina; Oshlack, Alicia; Georgeson, Peter; Thorne, Natalie; Gaff, Clara; White, Susan M

    2017-09-01

    Optimal use of whole-exome sequencing (WES) in the pediatric setting requires an understanding of who should be considered for testing and when it should be performed to maximize clinical utility and cost-effectiveness. To investigate the impact of WES in sequencing-naive children suspected of having a monogenic disorder and evaluate its cost-effectiveness if WES had been available at different time points in their diagnostic trajectory. This prospective study was part of the Melbourne Genomics Health Alliance demonstration project. At the ambulatory outpatient clinics of the Victorian Clinical Genetics Services at the Royal Children's Hospital, Melbourne, Australia, children older than 2 years suspected of having a monogenic disorder were prospectively recruited from May 1 through November 30, 2015, by clinical geneticists after referral from general and subspecialist pediatricians. All children had nondiagnostic microarrays and no prior single-gene or panel sequencing. All children underwent singleton WES with targeted phenotype-driven analysis. The study examined the clinical utility of a molecular diagnosis and the cost-effectiveness of alternative diagnostic trajectories, depending on timing of WES. Of 61 children originally assessed, 44 (21 [48%] male and 23 [52%] female) aged 2 to 18 years (mean age at initial presentation, 28 months; range, 0-121 months) were recruited, and a diagnosis was achieved in 23 (52%) by singleton WES. The diagnoses were unexpected in 8 of 23 (35%), and clinical management was altered in 6 of 23 (26%). The mean duration of the diagnostic odyssey was 6 years, with each child having a mean of 19 tests and 4 clinical genetics and 4 nongenetics specialist consultations, and 26 (59%) underwent a procedure while under general anesthetic for diagnostic purposes. Economic analyses of the diagnostic trajectory identified that WES performed at initial tertiary presentation resulted in an incremental cost savings of A$9020 (US$6838) per

  13. POSSIBLE RECESSION CURVE APPLICATIONS FOR RETENTION EVALUATION

    Directory of Open Access Journals (Sweden)

    Daniel Liberacki

    2015-11-01

    Full Text Available The objective of the article was to present possible applications of recession flow curve in a small lowland watershed retention discharge size evaluation. The examined woodland micro catchment area of 0.52 sq km is located in Puszcza Zielonka in central Wielkopolska. The Hutka catchment is typically woody with high retention abilities. The catchment of the Hutka watercourse is forested in 89%, the other 11% is covered by swamps and wasteland. The predominant sites are fresh mixed coniferous forest (BMśw, fresh coniferous forest (Bśw and alder carr forest (Ol. Landscape in catchment is characterized by a large number of interior depressions, filled partly with rainwater or peatbogs, with poorly developed natural drainage. The watercourses do not exceed 1 km in length, the mean width is approx. 0.5 m, while mean depth ranges from 0.2 to 0.3 m. During hydrological research conducted in 1997/1998–1999/2000, 35 major (characteristic raised water stages were observed in Hutka after substantial precipitation. The recession curve dating from 18–24 September 2000 has the α and n rates nearest to average. Comparing the model curve and the curve created by observing watercourse flow, one can notice their resemblance and that they have similar ordinate values as well as shape. In the case of other recession curves, the maximum differences of ordinate values are also about 0.1–0.2 l/s/km2. The measuured α and n rates do not reveal any regularities. There are no significant statistical Horton model parameter (for recession flow curves dependencies between α and n and e.g. initial flows (Qo or the whole period of high water waves (Qp. Consequently, calculated relation between these parameters is only an approximation for the general evaluation of the retention discharge in the catchment area towards retention with flow function.

  14. Financialisation, oil and the Great Recession

    International Nuclear Information System (INIS)

    Gkanoutas-Leventis, Angelos; Nesvetailova, Anastasia

    2015-01-01

    This article addresses the role of world oil price hike of 2007–08 in serving to transform the financial and banking crisis into what is commonly referred to the Great Recession. Existing literature on the global crisis of 2007–09 tends to view it as a financial or banking phenomenon, with analyses focusing mainly on state policies, governance mechanisms and market dynamics in transforming the banking crisis of 2007–08 into the economic recession of 2008-12/13 Although often attributing the global meltdown to wider phenomenon of financialisation, rarely do existing perspectives delve into the role of the commodity sector in the global credit crunch. In this paper, we aim to fill this gap, by inquiring into the role played by oil as a financial asset class in the political economy of the global crisis. - Highlights: • We study the oil price and its effects on the Great Recession. • We approach oil as a financial asset class. • We observe the transformation of oil through deregulation.

  15. Plasma levels of 27-hydroxycholesterol in humans and mice with monogenic disturbances of high density lipoprotein metabolism

    DEFF Research Database (Denmark)

    Karuna, Ratna; Holleboom, Adriaan G; Motazacker, Mohammad M

    2011-01-01

    Secretion of 27-hydroxycholesterol (27OHC) from macrophages is considered as an alternative to HDL-mediated reverse transport of excess cholesterol. We investigated 27OHC-concentrations in plasma of humans and mice with monogenic disorders of HDL metabolism. As compared to family controls mutations...... activities of LCAT and CETP, respectively, than the formation and transfer of cholesterylesters. 27OHC plasma levels were also decreased in apoA-I-, ABCA1- or LCAT-knockout mice but increased in SR-BI-knockout mice. Transplantation of ABCA1- and/or ABCG1-deficient bone marrow into LDL receptor deficient mice...... decreased plasma levels of 27OHC. In conclusion, mutations or absence of HDL genes lead to distinct alterations in the quantity, esterification or lipoprotein distribution of 27OHC. These findings argue against the earlier suggestion that 27OHC-metabolism in plasma occurs independently of HDL....

  16. Berberine slows cell growth in autosomal dominant polycystic kidney disease cells

    International Nuclear Information System (INIS)

    Bonon, Anna; Mangolini, Alessandra; Pinton, Paolo; Senno, Laura del; Aguiari, Gianluca

    2013-01-01

    Highlights: •Berberine at appropriate doses slows cell proliferation in ADPKD cystic cells. •Reduction of cell growth by berberine occurs by inhibition of ERK and p70-S6 kinase. •Higher doses of berberine cause an overall cytotoxic effect. •Berberine overdose induces apoptotic bodies formation and DNA fragmentation. •Antiproliferative properties of this drug make it a new candidate for ADPKD therapy. -- Abstract: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary monogenic disorder characterized by development and enlargement of kidney cysts that lead to loss of renal function. It is caused by mutations in two genes (PKD1 and PKD2) encoding for polycystin-1 and polycystin-2 proteins which regulate different signals including cAMP, mTOR and EGFR pathways. Abnormal activation of these signals following PC1 or PC2 loss of function causes an increased cell proliferation which is a typical hallmark of this disease. Despite the promising findings obtained in animal models with targeted inhibitors able to reduce cystic cell growth, currently, no specific approved therapy for ADPKD is available. Therefore, the research of new more effective molecules could be crucial for the treatment of this severe pathology. In this regard, we have studied the effect of berberine, an isoquinoline quaternary alkaloid, on cell proliferation and apoptosis in human and mouse ADPKD cystic cell lines. Berberine treatment slows cell proliferation of ADPKD cystic cells in a dose-dependent manner and at high doses (100 μg/mL) it induces cell death in cystic cells as well as in normal kidney tubule cells. However, at 10 μg/mL, berberine reduces cell growth in ADPKD cystic cells only enhancing G 0 /G 1 phase of cell cycle and inhibiting ERK and p70-S6 kinases. Our results indicate that berberine shows a selected antiproliferative activity in cellular models for ADPKD, suggesting that this molecule and similar natural compounds could open new opportunities

  17. Berberine slows cell growth in autosomal dominant polycystic kidney disease cells

    Energy Technology Data Exchange (ETDEWEB)

    Bonon, Anna; Mangolini, Alessandra [Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, 44121 Ferrara (Italy); Pinton, Paolo [Department of Morphology, Surgery and Experimental Medicine, Section of General Pathology, University of Ferrara, 44121 Ferrara (Italy); Senno, Laura del [Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, 44121 Ferrara (Italy); Aguiari, Gianluca, E-mail: dsn@unife.it [Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, 44121 Ferrara (Italy)

    2013-11-22

    Highlights: •Berberine at appropriate doses slows cell proliferation in ADPKD cystic cells. •Reduction of cell growth by berberine occurs by inhibition of ERK and p70-S6 kinase. •Higher doses of berberine cause an overall cytotoxic effect. •Berberine overdose induces apoptotic bodies formation and DNA fragmentation. •Antiproliferative properties of this drug make it a new candidate for ADPKD therapy. -- Abstract: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary monogenic disorder characterized by development and enlargement of kidney cysts that lead to loss of renal function. It is caused by mutations in two genes (PKD1 and PKD2) encoding for polycystin-1 and polycystin-2 proteins which regulate different signals including cAMP, mTOR and EGFR pathways. Abnormal activation of these signals following PC1 or PC2 loss of function causes an increased cell proliferation which is a typical hallmark of this disease. Despite the promising findings obtained in animal models with targeted inhibitors able to reduce cystic cell growth, currently, no specific approved therapy for ADPKD is available. Therefore, the research of new more effective molecules could be crucial for the treatment of this severe pathology. In this regard, we have studied the effect of berberine, an isoquinoline quaternary alkaloid, on cell proliferation and apoptosis in human and mouse ADPKD cystic cell lines. Berberine treatment slows cell proliferation of ADPKD cystic cells in a dose-dependent manner and at high doses (100 μg/mL) it induces cell death in cystic cells as well as in normal kidney tubule cells. However, at 10 μg/mL, berberine reduces cell growth in ADPKD cystic cells only enhancing G{sub 0}/G{sub 1} phase of cell cycle and inhibiting ERK and p70-S6 kinases. Our results indicate that berberine shows a selected antiproliferative activity in cellular models for ADPKD, suggesting that this molecule and similar natural compounds could open new

  18. Clinical and molecular analysis of the enamelin gene ENAM in Colombian families with autosomal dominant amelogenesis imperfecta

    Directory of Open Access Journals (Sweden)

    Sandra Gutiérrez

    2012-01-01

    Full Text Available In this study, we analyzed the phenotype, clinical characteristics and presence of mutations in the enamelin gene ENAM in five Colombian families with autosomal dominant amelogenesis imperfecta (ADAI. 22 individuals (15 affected and seven unaffected belonging to five Colombian families with ADAI and eight individuals (three affected and five unaffected belonging to three Colombian families with autosomal recessive amelogenesis imperfecta (ARAI that served as controls for molecular alterations and inheritance patterns were studied. Clinical, radiographic and genetic evaluations were done in all individuals. Eight exons and three intron-exon boundaries were sequenced for mutation analysis. Two of the five families with ADAI had the hypoplasic phenotype, two had the hypocalcified phenotype and one had the hypomaturative phenotype. Anterior open bite and mandibular retrognathism were the most frequent skeletal abnormalities in the families with ADAI. No mutations were found. These findings suggest that ADAI in these Colombian families was unrelated to previously described mutations in the ENAM gene. These results also indicate that other regions not included in this investigation, such as the promoter region, introns and other genes should be considered as potential ADAI candidates.

  19. Autosomal dominant distal myopathy due to a novel ACTA1 mutation.

    Science.gov (United States)

    Liewluck, Teerin; Sorenson, Eric J; Walkiewicz, Magdalena A; Rumilla, Kandelaria M; Milone, Margherita

    2017-08-01

    Mutations in skeletal muscle α-actin 1-encoding gene (ACTA1) cause autosomal dominant or recessive myopathies with marked clinical and pathological heterogeneity. Patients typically develop generalized or limb-girdle pattern of weakness, but recently a family with scapuloperoneal myopathy was reported. We describe a father and 2 children with childhood-to-juvenile onset distal myopathy, carrying a novel dominant ACTA1 variant, c.757G>C (p.Gly253Arg). Father had delayed motor development and developed significant proximal weakness later in life; he was initially misdiagnosed as having spinal muscular atrophy based on electromyographic findings. His children had predominant anterior distal leg and finger extensor involvement. Nemaline rods were abundant on the daughter's biopsy, absent on the father's initial biopsy, and extremely rare on the father's subsequent biopsy a decade later. The father's second biopsy also showed myofibrillar pathology and rare fibers with actin filament aggregates. The present family expands the spectrum of actinopathy to include a distal myopathy. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. The Great Recession, unemployment and suicide.

    Science.gov (United States)

    Norström, Thor; Grönqvist, Hans

    2015-02-01

    How have suicide rates responded to the marked increase in unemployment spurred by the Great Recession? Our paper puts this issue into a wider perspective by assessing (1) whether the unemployment-suicide link is modified by the degree of unemployment protection, and (2) whether the effect on suicide of the present crisis differs from the effects of previous economic downturns. We analysed the unemployment-suicide link using time-series data for 30 countries spanning the period 1960-2012. Separate fixed-effects models were estimated for each of five welfare state regimes with different levels of unemployment protection (Eastern, Southern, Anglo-Saxon, Bismarckian and Scandinavian). We included an interaction term to capture the possible excess effect of unemployment during the Great Recession. The largest unemployment increases occurred in the welfare state regimes with the least generous unemployment protection. The unemployment effect on male suicides was statistically significant in all welfare regimes, except the Scandinavian one. The effect on female suicides was significant only in the eastern European country group. There was a significant gradient in the effects, being stronger the less generous the unemployment protection. The interaction term capturing the possible excess effect of unemployment during the financial crisis was not significant. Our findings suggest that the more generous the unemployment protection the weaker the detrimental impact on suicide of the increasing unemployment during the Great Recession. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  1. Impact of recession on Swiss pension program.

    Science.gov (United States)

    McArdle, F B

    1978-04-01

    Legislation drafted in Switzerland in 1975--77 aims at countering the effects of inflation and recession by bringing increased revenues into the system, reducing expenditures, devising a mechanism to adjust pensions automatically, and improving income maintenance for the unemployed. The proposed legislation to place the social security system on a sound financial basis now needs voter approval in a referendum. Swiss voters meanwhile rejected (in mid-1977) a government-proposed value-added tax designed to finance increasing government contributions during 1978-82. Still to be resolved, therefore, is the problem of how the government will finance higher contributions and still achieve its staged goal of a balanced budget.

  2. Children's Physical Activity Behavior during School Recess

    DEFF Research Database (Denmark)

    Pawlowski, Charlotte Skau; Andersen, Henriette Bondo; Troelsen, Jens

    2016-01-01

    participated in go-along group interviews, and recess behavior was observed using an ethnographical participant observation approach. All data were analyzed separated systematically answering the Five W Questions. Children were categorized into Low, Middle and High physical activity groups and these groups...... quantitative GPS and accelerometer measurements with qualitative go-along group interviews and participant observations. Data were collected during three weekdays in a public school in Denmark. Eighty-one children (47 girls) wore an accelerometer (ActiGraph GT3X) and GPS (QStarz BT-Q1000xt), sixteen children...

  3. Simple Y-autosomal incompatibilities cause hybrid male sterility in reciprocal crosses between Drosophila virilis and D. americana.

    Science.gov (United States)

    Sweigart, Andrea L

    2010-03-01

    Postzygotic reproductive isolation evolves when hybrid incompatibilities accumulate between diverging populations. Here, I examine the genetic basis of hybrid male sterility between two species of Drosophila, Drosophila virilis and D. americana. From these analyses, I reach several conclusions. First, neither species carries any autosomal dominant hybrid male sterility alleles: reciprocal F(1) hybrid males are perfectly fertile. Second, later generation (backcross and F(2)) hybrid male sterility between D. virilis and D. americana is not polygenic. In fact, I identified only three genetically independent incompatibilities that cause hybrid male sterility. Remarkably, each of these incompatibilities involves the Y chromosome. In one direction of the cross, the D. americana Y is incompatible with recessive D. virilis alleles at loci on chromosomes 2 and 5. In the other direction, the D. virilis Y chromosome causes hybrid male sterility in combination with recessive D. americana alleles at a single QTL on chromosome 5. Finally, in contrast with findings from other Drosophila species pairs, the X chromosome has only a modest effect on hybrid male sterility between D. virilis and D. americana.

  4. State Government Revenue Recovery from the Great Recession

    OpenAIRE

    James Alm; David L. Sjoquist

    2014-01-01

    The "Great Recession" lasted from December 2007 to June 2009, and it wreaked havoc on the revenues of state (and local) governments. While the U.S. economy has improved since the end of the Great Recession, state government revenues have in most cases still not completely recovered. We use various indicators to measure how different states have -- or have not -- recovered in the aftermath of the Great Recession, and we also attempt to explain why these different patterns of recovery have emer...

  5. Cerebral Microbleeds and the Risk of Incident Ischemic Stroke in CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy).

    Science.gov (United States)

    Puy, Laurent; De Guio, François; Godin, Ophélia; Duering, Marco; Dichgans, Martin; Chabriat, Hugues; Jouvent, Eric

    2017-10-01

    Cerebral microbleeds are associated with an increased risk of intracerebral hemorrhage. Recent data suggest that microbleeds may also predict the risk of incident ischemic stroke. However, these results were observed in elderly individuals undertaking various medications and for whom causes of microbleeds and ischemic stroke may differ. We aimed to test the relationship between the presence of microbleeds and incident stroke in CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy)-a severe monogenic small vessel disease known to be responsible for both highly prevalent microbleeds and a high incidence of ischemic stroke in young patients. We assessed microbleeds on baseline MRI in all 378 patients from the Paris-Munich cohort study. Incident ischemic strokes were recorded during 54 months. Survival analyses were used to test the relationship between microbleeds and incident ischemic stroke. Three hundred sixty-nine patients (mean age, 51.4±11.4 years) were followed-up during a median time of 39 months (interquartile range, 19 months). The risk of incident ischemic stroke was higher in patients with microbleeds than in patients without (35.8% versus 19.6%, hazard ratio, 1.87; 95% confidence interval, 1.16-3.01; P =0.009). These results persisted after adjustment for history of ischemic stroke, age, sex, vascular risk factors, and antiplatelet agents use (hazard ratio, 1.89; 95% confidence interval, 1.10-3.26; P =0.02). The presence of microbleeds is an independent risk marker of incident ischemic stroke in CADASIL, emphasizing the need to carefully interpret MRI data. © 2017 American Heart Association, Inc.

  6. CT EVALUATION OF AZYGOESOPHAGEAL RECESS IN ADULTS

    Directory of Open Access Journals (Sweden)

    Kulamani Sahoo

    2015-02-01

    Full Text Available Azygoesophageal recess (AER is right posterior mediastinal recess . Knowledge of normal radiologic appearance and manifestations of disease in AER can facilitate the detection and diagnosis of many intrathoracic diseases ranging from infective processes to tumors involving mediastinum, lung/pleura, lymphatic system, upper gastrointestinal system (esophagus & stomach & cardio - vascular system. Aim of this study was to investigate various intrathoracic pathologies, altering the configuration of AER on CT in adults & to find out any significance with various disease processes. This study was carried out in CT center, Department of Radiodiagnosis, Krishna Institute of medical sciences, Karad from October 2012 - September 2014. CT thorax of 156 patients was studied for configuration of AER irrespective of pathology. In this study , configuration of AER was altered in descending order with pathologies belonging to following systems: Respiratory system (Lung parenchyma pathologies causing volume loss of right lower lobe particularly Koch’s , UIP , Malignancy , Pleural pathologies (Secondary more common than Primary >Lymphatic system(secondary subcarinal lymph node more common than Primary Lymphoma >Cardio - vascular system(Cardiomegaly particularly Left atrial enlargement >Gastrointestinal system ( hiatus herni a & esophageal Cancer > Mediastinum ( Koch’s of dorsal spine with paraspinal abscess.

  7. Child Poverty and the Great Recession in the United States

    OpenAIRE

    Marianne Bitler; Hilary Hoynes; Elira Kuka

    2014-01-01

    In the midst of the Great Recession, median real household income fell from $61,597 in 2007 to $57,025 in 2010 and $51,007 in 2012. Given that the effects of the Great Recession on unemployment were greater for less skilled workers the authors expect the effects of the Great Recession on household incomes to be larger in relative terms for individuals in the lower end of the income distribution. To explore this issue, in this paper, they comprehensively examine the effects of the Great Recess...

  8. Prognostic Indicators of Gingival Recession in Nigeria: Preliminary Findings

    Directory of Open Access Journals (Sweden)

    Michael Adedigba

    2010-06-01

    Full Text Available AIM: Literature is replete with studies on gingival recession, the apical shift of the gingival margin from the cemento-enamel junction. Chronic periodontitis and frequent toothbrushing are among its aetiological factors. Many of these were however prevalence studies. The current study was therefore aimed at separating prognostic indicators from determinants of the number of recessions. METHOD: 650 consecutive adult patients visiting a Nigerian teaching hospital were examined using a checklist including plaque, calculus, Miller’s class of recession and other parameters.. A total of 408 recession sites were identified. RESULTS: The mean age of the patients with recession was 42.3 years; mean number of recession was 4.74 Incisors had the highest number of recessions (35.7%. While a factor such as age was related both to the number and prognosis of recession sites, abrasion and plaque were only related to prognosis. Again, some of the factors previously significantly related to prognosis on univariate analysis like calculus and smoking, lost their significance on regression analysis. CONCLUSION: The three strongest predictors of prognosis (Miller’s class of recession were age, plaque and abrasion. [TAF Prev Med Bull 2010; 9(3.000: 187-194

  9. Gingival recession: a cross-sectional clinical investigation.

    Science.gov (United States)

    Goutoudi, P; Koidis, P T; Konstantinidis, A

    1997-06-01

    In this cross-sectional study, risk and potentially causative factors of gingival recession were examined and their relationship to apical migration of the gingival margin evaluated. Thirty eight patients (18-60 years), displaying one or more sites with gingival recession but without any significant periodontal disease participated. A total of 28 parameters were evaluated in both 'test' teeth (50 teeth with gingival recession) and 'control' teeth (50 contralateral teeth). The results revealed that gingival margin recession was associated with both high inflammatory and plaque scores, with decreased widths of keratinized and attached gingiva and with the subjects' toothbrush bristle hardness.

  10. Autosomal dominant hypercalciuria in a mouse model due to a mutation of the epithelial calcium channel, TRPV5.

    Directory of Open Access Journals (Sweden)

    Nellie Y Loh

    Full Text Available Hypercalciuria is a major cause of nephrolithiasis, and is a common and complex disorder involving genetic and environmental factors. Identification of genetic factors for monogenic forms of hypercalciuria is hampered by the limited availability of large families, and to facilitate such studies, we screened for hypercalciuria in mice from an N-ethyl-N-nitrosourea mutagenesis programme. We identified a mouse with autosomal dominant hypercalciuria (HCALC1. Linkage studies mapped the Hcalc1 locus to a 11.94 Mb region on chromosome 6 containing the transient receptor potential cation channel, subfamily V, members 5 (Trpv5 and 6 (Trpv6 genes. DNA sequence analysis of coding regions, intron-exon boundaries and promoters of Trpv5 and Trpv6 identified a novel T to C transition in codon 682 of TRPV5, mutating a conserved serine to a proline (S682P. Compared to wild-type littermates, heterozygous (Trpv5(682P/+ and homozygous (Trpv5(682P/682P mutant mice had hypercalciuria, polyuria, hyperphosphaturia and a more acidic urine, and ∼10% of males developed tubulointerstitial nephritis. Trpv5(682P/682P mice also had normal plasma parathyroid hormone but increased 1,25-dihydroxyvitamin D(3 concentrations without increased bone resorption, consistent with a renal defect for the hypercalciuria. Expression of the S682P mutation in human embryonic kidney cells revealed that TRPV5-S682P-expressing cells had a lower baseline intracellular calcium concentration than wild-type TRPV5-expressing cells, suggesting an altered calcium permeability. Immunohistological studies revealed a selective decrease in TRPV5-expression from the renal distal convoluted tubules of Trpv5(682P/+ and Trpv5(682P/682P mice consistent with a trafficking defect. In addition, Trpv5(682P/682P mice had a reduction in renal expression of the intracellular calcium-binding protein, calbindin-D(28K, consistent with a specific defect in TRPV5-mediated renal calcium reabsorption. Thus, our findings

  11. An epidemiological approach for the estimation of disease onset in Central Europe in central and peripheral monogenic retinal dystrophies.

    Science.gov (United States)

    Prokofyeva, Elena; Wilke, Robert; Lotz, Gunnar; Troeger, Eric; Strasser, Torsten; Zrenner, Eberhart

    2009-07-01

    To study clinical patterns of disease onset in monogenic retinal dystrophies (MRD), using an epidemiological approach. Records of patients with MRD, seen at the University Eye Hospital Tuebingen from 1994 to 1999, were selected from a database and retrospectively reviewed. For analysis, patients were divided into 2 groups by predominant part of visual field (VF) involvement: group 1 (predominantly central involvement) included Stargardt disease (ST), macular dystrophy (MD), and central areolar choroidal dystrophy (CACD), and group 2 (predominantly peripheral involvement) included Bardet-Biedl syndrome (BBD), Usher syndrome (USH) I and II, and choroideremia (CHD). Age, sex, age of first diagnosis, age of visual acuity (VA) decrease and VF emergence, night blindness and photophobia onset, types of VF defects and age of its onset, color discrimination defects and best corrected VA were analyzed. Records of 259 patients were studied. Men were more prevalent than women. Mean age of the patients was 47.2 (SD = 15.6) years old. Forty-five patients in the first group and 40 in the second were first diagnosed between 21 and 30 years of age. Ninety-four patients in the first group had VA decrease before 30 years of age; in the second group, 68 patients had VA decrease onset between 21 and 40 years of age. Forty-four patients in the first group noticed VF at an age between 21 and 30 years, and 74 patients between 11 and 30 years in the second group. Central scotoma was typical for the first group, and was detected in 115 patients. Concentric constriction was typical for the second group, and was found in 81 patients. Half of patients in both groups preserved best-corrected VA in the better eye at a level of 20/40 or better; 7% in the first group and 6% in the second group were registered as legally blind according to WHO criteria, having VA <1/50 or VF <5 degrees . Diagnosis frequency was USH I and II-34%, ST-31%, MD-18%, CHD-14%, BBD-5%. An epidemiological approach to the

  12. Characterization of a new full length TMPRSS3 isoform and identification of mutant alleles responsible for nonsyndromic recessive deafness in Newfoundland and Pakistan

    Directory of Open Access Journals (Sweden)

    Shotland Lawrence I

    2004-09-01

    Full Text Available Abstract Background Mutant alleles of TMPRSS3 are associated with nonsyndromic recessive deafness (DFNB8/B10. TMPRSS3 encodes a predicted secreted serine protease, although the deduced amino acid sequence has no signal peptide. In this study, we searched for mutant alleles of TMPRSS3 in families from Pakistan and Newfoundland with recessive deafness co-segregating with DFNB8/B10 linked haplotypes and also more thoroughly characterized the genomic structure of TMPRSS3. Methods We enrolled families segregating recessive hearing loss from Pakistan and Newfoundland. Microsatellite markers flanking the TMPRSS3 locus were used for linkage analysis. DNA samples from participating individuals were sequenced for TMPRSS3. The structure of TMPRSS3 was characterized bioinformatically and experimentally by sequencing novel cDNA clones of TMPRSS3. Results We identified mutations in TMPRSS3 in four Pakistani families with recessive, nonsyndromic congenital deafness. We also identified two recessive mutations, one of which is novel, of TMPRSS3 segregating in a six-generation extended family from Newfoundland. The spectrum of TMPRSS3 mutations is reviewed in the context of a genotype-phenotype correlation. Our study also revealed a longer isoform of TMPRSS3 with a hitherto unidentified exon encoding a signal peptide, which is expressed in several tissues. Conclusion Mutations of TMPRSS3 contribute to hearing loss in many communities worldwide and account for 1.8% (8 of 449 of Pakistani families segregating congenital deafness as an autosomal recessive trait. The newly identified TMPRSS3 isoform e will be helpful in the functional characterization of the full length protein.

  13. Autosomal dominant frontometaphyseal dysplasia : Delineation of the clinical phenotype

    NARCIS (Netherlands)

    Wade, Emma M.; Jenkins, Zandra A.; Daniel, Philip B.; Morgan, Tim; Addor, Marie C.; Ades, Lesley C.; Bertola, Debora; Bohring, Axel; Carter, Erin; Cho, Tae-Joon; de Geus, Christa M.; Duba, Hans-Christoph; Fletcher, Elaine; Hadzsiev, Kinga; Hennekam, Raoul C. M.; Kim, Chong A.; Krakow, Deborah; Morava, Eva; Neuhann, Teresa; Sillence, David; Superti-Furga, Andrea; Veenstra-Knol, Hermine E.; Wieczorek, Dagmar; Wilson, Louise C.; Markie, David M.; Robertson, Stephen P.

    Frontometaphyseal dysplasia (FMD) is caused by gain-of-function mutations in the X-linked gene FLNA in approximately 50% of patients. Recently we characterized an autosomal dominant form of FMD (AD-FMD) caused by mutations in MAP3K7, which accounts for the condition in the majority of patients who

  14. Autosomal dominant frontometaphyseal dysplasia: Delineation of the clinical phenotype

    NARCIS (Netherlands)

    Wade, Emma M.; Jenkins, Zandra A.; Daniel, Philip B.; Morgan, Tim; Addor, Marie C.; Adés, Lesley C.; Bertola, Debora; Bohring, Axel; Carter, Erin; Cho, Tae-Joon; de Geus, Christa M.; Duba, Hans-Christoph; Fletcher, Elaine; Hadzsiev, Kinga; Hennekam, Raoul C. M.; Kim, Chong A.; Krakow, Deborah; Morava, Eva; Neuhann, Teresa; Sillence, David; Superti-Furga, Andrea; Veenstra-Knol, Hermine E.; Wieczorek, Dagmar; Wilson, Louise C.; Markie, David M.; Robertson, Stephen P.

    2017-01-01

    Frontometaphyseal dysplasia (FMD) is caused by gain-of-function mutations in the X-linked gene FLNA in approximately 50% of patients. Recently we characterized an autosomal dominant form of FMD (AD-FMD) caused by mutations in MAP3K7, which accounts for the condition in the majority of patients who

  15. Genetics Home Reference: autosomal dominant partial epilepsy with auditory features

    Science.gov (United States)

    ... for This Condition ADLTE ADPEAF Autosomal dominant lateral temporal lobe epilepsy Epilepsy, partial, with auditory features ETL1 Related Information ... W, Nakken KO, Fischer C, Steinlein OK. Familial temporal lobe epilepsy with aphasic seizures and linkage to chromosome 10q22- ...

  16. A further patient with Pai syndrome with autosomal dominant inheritance?

    OpenAIRE

    Rudnik-Schöneborn, S; Zerres, K

    1994-01-01

    We report a patient with median cleft of the upper lip, cutaneous facial polyps, and lipoma of the corpus callosum who represents a further case of Pai syndrome. The father of the patient showed coloboma of the right iris and shared some facial dysmorphism with his son, thus raising the question of autosomal dominant inheritance.

  17. 3. Pattern of Inheritance of Autosome and Sex. Chromosome Linked ...

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 4; Issue 10. Teaching and Learning Genetics with Drosophila – Pattern of Inheritance of Autosome and Sex Chro-mosome Linked Genes/Characters. H A Ranganath M T Tanuja. Classroom Volume 4 Issue 10 October 1999 pp 78-87 ...

  18. Case report: Autosomal dominant non-epidermolytic palmoplantar ...

    African Journals Online (AJOL)

    Palmoplantar keratoderma (PPK) is a hereditary cutaneous disorder characterized by a marked hyperkeratosis of the palms and soles. A variant that was inherited in an autosomal dominant form was highlighted in a 20-month-old girl-child. The proband was brought to the Paediatric Outpatient Department by her mother ...

  19. Intimate Partner Violence in the Great Recession.

    Science.gov (United States)

    Schneider, Daniel; Harknett, Kristen; McLanahan, Sara

    2016-04-01

    In the United States, the Great Recession was marked by severe negative shocks to labor market conditions. In this study, we combine longitudinal data from the Fragile Families and Child Wellbeing Study with U.S. Bureau of Labor Statistics data on local area unemployment rates to examine the relationship between adverse labor market conditions and mothers' experiences of abusive behavior between 2001 and 2010. Unemployment and economic hardship at the household level were positively related to abusive behavior. Further, rapid increases in the unemployment rate increased men's controlling behavior toward romantic partners even after we adjust for unemployment and economic distress at the household level. We interpret these findings as demonstrating that the uncertainty and anticipatory anxiety that go along with sudden macroeconomic downturns have negative effects on relationship quality, above and beyond the effects of job loss and material hardship.

  20. Did the Great Recession influence retirement plans?

    Science.gov (United States)

    Szinovacz, Maximiliane E; Davey, Adam; Martin, Lauren

    2015-04-01

    The recent recession constitutes one of the macro forces that may have influenced workers' retirement plans. We evaluate a multilevel model that addresses the influence of macro-, meso-, and micro-level factors on retirement plans, changes in these plans, and expected retirement age. Using data from Waves 8 and 9 of the Health and Retirement Study (N=2,618), we find that individuals with defined benefit plans are more prone to change toward plans to stop work before the stock market declined, whereas the opposite trend holds for those without pensions. Debts, ability to reduce work hours, and firm unionization also influenced retirement plans. Findings suggest retirement planning education may be particularly important for workers without defined pensions, especially in times of economic volatility. © The Author(s) 2014.

  1. Mutations in the VNTR of the carboxyl-ester lipase gene (CEL) are a rare cause of monogenic diabetes.

    Science.gov (United States)

    Torsvik, Janniche; Johansson, Stefan; Johansen, Anders; Ek, Jakob; Minton, Jayne; Raeder, Helge; Ellard, Sian; Hattersley, Andrew; Pedersen, Oluf; Hansen, Torben; Molven, Anders; Njølstad, Pål R

    2010-01-01

    We have previously shown that heterozygous single-base deletions in the carboxyl-ester lipase (CEL) gene cause exocrine and endocrine pancreatic dysfunction in two multigenerational families. These deletions were found in the first and fourth repeats of a variable number of tandem repeats (VNTR), which has proven challenging to sequence due to high GC-content and considerable length variation. We have therefore developed a screening method consisting of a multiplex PCR followed by fragment analysis. The method detected putative disease-causing insertions and deletions in the proximal repeats of the VNTR, and determined the VNTR-length of each allele. When blindly testing 56 members of the two families with known single-base deletions in the CEL VNTR, the method correctly assessed the mutation carriers. Screening of 241 probands from suspected maturity-onset diabetes of the young (MODY) families negative for mutations in known MODY genes (95 individuals from Denmark and 146 individuals from UK) revealed no deletions in the proximal repeats of the CEL VNTR. However, we found one Danish patient with a short, novel CEL allele containing only three VNTR repeats (normal range 7-23 in healthy controls). This allele co-segregated with diabetes or impaired glucose tolerance in the patient's family as six of seven mutation carriers were affected. We also identified individuals who had three copies of a complete CEL VNTR. In conclusion, the CEL gene is highly polymorphic, but mutations in CEL are likely to be a rare cause of monogenic diabetes.

  2. Lipoprotein distribution and serum concentrations of 7α-hydroxy-4-cholesten-3-one and bile acids: effects of monogenic disturbances in high-density lipoprotein metabolism

    DEFF Research Database (Denmark)

    Steiner, Carine; Holleboom, Adriaan G; Karuna, Ratna

    2012-01-01

    BA (bile acid) formation is considered an important final step in RCT (reverse cholesterol transport). HDL (high-density lipoprotein) has been reported to transport BAs. We therefore investigated the effects of monogenic disturbances in human HDL metabolism on serum concentrations and lipoprotein...... concentrations of conjugated and secondary BAs differed between heterozygous carriers of SCARB1 (scavenger receptor class B1) mutations and unaffected individuals (P...

  3. The clinical application of genome-wide sequencing for monogenic diseases in Canada: Position Statement of the Canadian College of Medical Geneticists

    OpenAIRE

    Boycott, Kym; Hartley, Taila; Adam, Shelin; Bernier, Francois; Chong, Karen; Fernandez, Bridget A; Friedman, Jan M; Geraghty, Michael T; Hume, Stacey; Knoppers, Bartha M; Laberge, Anne-Marie; Majewski, Jacek; Mendoza-Londono, Roberto; Meyn, M Stephen; Michaud, Jacques L

    2015-01-01

    Purpose and scope The aim of this Position Statement is to provide recommendations for Canadian medical geneticists, clinical laboratory geneticists, genetic counsellors and other physicians regarding the use of genome-wide sequencing of germline DNA in the context of clinical genetic diagnosis. This statement has been developed to facilitate the clinical translation and development of best practices for clinical genome-wide sequencing for genetic diagnosis of monogenic diseases in Canada; it...

  4. Unemployment of Non-western Immigrants in the Great Recession

    NARCIS (Netherlands)

    Cervený, J.; van Ours, J.C.

    2013-01-01

    Abstract: This paper examines whether unemployment of non-western immigrant workers in the Netherlands was disproportionally affected by the Great Recession. We analyze unemployment data covering the period November 2007 to February 2013 finding that the Great Recession affected unemployment rates

  5. Who Suffers during Recessions? NBER Working Paper No. 17951

    Science.gov (United States)

    Hoynes, Hilary W.; Miller, Douglas L.; Schaller, Jessamyn

    2012-01-01

    In this paper we examine how business cycles affect labor market outcomes in the United States. We conduct a detailed analysis of how cycles affect outcomes differentially across persons of differing age, education, race, and gender, and we compare the cyclical sensitivity during the Great Recession to that in the early 1980s recession. We present…

  6. American undergraduate students' value development during the Great Recession.

    Science.gov (United States)

    Park, Heejung; Twenge, Jean M; Greenfield, Patricia M

    2017-02-01

    The Great Recession's influence on American undergraduate students' values was examined, testing Greenfield's and Kasser's theories concerning value development during economic downturns. Study 1 utilised aggregate-level data to investigate (a) population-level value changes between the pre-recession (2004-2006: n = 824,603) and recession freshman cohort (2008-2010: n = 662,262) and (b) overall associations of population-level values with national economic climates over long-term periods by correlating unemployment rates and concurrent aggregate-level values across 1966-2015 (n = 10 million). Study 2 examined individual-level longitudinal value development from freshman to senior year, and whether the developmental trajectories differed between those who completed undergraduate education before the Great Recession (freshmen in 2002, n = 12,792) versus those who encountered the Great Recession during undergraduate years (freshmen in 2006, n = 13,358). Results suggest American undergraduate students' increased communitarianism (supporting Greenfield) and materialism (supporting Kasser) during the Great Recession. The recession also appears to have slowed university students' development of positive self-views. Results contribute to the limited literature on the Great Recession's influence on young people's values. They also offer theoretical and practical implications, as values of this privileged group of young adults are important shapers of societal values, decisions, and policies. © 2016 International Union of Psychological Science.

  7. Unemployment of non-western immigrants in the Great Recession

    NARCIS (Netherlands)

    Cervený, J.; van Ours, J.C.

    2013-01-01

    This paper examines whether unemployment of non-western immigrant workers in the Netherlands was disproportionally affected by the Great Recession. We analyze unemployment data covering the period November 2007–February 2013 finding that the Great Recession affected unemployment rates of non-western

  8. Students with Attention Deficit Hyperactivity Disorder Participating in Recess

    Science.gov (United States)

    Lucas, Matthew D.; Justice, Michael J.; Rosko, Kelly M.

    2014-01-01

    The participation of a student with Attention Deficit Hyperactivity Disorder (ADHD) in recess can often be both challenging and rewarding for the student and teacher. This paper will address common characteristics of children with ADHD and present basic solutions to improve the experience of these children in the recess setting. Initially, the…

  9. Students with Sickle Cell Anemia Participating in Recess

    Science.gov (United States)

    Lucas, Matthew D.; Devlin, Katharine M.

    2011-01-01

    The participation of a student with Sickle Cell Anemia in recess can often be both challenging and rewarding for the student and teacher. This paper will address common characteristics of students with Sickle Cell Anemia and present basic solutions to improve the experience of these students in the recess setting. Initially the definition,…

  10. Mining of lethal recessive genetic variation in Danish cattle

    DEFF Research Database (Denmark)

    Das, Ashutosh

    2015-01-01

    in fertility. The primary objective of this PhD projekt was to identify recessive lethal gentic variants in the main Danish dairy cattle breed. Holstein-Friesian utilzing next generation sequencing (NGS) data. This study shows a potential for the use of the NGS-based reverse genetic approach in identifying...... lethal or semi-lethal recessive gentic variation...

  11. Africa and global recessions: Options for reducing vulnerability in ...

    African Journals Online (AJOL)

    Africa and global recessions: Options for reducing vulnerability in future. ... It concludes that traditional or conventional, market-based approaches do not adequately explain the root causes of global recessions and that the dominant counter-cyclical Keynesian-type fiscal and monetary policies that characterised the ...

  12. Business Recovery Strategies in the Economic Crisis of Recession ...

    African Journals Online (AJOL)

    This paper examines Nigeria's theoretical economic foundation, the consequence of recession generally and specifically on the Gross Domestic Product (GDP) growth rate (2008-2010) and on companies together with customers reaction. Business recovery strategies for an upturn over the economic crisis of recession in ...

  13. A etiologia multifatorial da recessão periodontal The etiologic factors of periodontal recession

    Directory of Open Access Journals (Sweden)

    Karen Ferreira Gazel Yared

    2006-12-01

    Full Text Available A literatura apresenta vários fatores relacionados na etiologia da recessão periodontal, além do processo inflamatório induzido pelo biofilme bacteriano, os quais incluem fatores externos e anatômicos locais. Por meio deste estudo, revistou-se a literatura sobre tais fatores, cujo conhecimento é de grande importância para o ortodontista, contribuindo durante o diagnóstico, planejamento e tratamento ortodôntico propriamente dito.The literature shows that besides dental plaque, some external and anatomic local factors are still related to gingival recession etiology. This study reviewed the literature about those factors, which knownledge is of great benefit to the orthodontist, contributing during diagnostic, planning and orthodontic treatment.

  14. Health Impacts of the Great Recession: A Critical Review.

    Science.gov (United States)

    Margerison-Zilko, Claire; Goldman-Mellor, Sidra; Falconi, April; Downing, Janelle

    2016-03-01

    The severity, sudden onset, and multipronged nature of the Great Recession (2007-2009) provided a unique opportunity to examine the health impacts of macroeconomic downturn. We comprehensively review empirical literature examining the relationship between the Recession and mental and physical health outcomes in developed nations. Overall, studies reported detrimental impacts of the Recession on health, particularly mental health. Macro- and individual-level employment- and housing-related sequelae of the Recession were associated with declining fertility and self-rated health, and increasing morbidity, psychological distress, and suicide, although traffic fatalities and population-level alcohol consumption declined. Health impacts were stronger among men and racial/ethnic minorities. Importantly, strong social safety nets in some European countries appear to have buffered those populations from negative health effects. This literature, however, still faces multiple methodological challenges, and more time may be needed to observe the Recession's full health impact. We conclude with suggestions for future work in this field.

  15. Bimedial faden recession versus augmented medial rectus recession in the treatment of high ac/a ratio partially accommodative esotropia with large distant near disparity

    Directory of Open Access Journals (Sweden)

    Mohammed F Farid

    2016-01-01

    Faden recession achieves marginal superior control of DND and high AC/A ratio in convergence excess partially accommodative ET. Augmented recession also works well with the possible development of consecutive exotropia in cases with extremely high DND. This study recommends Augmented recession for cases with mild to moderate DND and Faden recession for cases with extremely large DND.

  16. Progression of autosomal dominant kidney disease: measurement of the stage transitions of chronic kidney disease

    Directory of Open Access Journals (Sweden)

    Christopher M Blanchette

    2015-04-01

    to next stage may be useful for identification of ADPKD patients at risk of rapid progression. The results also suggest that medical claims with diagnosis codes for “unspecified PKD”, in absence of a diagnosis code for autosomal recessive polycystic kidney disease, may be a good proxy for ADPKD.

  17. Economic recession and suicidal behaviour: Possible mechanisms and ameliorating factors.

    Science.gov (United States)

    Haw, Camilla; Hawton, Keith; Gunnell, David; Platt, Stephen

    2015-02-01

    A growing body of research evidence from countries around the world indicates that economic recession is associated with increases in suicide, particularly in males of working age. To explore contributory and ameliorating factors associated with economic recession and suicide and thereby stimulate further research in this area and encourage policy makers to consider how best to reduce the impact of recession on mental health and suicidal behaviour. We conducted a selective review of the worldwide literature focusing on possible risk factors, mechanisms and preventative strategies for suicidal behaviour linked to economic recession. A model of how recession might affect suicide rates is presented. A major and often prolonged effect of recession is on unemployment and job insecurity. Other important effects include those exerted by financial loss, bankruptcy and home repossession. It is proposed these factors may lead directly or indirectly to mental health problems such as depression, anxiety and binge drinking and then to suicidal behaviour. Countries with active labour market programmes and sustained welfare spending during recessions have less marked increases in suicide rates than those that cut spending on welfare and job-search initiatives for the unemployed. Other measures likely to help include targeted interventions for unemployed people, membership of social organisations and responsible media reporting. Good primary care and mental health services are needed to cope with increased demand in times of economic recession but some governments have in fact reduced healthcare spending as an austerity measure. The research evidence linking recession, unemployment and suicide is substantial, but the evidence for the other mechanisms we have investigated is much more tentative. We describe the limitations of the existing body of research as well as make suggestions for future research into the effects of economic recession on suicidal behaviour. © The Author

  18. POU4F3 mutation screening in Japanese hearing loss patients: Massively parallel DNA sequencing-based analysis identified novel variants associated with autosomal dominant hearing loss.

    Directory of Open Access Journals (Sweden)

    Tomohiro Kitano

    Full Text Available A variant in a transcription factor gene, POU4F3, is responsible for autosomal dominant nonsyndromic hereditary hearing loss, DFNA15. To date, 14 variants, including a whole deletion of POU4F3, have been reported to cause HL in various ethnic groups. In the present study, genetic screening for POU4F3 variants was carried out for a large series of Japanese hearing loss (HL patients to clarify the prevalence and clinical characteristics of DFNA15 in the Japanese population. Massively parallel DNA sequencing of 68 target candidate genes was utilized in 2,549 unrelated Japanese HL patients (probands to identify genomic variations responsible for HL. The detailed clinical features in patients with POU4F3 variants were collected from medical charts and analyzed. Novel 12 POU4F3 likely pathogenic variants (six missense variants, three frameshift variants, and three nonsense variants were successfully identified in 15 probands (2.5% among 602 families exhibiting autosomal dominant HL, whereas no variants were detected in the other 1,947 probands with autosomal recessive or inheritance pattern unknown HL. To obtain the audiovestibular configuration of the patients harboring POU4F3 variants, we collected audiograms and vestibular symptoms of the probands and their affected family members. Audiovestibular phenotypes in a total of 24 individuals from the 15 families possessing variants were characterized by progressive HL, with a large variation in the onset age and severity with or without vestibular symptoms observed. Pure-tone audiograms indicated the most prevalent configuration as mid-frequency HL type followed by high-frequency HL type, with asymmetry observed in approximately 20% of affected individuals. Analysis of the relationship between age and pure-tone average suggested that individuals with truncating variants showed earlier onset and slower progression of HL than did those with non-truncating variants. The present study showed that variants

  19. ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q10 deficiency.

    Science.gov (United States)

    Lagier-Tourenne, Clotilde; Tazir, Meriem; López, Luis Carlos; Quinzii, Catarina M; Assoum, Mirna; Drouot, Nathalie; Busso, Cleverson; Makri, Samira; Ali-Pacha, Lamia; Benhassine, Traki; Anheim, Mathieu; Lynch, David R; Thibault, Christelle; Plewniak, Frédéric; Bianchetti, Laurent; Tranchant, Christine; Poch, Olivier; DiMauro, Salvatore; Mandel, Jean-Louis; Barros, Mario H; Hirano, Michio; Koenig, Michel

    2008-03-01

    Muscle coenzyme Q(10) (CoQ(10) or ubiquinone) deficiency has been identified in more than 20 patients with presumed autosomal-recessive ataxia. However, mutations in genes required for CoQ(10) biosynthetic pathway have been identified only in patients with infantile-onset multisystemic diseases or isolated nephropathy. Our SNP-based genome-wide scan in a large consanguineous family revealed a locus for autosomal-recessive ataxia at chromosome 1q41. The causative mutation is a homozygous splice-site mutation in the aarF-domain-containing kinase 3 gene (ADCK3). Five additional mutations in ADCK3 were found in three patients with sporadic ataxia, including one known to have CoQ(10) deficiency in muscle. All of the patients have childhood-onset cerebellar ataxia with slow progression, and three of six have mildly elevated lactate levels. ADCK3 is a mitochondrial protein homologous to the yeast COQ8 and the bacterial UbiB proteins, which are required for CoQ biosynthesis. Three out of four patients tested showed a low endogenous pool of CoQ(10) in their fibroblasts or lymphoblasts, and two out of three patients showed impaired ubiquinone synthesis, strongly suggesting that ADCK3 is also involved in CoQ(10) biosynthesis. The deleterious nature of the three identified missense changes was confirmed by the introduction of them at the corresponding positions of the yeast COQ8 gene. Finally, a phylogenetic analysis shows that ADCK3 belongs to the family of atypical kinases, which includes phosphoinositide and choline kinases, suggesting that ADCK3 plays an indirect regulatory role in ubiquinone biosynthesis possibly as part of a feedback loop that regulates ATP production.

  20. Screening for homozygosity by descent in families with autosomal

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Genetics; Volume 81; Issue 2 ... Perspectives Volume 81 Issue 2 August 2002 pp 59-63 ... disease locus in families with the recessive form of the disease, we used the approach of screening for homozygosity by descent in offspring of consanguineous and nonconsanguineous families with RP.

  1. A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome.

    Science.gov (United States)

    Ballew, Bari J; Joseph, Vijai; De, Saurav; Sarek, Grzegorz; Vannier, Jean-Baptiste; Stracker, Travis; Schrader, Kasmintan A; Small, Trudy N; O'Reilly, Richard; Manschreck, Chris; Harlan Fleischut, Megan M; Zhang, Liying; Sullivan, John; Stratton, Kelly; Yeager, Meredith; Jacobs, Kevin; Giri, Neelam; Alter, Blanche P; Boland, Joseph; Burdett, Laurie; Offit, Kenneth; Boulton, Simon J; Savage, Sharon A; Petrini, John H J

    2013-08-01

    Dyskeratosis congenita (DC) is a heterogeneous inherited bone marrow failure and cancer predisposition syndrome in which germline mutations in telomere biology genes account for approximately one-half of known families. Hoyeraal Hreidarsson syndrome (HH) is a clinically severe variant of DC in which patients also have cerebellar hypoplasia and may present with severe immunodeficiency and enteropathy. We discovered a germline autosomal recessive mutation in RTEL1, a helicase with critical telomeric functions, in two unrelated families of Ashkenazi Jewish (AJ) ancestry. The affected individuals in these families are homozygous for the same mutation, R1264H, which affects three isoforms of RTEL1. Each parent was a heterozygous carrier of one mutant allele. Patient-derived cell lines revealed evidence of telomere dysfunction, including significantly decreased telomere length, telomere length heterogeneity, and the presence of extra-chromosomal circular telomeric DNA. In addition, RTEL1 mutant cells exhibited enhanced sensitivity to the interstrand cross-linking agent mitomycin C. The molecular data and the patterns of inheritance are consistent with a hypomorphic mutation in RTEL1 as the underlying basis of the clinical and cellular phenotypes. This study further implicates RTEL1 in the etiology of DC/HH and immunodeficiency, and identifies the first known homozygous autosomal recessive disease-associated mutation in RTEL1.

  2. A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome.

    Directory of Open Access Journals (Sweden)

    Bari J Ballew

    2013-08-01

    Full Text Available Dyskeratosis congenita (DC is a heterogeneous inherited bone marrow failure and cancer predisposition syndrome in which germline mutations in telomere biology genes account for approximately one-half of known families. Hoyeraal Hreidarsson syndrome (HH is a clinically severe variant of DC in which patients also have cerebellar hypoplasia and may present with severe immunodeficiency and enteropathy. We discovered a germline autosomal recessive mutation in RTEL1, a helicase with critical telomeric functions, in two unrelated families of Ashkenazi Jewish (AJ ancestry. The affected individuals in these families are homozygous for the same mutation, R1264H, which affects three isoforms of RTEL1. Each parent was a heterozygous carrier of one mutant allele. Patient-derived cell lines revealed evidence of telomere dysfunction, including significantly decreased telomere length, telomere length heterogeneity, and the presence of extra-chromosomal circular telomeric DNA. In addition, RTEL1 mutant cells exhibited enhanced sensitivity to the interstrand cross-linking agent mitomycin C. The molecular data and the patterns of inheritance are consistent with a hypomorphic mutation in RTEL1 as the underlying basis of the clinical and cellular phenotypes. This study further implicates RTEL1 in the etiology of DC/HH and immunodeficiency, and identifies the first known homozygous autosomal recessive disease-associated mutation in RTEL1.

  3. Monogenic diabetes syndromes: Locus‐specific databases for Alström, Wolfram, and Thiamine‐responsive megaloblastic anemia

    Science.gov (United States)

    Astuti, Dewi; Sabir, Ataf; Fulton, Piers; Zatyka, Malgorzata; Williams, Denise; Hardy, Carol; Milan, Gabriella; Favaretto, Francesca; Yu‐Wai‐Man, Patrick; Rohayem, Julia; López de Heredia, Miguel; Hershey, Tamara; Tranebjaerg, Lisbeth; Chen, Jian‐Hua; Chaussenot, Annabel; Nunes, Virginia; Marshall, Bess; McAfferty, Susan; Tillmann, Vallo; Maffei, Pietro; Paquis‐Flucklinger, Veronique; Geberhiwot, Tarekign; Mlynarski, Wojciech; Parkinson, Kay; Picard, Virginie; Bueno, Gema Esteban; Dias, Renuka; Arnold, Amy; Richens, Caitlin; Paisey, Richard; Urano, Fumihiko; Semple, Robert; Sinnott, Richard

    2017-01-01

    Abstract We developed a variant database for diabetes syndrome genes, using the Leiden Open Variation Database platform, containing observed phenotypes matched to the genetic variations. We populated it with 628 published disease‐associated variants (December 2016) for: WFS1 (n = 309), CISD2 (n = 3), ALMS1 (n = 268), and SLC19A2 (n = 48) for Wolfram type 1, Wolfram type 2, Alström, and Thiamine‐responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1. We then investigated genotype–phenotype relations for the WFS1 gene. The presence of biallelic loss‐of‐function variants predicted Wolfram syndrome defined by insulin‐dependent diabetes and optic atrophy, with a sensitivity of 79% (95% CI 75%–83%) and specificity of 92% (83%–97%). The presence of minor loss‐of‐function variants in WFS1 predicted isolated diabetes, isolated deafness, or isolated congenital cataracts without development of the full syndrome (sensitivity 100% [93%–100%]; specificity 78% [73%–82%]). The ability to provide a prognostic prediction based on genotype will lead to improvements in patient care and counseling. The development of the database as a repository for monogenic diabetes gene variants will allow prognostic predictions for other diabetes syndromes as next‐generation sequencing expands the repertoire of genotypes and phenotypes. The database is publicly available online at https://lovd.euro-wabb.org. PMID:28432734

  4. Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia.

    Science.gov (United States)

    Astuti, Dewi; Sabir, Ataf; Fulton, Piers; Zatyka, Malgorzata; Williams, Denise; Hardy, Carol; Milan, Gabriella; Favaretto, Francesca; Yu-Wai-Man, Patrick; Rohayem, Julia; López de Heredia, Miguel; Hershey, Tamara; Tranebjaerg, Lisbeth; Chen, Jian-Hua; Chaussenot, Annabel; Nunes, Virginia; Marshall, Bess; McAfferty, Susan; Tillmann, Vallo; Maffei, Pietro; Paquis-Flucklinger, Veronique; Geberhiwot, Tarekign; Mlynarski, Wojciech; Parkinson, Kay; Picard, Virginie; Bueno, Gema Esteban; Dias, Renuka; Arnold, Amy; Richens, Caitlin; Paisey, Richard; Urano, Fumihiko; Semple, Robert; Sinnott, Richard; Barrett, Timothy G

    2017-07-01

    We developed a variant database for diabetes syndrome genes, using the Leiden Open Variation Database platform, containing observed phenotypes matched to the genetic variations. We populated it with 628 published disease-associated variants (December 2016) for: WFS1 (n = 309), CISD2 (n = 3), ALMS1 (n = 268), and SLC19A2 (n = 48) for Wolfram type 1, Wolfram type 2, Alström, and Thiamine-responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1. We then investigated genotype-phenotype relations for the WFS1 gene. The presence of biallelic loss-of-function variants predicted Wolfram syndrome defined by insulin-dependent diabetes and optic atrophy, with a sensitivity of 79% (95% CI 75%-83%) and specificity of 92% (83%-97%). The presence of minor loss-of-function variants in WFS1 predicted isolated diabetes, isolated deafness, or isolated congenital cataracts without development of the full syndrome (sensitivity 100% [93%-100%]; specificity 78% [73%-82%]). The ability to provide a prognostic prediction based on genotype will lead to improvements in patient care and counseling. The development of the database as a repository for monogenic diabetes gene variants will allow prognostic predictions for other diabetes syndromes as next-generation sequencing expands the repertoire of genotypes and phenotypes. The database is publicly available online at https://lovd.euro-wabb.org. © 2017 The Authors. **Human Mutation published by Wiley Periodicals, Inc.

  5. Autosomal dominant arteriopathy with sub cortical infarcts and leucoencephalopathy (CADASIL)

    International Nuclear Information System (INIS)

    Ojeda, Adriana; Tiezzi, Gerardo; Uriarte, Ana M.; Eguren, Leonor

    2002-01-01

    Cerebral autosomal dominant arteriopathy with sub cortical infarcts and leucoencephalopathy (CASADIL) is a systemic hereditary, vascular disease that involves small arteries. Recurrent ischemia, pseudo bulbar paralysis and dementia are characteristic. Other manifestations include migraine and depression. We report an Argentine family with VI generations with evidence of disease in IV. MR examinations were performed on 21 family members (both symptomatic and asymptomatic). The main findings on MR on symptomatic and asymptomatic patients were small lesions with high signal on T2 localised in periventricular white matter, brain stem, basal ganglia and thalamus, and confluent patches on white matter although with high signal on T2 images, usually symmetric. In conclusion we can assess that diffuse myelin loss and small infarcts occurring in cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy well demonstrated with MR. In addition, some of the abnormalities in pre symptomatic patients can be identified on MR images. (author)

  6. The Great Recession and America's Geography of Unemployment.

    Science.gov (United States)

    Thiede, Brian C; Monnat, Shannon M

    The Great Recession of 2007-2009 was the most severe and lengthy economic crisis in the U.S. since the Great Depression. The impacts on the population were multi-dimensional, but operated largely through local labor markets. To examine differences in recession-related changes in county unemployment rates and assess how population and place characteristics shaped these patterns. We calculate and decompose Theil Indexes to describe recession-related changes in the distribution of unemployment rates between counties and states. We use exploratory spatial statistics to identify geographic clusters of counties that experienced similar changes in unemployment. We use spatial regression to evaluate associations between county-level recession impacts on unemployment and demographic composition, industrial structure, and state context. The recession was associated with increased inequality between county labor markets within states, but declining between-state differences. Counties that experienced disproportionate recession-related increases in unemployment were spatially clustered and characterized by large shares of historically disadvantaged racial and ethnic minority populations, low educational attainment, and heavy reliance on pro-cyclical industries. Associations between these sources of vulnerability were partially explained by unobserved state-level factors. The local consequences of macroeconomic trends are associated with county population characteristics, as well as the structural contexts and policy environments in which they are embedded. The recession placed upward pressure on within-state inequality between local labor market conditions. To present new estimates of the recession's impact on local labor markets, quantify how heterogeneous impacts affected the distribution of unemployment prevalence, and identify county characteristics associated with disproportionately large recession-related increases in unemployment.

  7. Recent declines in cancer incidence: related to the Great Recession?

    Science.gov (United States)

    Gomez, Scarlett Lin; Canchola, Alison J; Nelson, David O; Keegan, Theresa H M; Clarke, Christina A; Cheng, Iona; Shariff-Marco, Salma; DeRouen, Mindy; Catalano, Ralph; Satariano, William A; Davidson-Allen, Kathleen; Glaser, Sally L

    2017-02-01

    In recent years, cancer case counts in the U.S. underwent a large, rapid decline-an unexpected change given population growth for older persons at highest cancer risk. As these declines coincided with the Great Recession, we examined whether they were related to economic conditions. Using California Cancer Registry data from California's 30 most populous counties, we analyzed trends in cancer incidence during pre-recession (1996-2007) and recession/recovery (2008-2012) periods for all cancers combined and the ten most common sites. We evaluated the recession's association with rates using a multifactorial index that measured recession impact, and modeled associations between case counts and county-level unemployment rates using Poisson regression. Yearly cancer incidence rate declines were greater during the recession/recovery (3.3% among males, 1.4% among females) than before (0.7 and 0.5%, respectively), particularly for prostate, lung, and colorectal cancers. Lower case counts, especially for prostate and liver cancer among males and breast cancer, melanoma, and ovarian cancer among females, were associated with higher unemployment rates, irrespective of time period, but independent of secular effects. The associations for melanoma translated up to a 3.6% decrease in cases with each 1% increase in unemployment. Incidence declines were not greater in counties with higher recession impact index. Although recent declines in incidence of certain cancers are not differentially impacted by economic conditions related to the Great Recession relative to pre-recession conditions, the large recent absolute declines in the case counts of some cancer may be attributable to the large declines in unemployment in the recessionary period. This may occur through decreased engagement in preventive health behaviors, particularly for clinically less urgent cancers. Continued monitoring of trends is important to detect any rises in incidence rates as deferred diagnoses come to

  8. The Great Recession and America's geography of unemployment

    Directory of Open Access Journals (Sweden)

    Brian Thiede

    2016-09-01

    Full Text Available Background: The Great Recession of 2007-2009 was the most severe and lengthy economic crisis in the US since the Great Depression of the 1930s. The impacts on the population were multi-dimensional, but operated largely through local labor markets. Objective: To examine differences in recession-related changes in county unemployment rates and assess how population and place characteristics shaped these patterns. Methods: We calculate and decompose Theil Indexes to describe recession-related changes in the distribution of unemployment rates between counties and states. We use exploratory spatial statistics to identify geographic clusters of counties that experienced similar changes in unemployment. We use spatial regression to evaluate associations between county-level recession impacts on unemployment and demographic composition, industrial structure, and state context. Results: The recession was associated with increased inequality between county labor markets within states, but declining between-state differences. Counties that experienced disproportionate recession-related increases in unemployment were spatially clustered and characterized by large shares of historically disadvantaged racial and ethnic minority populations, low educational attainment, and heavy reliance on pro-cyclical industries. Associations between these sources of vulnerability were partially explained by unobserved state-level factors. Conclusions: The local consequences of macroeconomic trends are associated with county population characteristics, and the structural contexts and policy environments in which they are embedded. The recession placed upward pressure on within-state disparities in local labor market conditions. Contribution: To present new estimates of the recession's impact on local labor markets, quantify how heterogeneous impacts affected the distribution of unemployment prevalence, and identify county characteristics associated with disproportionately

  9. Mutations in AAGAB underlie autosomal dominant punctate palmoplantar keratoderma.

    Science.gov (United States)

    Dinani, N; Ali, M; Liu, L; McGrath, J; Mellerio, J

    2017-04-01

    Punctate palmoplantar keratoderma type 1 (PPPK1) is a rare autosomal dominant inherited skin disease, characterized by multiple hyperkeratotic lesions on the palms and soles. The causative gene for PPPK1 has been identified as AAGAB, which encodes α- and γ-adaptin-binding protein p34. We describe the clinical features in three unrelated families with PPPK1, and report three recurrent causative mutations in AAGAB. © 2017 British Association of Dermatologists.

  10. Allele frequency distribution for 21 autosomal STR loci in Nepal.

    Science.gov (United States)

    Kraaijenbrink, T; van Driem, G L; Opgenort, J R M L; Tuladhar, N M; de Knijff, P

    2007-05-24

    The allele frequency distributions of 21 autosomal loci contained in the AmpFlSTR Identifiler, the Powerplex 16 and the FFFL multiplex PCR kits, was studied in 953 unrelated individuals from Nepal. Several new alleles (i.e. not yet reported in the NIST Short Tandem Repeat DNA Internet DataBase [http://www.cstl.nist.gov/biotech/strbase/]) have been detected in the process.

  11. THE FORCE METAPHOR IN CONCEPTUALIZING ECONOMIC RECESSION

    Directory of Open Access Journals (Sweden)

    Jurga Cibulskienė

    2013-04-01

    Full Text Available Cognitive metaphor analysts comprehend metaphor as a convenient way of not only talking about real life events but also thinking about them: connecting ideas, explaining abstract ideas that are difficult to grasp, conveying messages and emotions, etc. Thus, metaphor in real-world discourse is increasingly becoming the focus of many cognitive studies. In political discourse, metaphor is seen as an ideological tool of deliberate attempts to influence, persuade and manipulate people. As Charteris-Black (2005: 16 put it, politicians try to establish themselves in a positive light or legitimize themselves, i.e., by presenting evidence that they are charismatic leaders who are capable of running their country efficiently. Legitimization goes hand in hand with delegitimization, i.e., negative other-presentation. Metaphor as a cognitive mechanism of ideology may serve both as positive self-representation and as a tool for fault-finding in others. Thus, the study focuses on how three Lithuanian socio-political groups (the leading party, the opposition, and the media legitimize themselves and delegitimize their opponents by using force metaphors to conceptualize the worldwide economic recession. The findings indicate that although the same conceptual metaphor is used for legitimization and delegitimization, its fulfilment scenario appears to be markedly different and it carries different rhetorical implications in the three discourses.

  12. Alcohol use during the great recession of 2008-2009.

    Science.gov (United States)

    Bor, Jacob; Basu, Sanjay; Coutts, Adam; McKee, Martin; Stuckler, David

    2013-01-01

    The aim of this study was to assess changes in alcohol use in the USA during the Great Recession. Drinking participation, drinking frequency, drinking intensity, total alcohol consumption and frequency of binge drinking were assessed in a nationally representative sample of 2,050,431 US women and men aged 18 and older, interviewed between 2006 and 2010. The prevalence of any alcohol use significantly declined during the economic recession, from 52.0% in 2006-2007 to 51.6% in 2008-2009 (P Great Recession there was an increase in abstention from alcohol and a rise in frequent binging.

  13. The Role of Credit in Predicting US Recessions

    DEFF Research Database (Denmark)

    Pönkä, Harri

    are useful predictors of US recessions over and above the control variables both in and out of sample. Especially the excess bond premium, capturing the cyclical changes in the relationship between default risk and credit spreads, is found to be a powerful predictor. Overall, models that combine credit......We study the role of credit in forecasting US recession periods with probit models. We employ both classical recession predictors and common factors based on a large panel of financial and macroeconomic variables as control variables. Our findings suggest that a number of credit variables...

  14. Recessive Mutations in ACPT, Encoding Testicular Acid Phosphatase, Cause Hypoplastic Amelogenesis Imperfecta.

    Science.gov (United States)

    Seymen, Figen; Kim, Youn Jung; Lee, Ye Ji; Kang, Jenny; Kim, Tak-Heun; Choi, Hwajung; Koruyucu, Mine; Kasimoglu, Yelda; Tuna, Elif Bahar; Gencay, Koray; Shin, Teo Jeon; Hyun, Hong-Keun; Kim, Young-Jae; Lee, Sang-Hoon; Lee, Zang Hee; Zhang, Hong; Hu, Jan C-C; Simmer, James P; Cho, Eui-Sic; Kim, Jung-Wook

    2016-11-03

    Amelogenesis imperfecta (AI) is a heterogeneous group of genetic disorders affecting tooth enamel. The affected enamel can be hypoplastic and/or hypomineralized. In this study, we identified ACPT (testicular acid phosphatase) biallelic mutations causing non-syndromic, generalized hypoplastic autosomal-recessive amelogenesis imperfecta (AI) in individuals from six apparently unrelated Turkish families. Families 1, 4, and 5 were affected by the homozygous ACPT mutation c.713C>T (p.Ser238Leu), family 2 by the homozygous ACPT mutation c.331C>T (p.Arg111Cys), family 3 by the homozygous ACPT mutation c.226C>T (p.Arg76Cys), and family 6 by the compound heterozygous ACPT mutations c.382G>C (p.Ala128Pro) and 397G>A (p.Glu133Lys). Analysis of the ACPT crystal structure suggests that these mutations damaged the activity of ACPT by altering the sizes and charges of key amino acid side chains, limiting accessibility of the catalytic core, and interfering with homodimerization. Immunohistochemical analysis confirmed localization of ACPT in secretory-stage ameloblasts. The study results provide evidence for the crucial function of ACPT during amelogenesis. Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  15. Mutational characterization of the P3H1/CRTAP/CypB complex in recessive osteogenesis imperfecta.

    Science.gov (United States)

    Barbirato, C; Trancozo, M; Almeida, M G; Almeida, L S; Santos, T O; Duarte, J C G; Rebouças, M R G O; Sipolatti, V; Nunes, V R R; Paula, F

    2015-12-03

    Osteogenesis imperfecta (OI) is a genetic disease characterized by bone deformities and fractures. Most cases are caused by autosomal dominant mutations in the type I collagen genes COL1A1 and COL1A2; however, an increasing number of recessive mutations in other genes have been reported. The LEPRE1, CRTAP, and PPIB genes encode proteins that form the P3H1/CRTAP/CypB complex, which is responsible for posttranslational modifications of type I collagen. In general, mutations in these genes lead to severe and lethal phenotypes of recessive OI. Here, we describe sixteen genetic variations detected in LEPRE1, CRTAP, and PPIB from 25 Brazilian patients with OI. Samples were screened for mutations on single-strand conformation polymorphism gels and variants were determined by automated sequencing. Seven variants were detected in patients but were absent in control samples. LEPRE1 contained the highest number of variants, including the previously described West African allele (c.1080+1G>T) found in one patient with severe OI as well as a previously undescribed p.Trp675Leu change that is predicted to be disease causing. In CRTAP, one patient carried the c.558A>G homozygous mutation, predicted as disease causing through alteration of a splice site. Genetic variations detected in the PPIB gene are probably not pathogenic due to their localization or because of their synonymous effect. This study enhances our knowledge about the mutational pattern of the LEPRE1, CRTAP, and PPIB genes. In addition, the results strengthen the proposition that LEPRE1 should be the first gene analyzed in mutation detection studies in patients with recessive OI.

  16. Recession-Tolerant Sensors for Thermal Protection Systems, Phase II

    Data.gov (United States)

    National Aeronautics and Space Administration — The Phase II project will develop a suite of diagnostic sensors using Direct Write technology to measure temperature, surface recession depth, and heat flux of an...

  17. Ecohealth Approach to Flood Recession Farming in Okavango Delta ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    In the Okavango Delta, Botswana, flood-recession farming (molapu) is a lucrative but ... Moreover, some practices involved in molapu farming may pose a threat to the ... Linking research to urban planning at the ICLEI World Congress 2018.

  18. Quantitative fundus autofluorescence in recessive Stargardt disease.

    Science.gov (United States)

    Burke, Tomas R; Duncker, Tobias; Woods, Russell L; Greenberg, Jonathan P; Zernant, Jana; Tsang, Stephen H; Smith, R Theodore; Allikmets, Rando; Sparrow, Janet R; Delori, François C

    2014-05-01

    To quantify fundus autofluorescence (qAF) in patients with recessive Stargardt disease (STGD1). A total of 42 STGD1 patients (ages: 7-52 years) with at least one confirmed disease-associated ABCA4 mutation were studied. Fundus AF images (488-nm excitation) were acquired with a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference to account for variable laser power and detector sensitivity. The gray levels (GLs) of each image were calibrated to the reference, zero GL, magnification, and normative optical media density to yield qAF. Texture factor (TF) was calculated to characterize inhomogeneities in the AF image and patients were assigned to the phenotypes of Fishman I through III. Quantified fundus autofluorescence in 36 of 42 patients and TF in 27 of 42 patients were above normal limits for age. Young patients exhibited the relatively highest qAF, with levels up to 8-fold higher than healthy eyes. Quantified fundus autofluorescence and TF were higher in Fishman II and III than Fishman I, who had higher qAF and TF than healthy eyes. Patients carrying the G1916E mutation had lower qAF and TF than most other patients, even in the presence of a second allele associated with severe disease. Quantified fundus autofluorescence is an indirect approach to measuring RPE lipofuscin in vivo. We report that ABCA4 mutations cause significantly elevated qAF, consistent with previous reports indicating that increased RPE lipofuscin is a hallmark of STGD1. Even when qualitative differences in fundus AF images are not evident, qAF can elucidate phenotypic variation. Quantified fundus autofluorescence will serve to establish genotype-phenotype correlations and as an outcome measure in clinical trials.

  19. Quantitative Fundus Autofluorescence in Recessive Stargardt Disease

    Science.gov (United States)

    Burke, Tomas R.; Duncker, Tobias; Woods, Russell L.; Greenberg, Jonathan P.; Zernant, Jana; Tsang, Stephen H.; Smith, R. Theodore; Allikmets, Rando; Sparrow, Janet R.; Delori, François C.

    2014-01-01

    Purpose. To quantify fundus autofluorescence (qAF) in patients with recessive Stargardt disease (STGD1). Methods. A total of 42 STGD1 patients (ages: 7–52 years) with at least one confirmed disease-associated ABCA4 mutation were studied. Fundus AF images (488-nm excitation) were acquired with a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference to account for variable laser power and detector sensitivity. The gray levels (GLs) of each image were calibrated to the reference, zero GL, magnification, and normative optical media density to yield qAF. Texture factor (TF) was calculated to characterize inhomogeneities in the AF image and patients were assigned to the phenotypes of Fishman I through III. Results. Quantified fundus autofluorescence in 36 of 42 patients and TF in 27 of 42 patients were above normal limits for age. Young patients exhibited the relatively highest qAF, with levels up to 8-fold higher than healthy eyes. Quantified fundus autofluorescence and TF were higher in Fishman II and III than Fishman I, who had higher qAF and TF than healthy eyes. Patients carrying the G1916E mutation had lower qAF and TF than most other patients, even in the presence of a second allele associated with severe disease. Conclusions. Quantified fundus autofluorescence is an indirect approach to measuring RPE lipofuscin in vivo. We report that ABCA4 mutations cause significantly elevated qAF, consistent with previous reports indicating that increased RPE lipofuscin is a hallmark of STGD1. Even when qualitative differences in fundus AF images are not evident, qAF can elucidate phenotypic variation. Quantified fundus autofluorescence will serve to establish genotype-phenotype correlations and as an outcome measure in clinical trials. PMID:24677105

  20. Space, body, time and relationship experiences of recess physical activity

    DEFF Research Database (Denmark)

    Pawlowski, Charlotte Skau; Andersen, Henriette Bondo; Tjørnhøj-Thomsen, Tine

    2016-01-01

    BACKGROUND: Increasing recess physical activity has been the aim of several interventions, as this setting can provide numerous physical activity opportunities. However, it is unclear if these interventions are equally effective for all children, or if they only appeal to children who are already...... the classroom as a space for physical activity, designing schoolyards with smaller secluded spaces and varied facilities, improving children's self-esteem and body image, e.g., during physical education, and creating teacher organised play activities during recess....

  1. The Great Recession and America’s Geography of Unemployment

    Science.gov (United States)

    Thiede, Brian C.; Monnat, Shannon M.

    2017-01-01

    Background The Great Recession of 2007–2009 was the most severe and lengthy economic crisis in the U.S. since the Great Depression. The impacts on the population were multi-dimensional, but operated largely through local labor markets. Objective To examine differences in recession-related changes in county unemployment rates and assess how population and place characteristics shaped these patterns. Methods We calculate and decompose Theil Indexes to describe recession-related changes in the distribution of unemployment rates between counties and states. We use exploratory spatial statistics to identify geographic clusters of counties that experienced similar changes in unemployment. We use spatial regression to evaluate associations between county-level recession impacts on unemployment and demographic composition, industrial structure, and state context. Results The recession was associated with increased inequality between county labor markets within states, but declining between-state differences. Counties that experienced disproportionate recession-related increases in unemployment were spatially clustered and characterized by large shares of historically disadvantaged racial and ethnic minority populations, low educational attainment, and heavy reliance on pro-cyclical industries. Associations between these sources of vulnerability were partially explained by unobserved state-level factors. Conclusions The local consequences of macroeconomic trends are associated with county population characteristics, as well as the structural contexts and policy environments in which they are embedded. The recession placed upward pressure on within-state inequality between local labor market conditions. Contribution To present new estimates of the recession’s impact on local labor markets, quantify how heterogeneous impacts affected the distribution of unemployment prevalence, and identify county characteristics associated with disproportionately large recession

  2. A New Keynesian Perspective on the Great Recession

    OpenAIRE

    Peter N. Ireland

    2010-01-01

    With an estimated New Keynesian model, this paper compares the "Great Recession" of 2007-09 to its two immediate predecessors in 1990-91 and 2001. The model attributes all three downturns to a similar mix of aggregate demand and supply disturbances. The most recent series of adverse shocks lasted longer and became more severe, however, prolonging and deepening the Great Recession. In addition, the zero lower bound on the nominal interest rate prevented monetary policy from stabilizing the US ...

  3. Unemployment of Non-western Immigrants in the Great Recession

    OpenAIRE

    Cerveny, J.; Ours, J.C. van

    2013-01-01

    Abstract: This paper examines whether unemployment of non-western immigrant workers in the Netherlands was disproportionally affected by the Great Recession. We analyze unemployment data covering the period November 2007 to February 2013 finding that the Great Recession affected unemployment rates of non-western immigrant workers in absolute terms more than unemployment rates of native workers. However, in relative terms there is not much of a difference. We also find that the sensitivity of ...

  4. The Indian Stock Market and the Great Recession

    OpenAIRE

    Arindam MANDAL; Prasun BHATTACHARJEE

    2012-01-01

    This study analyzes the impact of the outbreak of the Great Recession of 2007 on the behavior of the Indian stock market. The SENSEX index of the Bombay Stock Exchange is analyzed for the prerecession period of January 2002 – November 2007 and the postrecession outbreak period of December 2007 – July 2010. Substantial increase in SENSEX return volatility observed during the post-recession outbreak period, whereas no substantial difference in returns between two periods is...

  5. Gingival recession: prevalence and risk indicators among young greek adults.

    Science.gov (United States)

    Chrysanthakopoulos, Nikolaos A

    2014-07-01

    The aim of the current research was to assess the prevalence of gingival recession and to investigate possible associations among this condition, periodontal and epidemiological variables in a sample of young Greek adults in a general dental practice. A total of 1,430 young adults was examined clinically and interviewed regarding several periodontal and epidemiological variables. Collected data included demographic variables, oral hygiene habits and smoking status. Clinical examination included the recording of dental plaque, supragingival calculus presence, gingival status and buccal gingival recession. Multivariate logistic regression analysis model was performed to access the possible association between gingival recession and several periodontal and epidemiological variables as potential risk factors. The overall prevalence of gingival recession was 63.9%. The statistical analysis indicated that higher educational level [OR= 2.12, 95% CI= 0.53-8.51], cigarette smoking [OR= 1.97, 95% CI= 1.48-7.91], frequent tooth brushing [OR= 0.98, 95% CI= 0.56-1.96], presence of oral piercing [OR= 0.92, 95% CI= 0.38-1.58], presence of gingival inflammation [OR= 4.54, 95% CI= 1.68-7.16], presence of dental plaque [OR= 1.67, 95% CI= 0.68-2.83] and presence of supragingival calculus [OR=1.34, 95% CI= 0.59-1.88], were the most important associated factors of gingival recession. The observations of the current research supported the results from previous authors that several periodontal factors, educational level and smoking were significantly associated with the presence of gingival recession, while presence of oral piercing was a new factor that was found to be associated with gingival recession. Key words:Gingival recession, prevalence, risk factors, young adults.

  6. Formal identity of gravitational and weakly interacting recession

    International Nuclear Information System (INIS)

    Muheim, J.T.

    1982-01-01

    The author discusses the construction of models using the five elementary constants esub(s), h/2π, G, c and ksub(B) which can produce a macro or micro world with exacticity. All physical processes in nature determine the gravitational universe recession. A diagram is presented comparing the gravitational and weakly interacting recession. The Big-Bang model is discussed. (A.N.K.)

  7. Systematic review of recess interventions to increase physical activity.

    Science.gov (United States)

    Ickes, Melinda J; Erwin, Heather; Beighle, Aaron

    2013-08-01

    With the rapid increase in obesity rates among youth, efforts to increase physical activity (PA) have become a priority. School-based strategies for PA promotion must be cost-effective, unobtrusive, and linked to improved academic performance. Efforts to maximize recess PA are advocated because of both health and academic benefits. The purpose of this manuscript was to review recess interventions aimed to improve PA among youth, and make recommendations to develop related best practices. An extensive literature search was conducted to include all primary research articles evaluating any recess intervention with PA as an outcome. The included 13 interventions represented both settings within the U.S and internationally, among preschools and elementary/primary schools. A variety of strategies were used within the design and implementation of each of the interventions including: added equipment/materials, markings, zones, teacher involvement, active video games, activity of the week, and activity cards. Of the included studies, 95% demonstrated positive outcomes as a result of the recess intervention. A number of simple, low-cost strategies can be implemented to maximize the amount of recess time students are allotted. Long-term follow-up studies are warranted for each of the recess strategies identified to be effective.

  8. Polytene chromosomes of monogenic and amphogenic Chrysomya species (Calliphoridae, Diptera): analysis of banding patterns and in situ hybridization with Drosophila sex determining gene sequences.

    Science.gov (United States)

    Puchalla, S

    1994-03-01

    Standard maps for the five banded polytene chromosomes found in trichogen cell nuclei of the monogenic blowfly Chrysomya rufifacies and the amphogenic Chrysomya pinguis are presented. The chromosomes are highly homologous in the two species; differences in banding patterns are predominantly caused by one pericentric and ten paracentric inversions. In chromosome 5 of the amphogenic Chrysomya phaonis, also analysed in this paper, an additional paracentric inversion was observed. The distribution of species specific inversions indicates that the monogenic C. rufifacies is phylogenetically older than the amphogenic species. The maternal sex realizer locus F'/f on polytene chromosome 5 of C. rufifacies is not associated with a structural heterozygosity. Chromosome pair 6 of C. rufifacies and the sex chromosome pair of C. pinguis are under-replicated in polytene nuclei; they consist of irregular chromatin granules, frequently associated with nucleolus material. Evolution of heteromorphic sex chromosomes in Chrysomya is probably correlated with heterochromatin accumulation. A search for sex determining genes in Chrysomya was initiated using sex determining sequences from Drosophila melanogaster for in situ hybridization. The polytene band 41A1 on chromosome 5 of monogenic and amphogenic Chrysomya species contains sequences homologous to the maternal sex determining gene daughterless (da). Homology to the zygotic gene Sex-lethal (Sxl) of Drosophila is detected in band 39A1 on chromosome 5 of C. rufifacies. The findings reported here are the first evidence for a possible homology between the da gene of Drosophila and the maternal sex realizer F' of C. rufifacies. An hypothesis for the evolution of the maternal effect sex determination of C. rufifacies is proposed.

  9. Monogenic diabetes syndromes

    DEFF Research Database (Denmark)

    Astuti, Dewi; Sabir, Ataf; Fulton, Piers

    2017-01-01

    (n = 268), and SLC19A2 (n = 48) for Wolfram type 1, Wolfram type 2, Alström, and Thiamine-responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1. We then investigated genotype-phenotype relations...

  10. Precarious Slopes? The Great Recession, Federal Stimulus, and New Jersey Schools. Working Paper #02-12

    Science.gov (United States)

    Chakrabarti, Rajashri; Sutherland, Sarah

    2012-01-01

    While sparse literature exists investigating the impact of the Great Recession on various sectors of the economy, there is virtually no research that studies the effect of the Great Recession, or past recessions, on schools. This paper starts to fill the void. Studying school funding during the recession is of paramount importance because schools…

  11. Characterization of Large Structural Genetic Mosaicism in Human Autosomes

    Science.gov (United States)

    Machiela, Mitchell J.; Zhou, Weiyin; Sampson, Joshua N.; Dean, Michael C.; Jacobs, Kevin B.; Black, Amanda; Brinton, Louise A.; Chang, I-Shou; Chen, Chu; Chen, Constance; Chen, Kexin; Cook, Linda S.; Crous Bou, Marta; De Vivo, Immaculata; Doherty, Jennifer; Friedenreich, Christine M.; Gaudet, Mia M.; Haiman, Christopher A.; Hankinson, Susan E.; Hartge, Patricia; Henderson, Brian E.; Hong, Yun-Chul; Hosgood, H. Dean; Hsiung, Chao A.; Hu, Wei; Hunter, David J.; Jessop, Lea; Kim, Hee Nam; Kim, Yeul Hong; Kim, Young Tae; Klein, Robert; Kraft, Peter; Lan, Qing; Lin, Dongxin; Liu, Jianjun; Le Marchand, Loic; Liang, Xiaolin; Lissowska, Jolanta; Lu, Lingeng; Magliocco, Anthony M.; Matsuo, Keitaro; Olson, Sara H.; Orlow, Irene; Park, Jae Yong; Pooler, Loreall; Prescott, Jennifer; Rastogi, Radhai; Risch, Harvey A.; Schumacher, Fredrick; Seow, Adeline; Setiawan, Veronica Wendy; Shen, Hongbing; Sheng, Xin; Shin, Min-Ho; Shu, Xiao-Ou; VanDen Berg, David; Wang, Jiu-Cun; Wentzensen, Nicolas; Wong, Maria Pik; Wu, Chen; Wu, Tangchun; Wu, Yi-Long; Xia, Lucy; Yang, Hannah P.; Yang, Pan-Chyr; Zheng, Wei; Zhou, Baosen; Abnet, Christian C.; Albanes, Demetrius; Aldrich, Melinda C.; Amos, Christopher; Amundadottir, Laufey T.; Berndt, Sonja I.; Blot, William J.; Bock, Cathryn H.; Bracci, Paige M.; Burdett, Laurie; Buring, Julie E.; Butler, Mary A.; Carreón, Tania; Chatterjee, Nilanjan; Chung, Charles C.; Cook, Michael B.; Cullen, Michael; Davis, Faith G.; Ding, Ti; Duell, Eric J.; Epstein, Caroline G.; Fan, Jin-Hu; Figueroa, Jonine D.; Fraumeni, Joseph F.; Freedman, Neal D.; Fuchs, Charles S.; Gao, Yu-Tang; Gapstur, Susan M.; Patiño-Garcia, Ana; Garcia-Closas, Montserrat; Gaziano, J. Michael; Giles, Graham G.; Gillanders, Elizabeth M.; Giovannucci, Edward L.; Goldin, Lynn; Goldstein, Alisa M.; Greene, Mark H.; Hallmans, Goran; Harris, Curtis C.; Henriksson, Roger; Holly, Elizabeth A.; Hoover, Robert N.; Hu, Nan; Hutchinson, Amy; Jenab, Mazda; Johansen, Christoffer; Khaw, Kay-Tee; Koh, Woon-Puay; Kolonel, Laurence N.; Kooperberg, Charles; Krogh, Vittorio; Kurtz, Robert C.; LaCroix, Andrea; Landgren, Annelie; Landi, Maria Teresa; Li, Donghui; Liao, Linda M.; Malats, Nuria; McGlynn, Katherine A.; McNeill, Lorna H.; McWilliams, Robert R.; Melin, Beatrice S.; Mirabello, Lisa; Peplonska, Beata; Peters, Ulrike; Petersen, Gloria M.; Prokunina-Olsson, Ludmila; Purdue, Mark; Qiao, You-Lin; Rabe, Kari G.; Rajaraman, Preetha; Real, Francisco X.; Riboli, Elio; Rodríguez-Santiago, Benjamín; Rothman, Nathaniel; Ruder, Avima M.; Savage, Sharon A.; Schwartz, Ann G.; Schwartz, Kendra L.; Sesso, Howard D.; Severi, Gianluca; Silverman, Debra T.; Spitz, Margaret R.; Stevens, Victoria L.; Stolzenberg-Solomon, Rachael; Stram, Daniel; Tang, Ze-Zhong; Taylor, Philip R.; Teras, Lauren R.; Tobias, Geoffrey S.; Viswanathan, Kala; Wacholder, Sholom; Wang, Zhaoming; Weinstein, Stephanie J.; Wheeler, William; White, Emily; Wiencke, John K.; Wolpin, Brian M.; Wu, Xifeng; Wunder, Jay S.; Yu, Kai; Zanetti, Krista A.; Zeleniuch-Jacquotte, Anne; Ziegler, Regina G.; de Andrade, Mariza; Barnes, Kathleen C.; Beaty, Terri H.; Bierut, Laura J.; Desch, Karl C.; Doheny, Kimberly F.; Feenstra, Bjarke; Ginsburg, David; Heit, John A.; Kang, Jae H.; Laurie, Cecilia A.; Li, Jun Z.; Lowe, William L.; Marazita, Mary L.; Melbye, Mads; Mirel, Daniel B.; Murray, Jeffrey C.; Nelson, Sarah C.; Pasquale, Louis R.; Rice, Kenneth; Wiggs, Janey L.; Wise, Anastasia; Tucker, Margaret; Pérez-Jurado, Luis A.; Laurie, Cathy C.; Caporaso, Neil E.; Yeager, Meredith; Chanock, Stephen J.

    2015-01-01

    Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10−31) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population. PMID:25748358

  12. Pathogenesis and potential therapy of autosomal dominant polycystic kidney disease

    Directory of Open Access Journals (Sweden)

    O.O. Melnyk

    2017-10-01

    Full Text Available Autosomal dominant polycystic kidney disease (ADPKD is a hereditary disease characterized by progressive growth of the cyst and an increase in the total volume of the kidneys which leads to kidney failure. The main causes of ADPKD are mutations in the genes PKD1 and PKD2 which encode the formation of polycystin-1 and polycystin-2 proteins. There is a connection between structural and functional defects in the primary cilia with the ADPKD. The most promising drugs for the treatment of ADPKD today are vasopressin-2 receptor antagonists, m-TOR and c-AMP inhibitors.

  13. Stream recession curves and storage variability in small watersheds

    Directory of Open Access Journals (Sweden)

    N. Y. Krakauer

    2011-07-01

    Full Text Available The pattern of streamflow recession after rain events offers clues about the relationship between watershed runoff (observable as river discharge and water storage (not directly observable and can help in water resource assessment and prediction. However, there have been few systematic assessments of how streamflow recession varies across flow rates and how it relates to independent assessments of terrestrial water storage. We characterized the streamflow recession pattern in 61 relatively undisturbed small watersheds (1–100 km2 across the coterminous United States with multiyear records of hourly streamflow from automated gauges. We used the North American Regional Reanalysis to help identify periods where precipitation, snowmelt, and evaporation were small compared to streamflow. The order of magnitude of the recession timescale increases from 1 day at high flow rates (~1 mm h−1 to 10 days at low flow rates (~0.01 mm h−1, leveling off at low flow rates. There is significant variability in the recession timescale at a given flow rate between basins, which correlates with climate and geomorphic variables such as the ratio of mean streamflow to precipitation and soil water infiltration capacity. Stepwise multiple regression was used to construct a six-variable predictive model that explained some 80 % of the variance in recession timescale at high flow rates and 30–50 % at low flow rates. Seasonal and interannual variability in inferred storage shows similar time evolution to regional-scale water storage variability estimated from GRACE satellite gravity data and from land surface modeling forced by observed meteorology, but is up to a factor of 10 smaller. Study of this discrepancy in the inferred storage amplitude may provide clues to the range of validity of the recession curve approach to relating runoff and storage.

  14. Autosomal dominant Carvajal plus syndrome due to the novel desmoplakin mutation c.1678A > T (p.Ile560Phe).

    Science.gov (United States)

    Finsterer, Josef; Stöllberger, Claudia; Wollmann, Eva; Dertinger, Susanne; Laccone, Franco

    2016-09-01

    Carvajal syndrome is an autosomal dominant or autosomal recessive disorder, manifesting with dilated cardiomyopathy, woolly hair, and palmoplantar keratoma. Additional manifestations can be occasionally found. Carvajal syndrome may be due to mutations in the desmocollin-2, desmoplakin, or plakophilin-2 gene. We report a family with Carvajal syndrome which additionally presented with hypoacusis, noncompaction, recurrent pharyngeal infections, oligodontia, and recurrent diarrhoea. Father and brother were also affected and had died suddenly, the father despite implantation of a cardioverter defibrillator (ICD). Genetic studies revealed the novel pathogenic mutation c.1678A > T in the desmoplakin gene resulting in the amino acid change Ile to Phe at position 560 in the index case and her brother. The index case underwent ICD implantation recently. Phenotypic manifestations of Carvajal syndrome are even broader than so far anticipated, the number of mutations in the desmoplakin gene responsible for Carvajal syndrome is still increasing, and these patients require implantation of an ICD as soon as their diagnosis is established.

  15. Non-invasive prenatal diagnosis of monogenic disorders: an optimized protocol using MEMO qPCR with miniSTR as internal control.

    Science.gov (United States)

    Guissart, Claire; Debant, Vanessa; Desgeorges, Marie; Bareil, Corinne; Raynal, Caroline; Toga, Caroline; Pritchard, Victoria; Koenig, Michel; Claustres, Mireille; Vincent, Marie-Claire

    2015-02-01

    Analysis of circulating cell-free fetal DNA (cffDNA) in maternal plasma is very promising for early diagnosis of monogenic diseases. However, this approach is not yet available for routine use and remains technically challenging because of the low concentration of cffDNA, which is swamped by the overwhelming maternal DNA. To make clinical applications more readily accessible, we propose a new approach based on mutant enrichment with 3'-modified oligonucleotides (MEMO) PCR along with real-time PCR to selectively amplify from the maternal blood the paternally inherited fetal allele that is not present in the maternal genome. The first proof of concept of this strategy was displayed for cystic fibrosis by the accuracy of our detection of the p.Gly542* mutation used as the initial developmental model. Subsequently, a retrospective study of plasmas originating from two pregnant women carrying a fetus with private mutation confirmed the effectiveness of our method. We confirmed the presence of cffDNA in the studied samples by the identification of a tri-allelic DNA profile using a miniSTR kit. This new non-invasive prenatal diagnosis test offers numerous advantages over current methods: it is simple, cost effective, time efficient and does not require complex equipment or bioinformatics settings. Moreover, our assays for different private mutations demonstrate the viability of this approach in clinical settings for monogenic disorders.

  16. A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders.

    Science.gov (United States)

    Stark, Zornitza; Tan, Tiong Y; Chong, Belinda; Brett, Gemma R; Yap, Patrick; Walsh, Maie; Yeung, Alison; Peters, Heidi; Mordaunt, Dylan; Cowie, Shannon; Amor, David J; Savarirayan, Ravi; McGillivray, George; Downie, Lilian; Ekert, Paul G; Theda, Christiane; James, Paul A; Yaplito-Lee, Joy; Ryan, Monique M; Leventer, Richard J; Creed, Emma; Macciocca, Ivan; Bell, Katrina M; Oshlack, Alicia; Sadedin, Simon; Georgeson, Peter; Anderson, Charlotte; Thorne, Natalie; Melbourne Genomics Health Alliance; Gaff, Clara; White, Susan M

    2016-11-01

    To prospectively evaluate the diagnostic and clinical utility of singleton whole-exome sequencing (WES) as a first-tier test in infants with suspected monogenic disease. Singleton WES was performed as a first-tier sequencing test in infants recruited from a single pediatric tertiary center. This occurred in parallel with standard investigations, including single- or multigene panel sequencing when clinically indicated. The diagnosis rate, clinical utility, and impact on management of singleton WES were evaluated. Of 80 enrolled infants, 46 received a molecular genetic diagnosis through singleton WES (57.5%) compared with 11 (13.75%) who underwent standard investigations in the same patient group. Clinical management changed following exome diagnosis in 15 of 46 diagnosed participants (32.6%). Twelve relatives received a genetic diagnosis following cascade testing, and 28 couples were identified as being at high risk of recurrence in future pregnancies. This prospective study provides strong evidence for increased diagnostic and clinical utility of singleton WES as a first-tier sequencing test for infants with a suspected monogenic disorder. Singleton WES outperformed standard care in terms of diagnosis rate and the benefits of a diagnosis, namely, impact on management of the child and clarification of reproductive risks for the extended family in a timely manner.Genet Med 18 11, 1090-1096.

  17. Recurrent Skin and Lung Infections in Autosomal Dominant Hyper IgE Syndrome with Transactivation Domain STAT3 Mutation

    Directory of Open Access Journals (Sweden)

    Chad J. Cooper

    2014-01-01

    Full Text Available Background. Hyper IgE is a rare systemic disease characterized by the clinical triad of high serum levels of IgE (>2000 IU/mL, eczema, and recurrent staphylococcal skin and lung infections. The presentation of hyper IgE syndrome is highly variable, which makes it easy to confuse the diagnosis with that of severe atopy or other rare immunodeficiency disorders. Case Report. A 23-year-old Hispanic presented with history of frequent respiratory and gastrointestinal infections as a child and multiple episodes of skin and lung infections (abscess with Staphylococcus aureus throughout his adult life. He had multiple eczematous lesions and folliculitis over his entire body, oral/esophageal candidiasis, and retention of his primary teeth. The IgE was elevated (>5000 IU/mL. Genetic mutation analysis revealed a mutation affecting the transactivation domain of the STAT3 gene. Conclusion. The hallmark of hyper IgE syndrome is serum IgE of >2000 IU/mL. Hyper IgE syndrome is a genetic disorder that is either autosomal dominant or recessive. A definite diagnosis can be made with genetic mutation analysis, and in this case, it revealed a very rare finding of the transactivation domain STAT3 mutation. Hyper IgE syndrome is a challenge for clinicians in establishing a diagnosis in suspected cases.

  18. Autosomal dominant inheritance of Williams-Beuren syndrome in a father and son with haploinsufficiency for FKBP6.

    Science.gov (United States)

    Metcalfe, Kay; Simeonov, Emil; Beckett, William; Donnai, Dian; Tassabehji, May

    2005-04-01

    Williams-Beuren syndrome (WBS) is a neurodevelopmental microdeletion disorder that usually occurs sporadically due to its location within a highly repetitive genomic region that is unstable and prone to unequal cross-over during meiosis. The consequential loss of chromosomal material includes approximately 1.5 Mb of DNA at 7q11.23. Whilst cases of dominant inheritance have been described in the literature, there have been few reports of molecular confirmation and none have carried out detailed genotyping. We describe a Bulgarian father and son with WBS detected by fluorescent in situ hybridisation (with an elastin gene probe) and loss of heterozygosity mapping using microsatellite markers located in the critical region. These individuals appear to have a common WBS heterozygous deletion, confirming the expected dominant transmission and adding to the few familial cases reported. The deletion includes the gene FKBP6 which has recently been shown to play a role in homologous chromosome pairing in meiosis and male fertility in mouse models. Homozygous Fkbp6 -/- male mice are infertile and our data suggests that haploinsufficiency for FKBP6 does not appear to preclude male fertility in WBS, although male infertility involving this gene has the potential to follow the mouse model as a human autosomal recessive condition.

  19. Autosomal dominant distal myopathy: Linkage to chromosome 14

    Energy Technology Data Exchange (ETDEWEB)

    Laing, N.G.; Laing, B.A.; Wilton, S.D.; Dorosz, S.; Mastaglia, F.L.; Kakulas, B.A. [Australian Neuromuscular Research Institute, Perth (Australia); Robbins, P.; Meredith, C.; Honeyman, K.; Kozman, H.

    1995-02-01

    We have studied a family segregating a form of autosomal dominant distal myopathy (MIM 160500) and containing nine living affected individuals. The myopathy in this family is closest in clinical phenotype to that first described by Gowers in 1902. A search for linkage was conducted using microsatellite, VNTR, and RFLP markers. In total, 92 markers on all 22 autosomes were run. Positive linkage was obtained with 14 of 15 markers tested on chromosome 14, with little indication of linkage elsewhere in the genome. Maximum two-point LOD scores of 2.60 at recombination fraction .00 were obtained for the markers MYH7 and D14S64 - the family structure precludes a two-point LOD score {ge} 3. Recombinations with D14S72 and D14S49 indicate that this distal myopathy locus, MPD1, should lie between these markers. A multipoint analysis assuming 100% penetrance and using the markers D14S72, D14S50, MYH7, D14S64, D14S54, and D14S49 gave a LOD score of exactly 3 at MYH7. Analysis at a penetrance of 80% gave a LOD score of 2.8 at this marker. This probable localization of a gene for distal myopathy, MPD1, on chromosome 14 should allow other investigators studying distal myopathy families to test this region for linkage in other types of the disease, to confirm linkage or to demonstrate the likely genetic heterogeneity. 24 refs., 3 figs., 1 tab.

  20. Novel autosomal dominant TNNT1 mutation causing nemaline myopathy.

    Science.gov (United States)

    Konersman, Chamindra G; Freyermuth, Fernande; Winder, Thomas L; Lawlor, Michael W; Lagier-Tourenne, Clotilde; Patel, Shailendra B

    2017-11-01

    Nemaline myopathy (NEM) is one of the three major forms of congenital myopathy and is characterized by diffuse muscle weakness, hypotonia, respiratory insufficiency, and the presence of nemaline rod structures on muscle biopsy. Mutations in troponin T1 (TNNT1) is 1 of 10 genes known to cause NEM. To date, only homozygous nonsense mutations or compound heterozygous truncating or internal deletion mutations in TNNT1 gene have been identified in NEM. This extended family is of historical importance as some members were reported in the 1960s as initial evidence that NEM is a hereditary disorder. Proband and extended family underwent Sanger sequencing for TNNT1. We performed RT-PCR and immunoblot on muscle to assess TNNT1 RNA expression and protein levels in proband and father. We report a novel heterozygous missense mutation of TNNT1 c.311A>T (p.E104V) that segregated in an autosomal dominant fashion in a large family residing in the United States. Extensive sequencing of the other known genes for NEM failed to identify any other mutant alleles. Muscle biopsies revealed a characteristic pattern of nemaline rods and severe myofiber hypotrophy that was almost entirely restricted to the type 1 fiber population. This novel mutation alters a residue that is highly conserved among vertebrates. This report highlights not only a family with autosomal dominant inheritance of NEM, but that this novel mutation likely acts via a dominant negative mechanism. © 2017 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.