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Sample records for autosome recessive lethals

  1. 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

  2. Autosomal recessive cerebellar ataxias

    Directory of Open Access Journals (Sweden)

    Palau Francesc

    2006-11-01

    Full Text Available Abstract Autosomal recessive cerebellar ataxias (ARCA are a heterogeneous group of rare neurological disorders involving both central and peripheral nervous system, and in some case other systems and organs, and characterized by degeneration or abnormal development of cerebellum and spinal cord, autosomal recessive inheritance and, in most cases, early onset occurring before the age of 20 years. This group encompasses a large number of rare diseases, the most frequent in Caucasian population being Friedreich ataxia (estimated prevalence 2–4/100,000, ataxia-telangiectasia (1–2.5/100,000 and early onset cerebellar ataxia with retained tendon reflexes (1/100,000. Other forms ARCA are much less common. Based on clinicogenetic criteria, five main types ARCA can be distinguished: congenital ataxias (developmental disorder, ataxias associated with metabolic disorders, ataxias with a DNA repair defect, degenerative ataxias, and ataxia associated with other features. These diseases are due to mutations in specific genes, some of which have been identified, such as frataxin in Friedreich ataxia, α-tocopherol transfer protein in ataxia with vitamin E deficiency (AVED, aprataxin in ataxia with oculomotor apraxia (AOA1, and senataxin in ataxia with oculomotor apraxia (AOA2. Clinical diagnosis is confirmed by ancillary tests such as neuroimaging (magnetic resonance imaging, scanning, electrophysiological examination, and mutation analysis when the causative gene is identified. Correct clinical and genetic diagnosis is important for appropriate genetic counseling and prognosis and, in some instances, pharmacological treatment. Due to autosomal recessive inheritance, previous familial history of affected individuals is unlikely. For most ARCA there is no specific drug treatment except for coenzyme Q10 deficiency and abetalipoproteinemia.

  3. 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

  4. Genetics Home Reference: autosomal recessive primary microcephaly

    Science.gov (United States)

    ... Disorders ClinicalTrials.gov (1 link) ClinicalTrials.gov Scientific Articles on PubMed (1 link) PubMed OMIM (7 links) MICROCEPHALY 1, PRIMARY, AUTOSOMAL RECESSIVE MICROCEPHALY 2, PRIMARY, AUTOSOMAL ...

  5. Lethal autosomal recessive epidermolytic ichthyosis due to a novel donor splice-site mutation in KRT10.

    Science.gov (United States)

    Covaciu, C; Castori, M; De Luca, N; Ghirri, P; Nannipieri, A; Ragone, G; Zambruno, G; Castiglia, D

    2010-06-01

    Epidermolytic ichthyosis (EI; MIM 113800), previously named bullous congenital ichthyosiform erythroderma or epidermolytic hyperkeratosis, is a rare and clinically variable defect of cornification characterized by generalized erythema, erosions, scaling and easily breaking blisters that become less frequent later in life while hyperkeratosis increases. EI is caused by dominant mutations in either KRT1 or KRT10, encoding keratin 1 (K1) and keratin 10 (K10), respectively. Usually, mutations are missense substitutions into the highly conserved α-helical rod domains of the proteins. However, three inbred pedigrees in which EI is transmitted as a recessive trait due to KRT10 null mutations have been described. © 2010 The Authors. Journal Compilation © 2010 British Association of Dermatologists.

  6. Carrier testing for autosomal-recessive disorders.

    Science.gov (United States)

    Vallance, Hilary; Ford, Jason

    2003-08-01

    The aim of carrier testing is to identify carrier couples at risk of having offspring with a serious genetic (autosomal recessive) disorder. Carrier couples are offered genetic consultation where their reproductive options, including prenatal diagnosis, are explained. The Ashkenazi Jewish population is at increased risk for several recessively inherited disorders (Tay-Sachs disease, Cystic fibrosis, Canavan disease, Gaucher disease, Familial Dysautonomia, Niemann-Pick disease, Fanconi anemia, and Bloom syndrome). Unlike Tay-Sachs disease, there is no simple biochemical or enzymatic test to detect carriers for these other disorders. However, with the rapid identification of disease-causing genes in recent years, DNA-based assays are increasingly available for carrier detection. Approximately 5% of the world's population carries a mutation affecting the globin chains of the hemoglobin molecule. Among the most common of these disorders are the thalassemias. The global birth rate of affected infants is at least 2 per 1000 (in unscreened populations), with the greatest incidence in Southeast Asian, Indian, Mediterranean, and Middle Eastern ethnic groups. Carriers are detected by evaluation of red cell indices and morphology, followed by more sophisticated hematological testing and molecular analyses. The following issues need to be considered in the development of a carrier screening program: (1) test selection based on disease severity and test accuracy; (2) funding for testing and genetic counselling; (3) definition of the target population to be screened; (4) development of a public and professional education program; (5) informed consent for screening; and (6) awareness of community needs.

  7. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    ... Diseases Health Topic: Pneumonia Health Topic: Skin Infections Genetic and Rare Diseases Information Center (1 link) Autosomal recessive hyper IgE syndrome Additional NIH Resources (2 links) National Institute of Allergy and Infectious Diseases: DOCK8 Deficiency National Institute of Allergy and ...

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

    Indian Academy of Sciences (India)

    Table 1. Autosomal recessive nonsyndromic hearing loss loci and related genes. STR-markers and primers used for screening the loci are listed. Repeated sequence. Locus. Gene STR marker. Position. Forward primer. Reverse primer. Length (bp). DFNB2 MYOTA D11s911 77448582-77448892 CA. D11S937. 77854318- ...

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

    NARCIS (Netherlands)

    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

  12. Mining of lethal recessive genetic variation in Danish cattle

    DEFF Research Database (Denmark)

    Das, Ashutosh

    2015-01-01

    The widespread use of artificial insemination in cattle breeding Worldwide leads to reduced effective population sizes and increased inbreeding levels. Increased inbreeding result in increased probalility of expression of recessive defective alleles, which probably is reflected in a decline...... 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...

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

    Science.gov (United States)

    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.

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

    International Nuclear Information System (INIS)

    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

    Energy Technology Data Exchange (ETDEWEB)

    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. Mutations of the tyrosinase gene produce autosomal recessive ocular albinism

    Energy Technology Data Exchange (ETDEWEB)

    King, R.A.; Summers, C.G.; Oetting, W.S. [Univ. of Minnesota, Minneapolis, MN (United States)] [and others

    1994-09-01

    Albinism has historically been divided into ocular (OA) and oculocutaneous (OCA) types based on the presence or absence of clinically apparent skin and hair involvement in an individual with the ocular features of albinism. The major genes for OCA include the tyrosinase gene in OCA1 and the P gene in OCA2. X-linked and autosomal recessive OA have been described and the responsible genes have not been identified. We now present six Caucasian individuals who have the phenotype of autosomal recessive OA but who have OCA1 as shown by the presence of mutations of the tyrosinase. They had white or very light hair and white skin at birth, and cutaneous pigment developed in the first decade of life. At ages ranging from 1.5-23 years, hair color was dark blond to light brown. The skin had generalized pigment and well developed tan was present on the exposed arm and face skin of four. Iris pigment was present and iris translucency varied. Molecular analysis of the tyrosinase gene, using PCR amplification and direct di-deoxy sequencing showed the following mutations: E398Z/E398Q, P406S/g346a, R402E/T373K, ?/D383N, and H211N/T373K. The homozygous individual was not from a known consanguineous mating. T373K is the most common tyrosinase gene mutation in our laboratory. Three of these mutations are associated with a total loss of tyrosinase activity (g346a splice-site, T373K, and D383N), while four are associated with residual enzyme activity (H211N, R402E, E398Q, and P406S). These studies show that mutations of the tyrosinase gene can produce the phenotype of autosomal recessive OA in an individual who has normal amounts of cutaneous pigment and the ability to tan after birth. This extends the phenotypic range of OCA1 to normal cutaneous pigment after early childhood, and suggest that mutations of the tyrosinase gene account for a significant number of individuals with autosomal recessive OA.

  17. Mutations in PCDH21 cause autosomal recessive cone-rod dystrophy

    DEFF Research Database (Denmark)

    Østergaard, Elsebet; Batbayli, M; Dunø, Morten

    2010-01-01

    Cone-rod dystrophy is a retinal dystrophy with early loss of cone photoreceptors and a parallel or subsequent loss of rod photoreceptors. It may be syndromic, but most forms are non-syndromic with autosomal dominant, autosomal recessive or X-linked recessive inheritance.......Cone-rod dystrophy is a retinal dystrophy with early loss of cone photoreceptors and a parallel or subsequent loss of rod photoreceptors. It may be syndromic, but most forms are non-syndromic with autosomal dominant, autosomal recessive or X-linked recessive inheritance....

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

    Science.gov (United States)

    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.

  19. Crossover suppressors and balanced recessive lethals in Caenorhabditis elegans

    International Nuclear Information System (INIS)

    Herman, R.K.

    1978-01-01

    Two dominant suppressors of crossing over have been identified following x-ray treatment of the small nematode C. elegans. They suppress crossing over in linkage group II (LGII) about 100-fold and 50-fold and are both tightly linked to LGII markers. One, called C1, segregates independently of all other linkage groups and is homozygous fertile. The other is a translocation involving LGII and X. The translocation also suppresses crossing over along the right half of X and is homozygous lethal. C1 has been used as a balancer of LGII recessive lethal and sterile mutations induced by EMS. The frequencies of occurrence of lethals and steriles were approximately equal. Fourteen mutations were assigned to complementation groups and mapped. They tended to map in the same region where LGII visibles are clustered

  20. Linkage of autosomal recessive lamellar ichthyosis to chromosome 14q

    Energy Technology Data Exchange (ETDEWEB)

    Russell, L.J.; Compton, J.G.; Bale, S.J. [National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD (United States); DiGiovanna, J.J. [National Cancer Institute, Bethesda, MD (United States); Hashem, N. [Ains-Shams Univ. Medical Genetics Center, Cairo (Egypt)

    1994-12-01

    The authors have mapped the locus for lamellar ichthyosis (LI), an autosomal recessive skin disease characterized by abnormal cornification of the epidermis. Analysis using both inbred and outbred families manifesting severe LI showed complete linkage to several markers within a 9.3-cM region on chromosome 14q11. Affected individuals in inbred families were also found to have striking homozygosity for markers in this region. Linkage-based genetic counseling and prenatal diagnosis is now available for informative at-risk families. Several transcribed genes have been mapped to the chromosome 14 region containing the LI gene. The transglutaminase 1 gene (TGM1), which encodes one of the enzymes responsible for cross-linking epidermal proteins during formation of the stratum corneum, maps to this interval. The TGM1 locus was completely linked to LI (Z = 9.11), suggesting that TGM1 is a good candidate for further investigation of this disorder. The genes for four serine proteases also map to this region but are expressed only in hematopoietic or mast cells, making them less likely candidates.

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

    Science.gov (United States)

    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.

  2. Spectrum of Autosomal Recessive Congenital Ichthyosis in Scandinavia

    DEFF Research Database (Denmark)

    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...

  3. MR cholangiography in children with autosomal recessive polycystic kidney disease

    International Nuclear Information System (INIS)

    Jung, G.; Benz-Bohm, G.; Kugel, H.; Keller, K.M.; Querfeld, U.

    1999-01-01

    Background. Magnetic resonance cholangiography (MRC) is a relatively new, non-invasive imaging technique of the biliary tree that has shown good correlation with endoscopic retrograde cholangiopancreatography. The liver manifestation of autosomal recessive polycystic kidney disease (ARPKD) is congenital hepatic fibrosis (CHF). CHF may be accompanied by Caroli's disease, which is characterised by a non-obstructive dilation of the intrahepatic bile ducts. Objective. A prospective study was conducted to determine the presence and extent of Caroli's disease in children with ARPKD. Materials and methods. Seven children with ARPKD aged from 3.0 to 10.1 years were examined. CHF was confirmed in all biopsied cases (5 of 7). All children had been followed by repeated abdominal US examinations for many years. The MR examination included a morphological imaging study using a T2-weighted turbo spin-echo sequence and a heavily T2-weighted inversion-recovery turbo spin-echo sequence with three-dimensional maximum intensity projection (MIP) reconstructions for MRC. Results. The diagnosis of Caroli's disease could be made in one case by US; in two other children Caroli's disease was suspected, but the differentiation from hepatic cysts was not possible. By MRC, Caroli's disease could be diagnosed in three of seven children. Furthermore, MRC with MIP reconstructions demonstrated the extent of the disease by showing the entire biliary tree from different angles. Conclusions. MRC is a valuable method to establish the diagnosis and demonstrate the extent of Caroli's disease. (orig.)

  4. Autosomal recessive agammaglobulinemia: a novel non-sense mutation in CD79a.

    Science.gov (United States)

    Khalili, Abbas; Plebani, Alessandro; Vitali, Massimiliano; Abolhassani, Hassan; Lougaris, Vassilios; Mirminachi, Babak; Rezaei, Nima; Aghamohammadi, Asghar

    2014-02-01

    This study describes the fifth case worldwide of autosomal recessive agammaglobulinemia due to a novel non-sense mutation in CD79a gene with a severe unusual onset due to an invasive central nervous system infection.

  5. Autosomal Recessive Polycystic Kidney Disease and Epidemiologic Factors

    Directory of Open Access Journals (Sweden)

    Parsa Yousefichaijan

    2017-01-01

    Full Text Available Background Autosomal recessive polycystic kidney disease (ARPKD is a heterogeneous inherited disorder most commonly seen in childhood. The presentation is usually a palpable large mass in the flank or abdomen appearing at infancy or birth, leading to electrolyte abnormalities, pulmonary hypoplasia, oligohydramnious and the Potter’s syndrome. The survival rate of this disease is 70%. Multiple mutations of the polycystic kidney and hepatic disease 1 (PKHD1 are known that can cause ARPKD. On the other hand, mutations in PKHD1 have also been identified in about 30% of children with congenital hepatic fibrosis (the Caroli’s syndrome without any evidence of kidney involvement. Based on this evidence, not everyone with PKHD1 mutations will present with ARPKD. Recent studies have shown that nongenetic factors, including environmental exposures had a significant effect on manifestations of ARPKD. The present study aimed at investigating the possible link between ARPKD and its epidemiologic factors, hypothesizing that these epidemiologic conditions would influence the incidence of ARPKD. Objectives The present study aimed at evaluating a possible link between the ARPKD and its epidemiologic factors. Methods In this case-control study, children with ARPKD referred to Amirkabir hospital in Arak city, Iran, were compared with noninfected children. Examinations, interviews, and questionnaires were performed to collect data and the disease was diagnosed by a physician. Results The results of this study showed no significant relationship between epidemiological factors such as age, place of residence for families, sex, family education/occupation/ income, body mass index, stunted growth, slow growth, good growth, milk intake, water intake, failure to thrive and ARPKD. Conclusions Based on our findings, epidemiological factors did not have a significant effect on the occurrence of ARPKD.

  6. 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

  7. 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.

  8. A quick method for testing recessive lethal damage with a diploid strain of Aspergillus nidulans

    International Nuclear Information System (INIS)

    Morpurgo, G.; Puppo, S.; Gualandi, G.; Conti, L.

    1978-01-01

    A simple method capable of detecting recessive lethal damage in a diploid strain of Aspergillus nidulans is described. The method scores the recessive lethals on the 1st, the 3rd and the 5th chromosomes, which represent about 40% of the total map of A. nidulans. Two examples of induced lethals, with ultraviolet irradiation and methyl methanesulfonate are shown. The frequency of lethals may reach 36% of the total population with UV irradiation. (Auth.)

  9. 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

  10. 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

  11. An autosomal recessive disorder with retardation of growth, mental deficiency, ptosis, pectus excavatum and camptodactyly

    International Nuclear Information System (INIS)

    Khaldi, F.; Bennaceur, B.; Hammou, A.; Hamza, M.; Gharbi, H.A.

    1988-01-01

    Two strikingly similar brothers issued from consanguineous parents in the second degree present the following patterns of anomalies: Retardation of growth, mental deficiency, ocular abnormalities, pectus excavatum and camptodactyly. The ocular abnormalities include ptosis, microphthalmia and hypertelorism. No endocrine or metabolic aberrations are found. The authors conclude that the disorder has probably an autosomal recessive mode of transmission. (orig.)

  12. 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

    Autosomal recessive renal tubular dysgenesis (RTD) is a severe disorder of renal tubular development characterized by early onset and persistent fetal anuria leading to oligohydramnios and the Potter sequence, associated with skull ossification defects. Early death occurs in most cases from anuri...

  13. Confirmation of ADAMTSL4 mutations for autosomal recessive isolated bilateral ectopia lentis.

    Science.gov (United States)

    Greene, V Bennouna; Stoetzel, C; Pelletier, V; Perdomo-Trujillo, Y; Liebermann, L; Marion, V; De Korvin, H; Boileau, C; Dufier, J L; Dollfus, H

    2010-03-01

    Ectopia lentis (EL) is a zonular disease where alteration of the zonular fibers leads progressively to lens dislocation. It is most often associated with systemic diseases such as Marfan syndrome, Weill-Marchesani syndrome or homocystinuria. Isolated non syndromic ectopia lentis (IEL) is reported in families with autosomal inheritance, with dominant forms being more common than recessive. LTBP2 truncating mutations have been described as a cause of autosomal recessive ectopia lentis as a primary or secondary feature in patients showing ocular (eg, glaucoma) or extraocular manifestations (eg, Marfanoid habitus). Recently, ADAMTSL4 has been shown to be responsible for isolated autosomal recessive ectopia lentis in an inbred family. Herein we show a consanguineous family that carries a novel homozygous splice mutation IVS4-1G>A/IVS4-1G>A in ADAMTSL4 responsible for isolated autosomal recessive EL, thus confirming the involvement of this gene in this condition and underlining the major role of ADAMTS proteases in zonular fibers homeostasis.

  14. Prenatal diagnosis of autosomal recessive Robinow syndrome using 3D ultrasound

    DEFF Research Database (Denmark)

    Jeppesen, Bolette F.; Buciek, Hanne Hove; Kreiborg, Sven

    2017-01-01

    This article hypothesizes that it is possible to detect and diagnose both the autosomal recessive and dominant forms prenatally using ultrasound. By focusing on the characteristic phenotypical presentation, the examinator is able to diagnose the syndrome prenatally, which is of clinical importance...

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

    NARCIS (Netherlands)

    Huet, R.A.C. van; Pierrache, L.H.; Meester-Smoor, M.A.; Klaver, C.C.; Born, L.I. van den; Hoyng, C.B.; Wijs, I.J. de; Collin, R.W.J.; Hoefsloot, L.H.; Klevering, B.J.

    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

  16. Biallelic Mutations in CRB1 Underlie Autosomal Recessive Familial Foveal Retinoschisis

    NARCIS (Netherlands)

    Vincent, A.; Ng, J.; Gerth-Kahlert, C.; Tavares, E.; Maynes, J.T.; Wright, T.; Tiwari, A.; Tumber, A.; Li, S.; Hanson, J.V.; Bahr, A.; MacDonald, H.; Bahr, L.; Westall, C.; Berger, W.; Cremers, F.P.M.; Hollander, A.I. den; Heon, E

    2016-01-01

    PURPOSE: To identify the genetic cause of autosomal recessive familial foveal retinoschisis (FFR). METHODS: A female sibship with FFR was identified (Family-A; 17 and 16 years, respectively); panel based genetic sequencing (132 genes) and comparative genome hybridization (142 genes) were performed.

  17. Mutations in AGBL5, Encoding alpha-Tubulin Deglutamylase, Are Associated With Autosomal Recessive Retinitis Pigmentosa

    NARCIS (Netherlands)

    Astuti, G.D.; Arno, G.; Hull, S.; Pierrache, L.; Venselaar, H.; Carss, K.; Raymond, F.L.; Collin, R.W.J.; Faradz, S.M.; Born, L.I. van den; Webster, A.R.; Cremers, F.P.

    2016-01-01

    Purpose: AGBL5, encoding ATP/GTP binding protein-like 5, was previously proposed as an autosomal recessive retinitis pigmentosa (arRP) candidate gene based on the identification of missense variants in two families. In this study, we performed next-generation sequencing to reveal additional RP cases

  18. CNGB3 mutations account for 50% of all cases with autosomal recessive achromatopsia.

    NARCIS (Netherlands)

    Kohl, S.; Varsanyi, B.; Antunes, G.A.; Baumann, B.; Hoyng, C.B.; Jagle, H.; Rosenberg, T.; Kellner, U.; Lorenz, B.; Salati, R.; Jurklies, B.; Farkas, A.; Andreasson, S.; Weleber, R.G.; Jacobson, S.G.; Rudolph, G.; Castellan, C.; Dollfus, H.; Legius, E.; Anastasi, M.; Bitoun, P.; Lev, D.; Sieving, P.A.; Munier, F.L.; Zrenner, E.; Sharpe, L.T.; Cremers, F.P.M.; Wissinger, B.

    2005-01-01

    Achromatopsia is a congenital, autosomal recessively inherited disorder characterized by a lack of color discrimination, low visual acuity (<0.2), photophobia, and nystagmus. Mutations in the genes for CNGA3, CNGB3, and GNAT2 have been associated with this disorder. Here, we analyzed the spectrum

  19. A Nonsense Mutation in PDE6H Causes Autosomal-Recessive Incomplete Achromatopsia.

    NARCIS (Netherlands)

    Kohl, S.; Coppieters, F.; Meire, F.; Schaich, S.; Roosing, S.; Brennenstuhl, C.; Bolz, S.; Genderen, M.M. van; Riemslag, F.C.; Lukowski, R.; Hollander, A.I. den; Cremers, F.P.M.; Baere, E. de; Hoyng, C.B.; Wissinger, B.

    2012-01-01

    Achromatopsia (ACHM) is an autosomal-recessive retinal dystrophy characterized by color blindness, photophobia, nystagmus, and severely reduced visual acuity. Its prevalence has been estimated to about 1 in 30,000 individuals. Four genes, GNAT2, PDE6C, CNGA3, and CNGB3, have been implicated in ACHM,

  20. 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

  1. Autosomal recessive transmission of MYBPC3 mutation results in malignant phenotype of hypertrophic cardiomyopathy.

    Directory of Open Access Journals (Sweden)

    Yilu Wang

    Full Text Available BACKGROUND: Hypertrophic cardiomyopathy (HCM due to mutations in genes encoding sarcomere proteins is most commonly inherited as an autosomal dominant trait. Since nearly 50% of HCM cases occur in the absence of a family history, a recessive inheritance pattern may be involved. METHODS: A pedigree was identified with suspected autosomal recessive transmission of HCM. Twenty-six HCM-related genes were comprehensively screened for mutations in the proband with targeted second generation sequencing, and the identified mutation was confirmed with bi-directional Sanger sequencing in all family members and 376 healthy controls. RESULTS: A novel missense mutation (c.1469G>T, p.Gly490Val in exon 17 of MYBPC3 was identified. Two siblings with HCM were homozygous for this mutation, whereas other family members were either heterozygous or wild type. Clinical evaluation showed that both homozygotes manifested a typical HCM presentation, but none of others, including 5 adult heterozygous mutation carriers up to 71 years of age, had any clinical evidence of HCM. CONCLUSIONS: Our data identified a MYBPC3 mutation in HCM, which appeared autosomal recessively inherited in this family. The absence of a family history of clinical HCM may be due to not only a de novo mutation, but also recessive mutations that failed to produce a clinical phenotype in heterozygous family members. Therefore, consideration of recessive mutations leading to HCM is essential for risk stratification and genetic counseling.

  2. 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...

  3. 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.

  4. 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

  5. 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

  6. 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.

  7. 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.

  8. 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.

  9. One-step noninvasive prenatal testing (NIPT) for autosomal recessive homozygous point mutations using digital PCR.

    Science.gov (United States)

    Chang, Mun Young; Ahn, Soyeon; Kim, Min Young; Han, Jin Hee; Park, Hye-Rim; Seo, Han Kyu; Yoon, Jinsun; Lee, Seungmin; Oh, Doo-Yi; Kang, Changsoo; Choi, Byung Yoon

    2018-02-13

    Previously, we introduced a noninvasive prenatal testing (NIPT) protocol for diagnosing compound heterozygous autosomal recessive point mutations via maternal plasma DNA and simulated control genomic DNA sampling based on fetal DNA fraction. In our present study, we have improved our NIPT protocol to make it possible to diagnose homozygous autosomal recessive point mutations without the need to acquire fetal DNA fraction. Moreover, chi-squared test and empirical statistical range based on the proportion of mutant allele reads among the total reads served as the gatekeeping method. If this method yielded inconclusive results, then the Bayesian method was performed; final conclusion was drawn from the results of both methods. This protocol was applied to three families co-segregating congenital sensorineural hearing loss with monogenic homozygous mutations in prevalent deafness genes. This protocol successfully predicted the fetal genotypes from all families without the information about fetal DNA fraction using one-step dPCR reactions at least for these three families. Furthermore, we suspect that confirmatory diagnosis under this protocol is possible, not only by using picodroplet dPCR, but also by using the more readily available chip-based dPCR, making our NIPT protocol more useful in the diagnosis of autosomal recessive point mutations in the future.

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

    Directory of Open Access Journals (Sweden)

    K J Kelly

    Full Text Available 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.

  11. A novel autosomal recessive GJA1 missense mutation linked to Craniometaphyseal dysplasia.

    Directory of Open Access Journals (Sweden)

    Ying Hu

    Full Text Available Craniometaphyseal dysplasia (CMD is a rare sclerosing skeletal disorder with progressive hyperostosis of craniofacial bones. CMD can be inherited in an autosomal dominant (AD trait or occur after de novo mutations in the pyrophosphate transporter ANKH. Although the autosomal recessive (AR form of CMD had been mapped to 6q21-22 the mutation has been elusive. In this study, we performed whole-exome sequencing for one subject with AR CMD and identified a novel missense mutation (c.716G>A, p.Arg239Gln in the C-terminus of the gap junction protein alpha-1 (GJA1 coding for connexin 43 (Cx43. We confirmed this mutation in 6 individuals from 3 additional families. The homozygous mutation cosegregated only with affected family members. Connexin 43 is a major component of gap junctions in osteoblasts, osteocytes, osteoclasts and chondrocytes. Gap junctions are responsible for the diffusion of low molecular weight molecules between cells. Mutations in Cx43 cause several dominant and recessive disorders involving developmental abnormalities of bone such as dominant and recessive oculodentodigital dysplasia (ODDD; MIM #164200, 257850 and isolated syndactyly type III (MIM #186100, the characteristic digital anomaly in ODDD. However, characteristic ocular and dental features of ODDD as well as syndactyly are absent in patients with the recessive Arg239Gln Cx43 mutation. Bone remodeling mechanisms disrupted by this novel Cx43 mutation remain to be elucidated.

  12. 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.

  13. UV-induced recessive lethals in uvs strains of Neurospora which are deficient in UV mutagenesis

    International Nuclear Information System (INIS)

    Kaefer, E.

    1984-01-01

    The frequencies of spontaneous and UV-induced recessive lethal mutations were compared for UV-sensitive and wild-type heterokaryons of Neurospora crassa. These heterokaryons were homokaryotic either for one of two alleles of uvs-3, or for uvs-6 or uvs + . For uvs-3, which is known to have mutator effects, spontaneous recessive lethals were found to be 4-6 times more frequent than observed in uvs + . After correction for clonal distribution of spontaneous mutants, an observed 2-fold increase for uvs-6 was not statistically significant and may have been due to chance occurrence of a few large clones of mutants. Treatment with low doses of UV (50-200 J/m 2 ) produced very similar overall rates of increase for recessive lethals in uvs and uvs + heterokaryons. This means, that in contrast to results obtained when mutation to ad-3 was measured, both uvs-3 alleles showed highly significant increases for recessive lethals when treated with UV. It is proposed that certain types of UV damage may be processed into recessive lethal mutations by an alternate mechanism from that responsible for viable mutations. (Auth.)

  14. 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.

  15. 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.

  16. 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...

  17. 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.

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

    Science.gov (United States)

    Casal, Margret L; Wang, Ping; Mauldin, Elizabeth A; Lin, Gloria; Henthorn, Paula S

    2017-01-01

    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.

  19. 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.

  20. More Than Ataxia: Hyperkinetic Movement Disorders in Childhood Autosomal Recessive Ataxia Syndromes

    Science.gov (United States)

    Pearson, Toni S.

    2016-01-01

    Background The autosomal recessive ataxias are a heterogeneous group of disorders that are characterized by complex neurological features in addition to progressive ataxia. Hyperkinetic movement disorders occur in a significant proportion of patients, and may sometimes be the presenting motor symptom. Presentations with involuntary movements rather than ataxia are diagnostically challenging, and are likely under-recognized. Methods A PubMed literature search was performed in October 2015 utilizing pairwise combinations of disease-related terms (autosomal recessive ataxia, ataxia–telangiectasia, ataxia with oculomotor apraxia type 1 (AOA1), ataxia with oculomotor apraxia type 2 (AOA2), Friedreich ataxia, ataxia with vitamin E deficiency), and symptom-related terms (movement disorder, dystonia, chorea, choreoathetosis, myoclonus). Results Involuntary movements occur in the majority of patients with ataxia–telangiectasia and AOA1, and less frequently in patients with AOA2, Friedreich ataxia, and ataxia with vitamin E deficiency. Clinical presentations with an isolated hyperkinetic movement disorder in the absence of ataxia include dystonia or dystonia with myoclonus with predominant upper limb and cervical involvement (ataxia–telangiectasia, ataxia with vitamin E deficiency), and generalized chorea (ataxia with oculomotor apraxia type 1, ataxia-telangiectasia). Discussion An awareness of atypical presentations facilitates early and accurate diagnosis in these challenging cases. Recognition of involuntary movements is important not only for diagnosis, but also because of the potential for effective targeted symptomatic treatment. PMID:27536460

  1. Identification of C12orf4 as a gene for autosomal recessive intellectual disability.

    Science.gov (United States)

    Philips, A K; Pinelli, M; de Bie, C I; Mustonen, A; Määttä, T; Arts, H H; Wu, K; Roepman, R; Moilanen, J S; Raza, S; Varilo, T; Scala, G; Cocozza, S; Gilissen, C; van Gassen, K L I; Järvelä, I

    2017-01-01

    Intellectual disability (ID) is a major health problem in our society. Genetic causes of ID remain unknown because of its vast heterogeneity. Here we report two Finnish families and one Dutch family with affected individuals presenting with mild to moderate ID, neuropsychiatric symptoms and delayed speech development. By utilizing whole exome sequencing (WES), we identified a founder missense variant c.983T>C (p.Leu328Pro) in seven affected individuals from two Finnish consanguineous families and a deletion c.799_1034-429delinsTTATGA (p.Gln267fs) in one affected individual from a consanguineous Dutch family in the C12orf4 gene on chromosome 12. Both the variants co-segregated in the respective families as an autosomal recessive trait. Screening of the p.Leu328Pro variant showed enrichment in the North Eastern sub-isolate of Finland among anonymous local blood donors with a carrier frequency of 1:53, similar to other disease mutations with a founder effect in that region. To date, only one Arab family with a three affected individuals with a frameshift insertion variant in C12orf4 has been reported. In summary, we expand and establish the clinical and mutational spectrum of C12orf4 variants. Our findings implicate C12orf4 as a causative gene for autosomal recessive ID. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. When a Fly Has to Fly to Reproduce: Selection against Conditional Recessive Lethals in "Drosophila"

    Science.gov (United States)

    Plunkett, Andrea D.; Yampolsky, Lev Y.

    2010-01-01

    We propose an experimental model suitable for demonstrating allele frequency change in Drosophila melanogaster populations caused by selection against an easily scorable conditional lethal, namely recessive flightless alleles such as apterous and vestigial. Homozygotes for these alleles are excluded from reproduction because the food source used…

  3. 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; Klevering, B Jeroen

    2015-01-01

    To determine the efficacy of multiple versions of a commercially available arrayed primer extension (APEX) microarray chip for autosomal recessive retinitis pigmentosa (arRP). 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. 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). 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.

  4. [Autosomal recessive polycystic kidney disease and complex nephronophtisis medullary cystic disease].

    Science.gov (United States)

    2008-12-01

    Reseach during the past decade has led to the discovery that defects in some proteins that localize to primary cilia or the basal body are the main contributors to renal cyst development. Autosomal recessive polycystic disease and nephronophthisis- medullary cystic kidney disease are named ciliopathies. The cilium is a microtubule-based organelle that is found on most mammalian cells. Cilia-mediated hypothesis has evolved into the concept of cystogenesis, cilia bend by fluid initiate a calcium influx that prevents cyst formation. Cilia might sense stimuli in the cell enviroment and control cell polarity and mitosis. A new set of pathogenic mechanisms in renal cystic disease defined new therapeutic targets, control of intracellular calcium, inhibition of cAMP and down regulation cannonical Wnt signaling.

  5. SBF1 mutations associated with autosomal recessive axonal neuropathy with cranial nerve involvement.

    Science.gov (United States)

    Manole, Andreea; Horga, Alejandro; Gamez, Josep; Raguer, Nuria; Salvado, Maria; San Millán, Beatriz; Navarro, Carmen; Pittmann, Alan; Reilly, Mary M; Houlden, Henry

    2017-01-01

    Biallelic mutations in the SBF1 gene have been identified in one family with demyelinating Charcot-Marie-Tooth disease (CMT4B3) and two families with axonal neuropathy and additional neurological and skeletal features. Here we describe novel sequence variants in SBF1 (c.1168C>G and c.2209_2210del) as the potential causative mutations in two siblings with severe axonal neuropathy, hearing loss, facial weakness and bulbar features. Pathogenicity of these variants is supported by co-segregation and in silico analyses and evolutionary conservation. Our findings suggest that SBF1 mutations may cause a syndromic form of autosomal recessive axonal neuropathy (AR-CMT2) in addition to CMT4B3.

  6. 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

    a large consanguineous family were described as ARCI due to a homozygous mutation in LIPN.(7) However, the first symptoms appeared only from the age of 5 years and the criterion of a congenital form of ichthyosis is not fulfilled. In this study we report the clinical and molecular findings of seven ARCI......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...... patients who carried five previously unreported mutations in SDR9C7. This article is protected by copyright. All rights reserved....

  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. Autosomal recessive chronic granulomatous disease presenting with cutaneous dermatoses and ocular infection.

    Science.gov (United States)

    Low, L C M; Manson, A L; Hardman, C; Carton, J; Seneviratne, S L; Ninis, N

    2013-04-01

    Dermatoses such as eczematous dermatitis and cutaneous infection are recognized presentations of primary immunodeficiency (PID). However, atopic dermatitis affects approximately 10% of infants, and cutaneous infections are not uncommon in children, therefore the challenge for the dermatologist is to distinguish the few patients that have PID from the many that do not. We report on a 6-year-old girl who was ultimately diagnosed with autosomal recessive chronic granulomatous disease (AR-CGD) after presenting to various hospitals with dermatitis, scalp plaques recalcitrant to treatment, and recurrent infections over a 3-year period, and describe some aspects of her diagnosis and management. This report highlights the importance of considering rare disorders such as AR-CGD in the differential diagnosis of recurrent or recalcitrant dermatological infections in children. © The Author(s). CED © 2012 British Association of Dermatologists.

  9. Diagnosis and Management of Hepatobiliary Complications in Autosomal Recessive Polycystic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Andrew Wehrman

    2017-05-01

    Full Text Available Autosomal recessive polycystic kidney disease (ARPKD is a congenital hepatorenal fibrocystic disease. The hepatic manifestations of ARPKD can range from asymptomatic to portal hypertension and massively dilated biliary system that results in liver transplantation. Hepatic complications of ARPKD typically present with signs of portal hypertension (splenomegaly and thrombocytopenia or cholangitis. Liver disease in ARPKD does not always correlate with severity of renal disease. Management of ARPKD-related liver disease is largely treating specific symptoms, such as antibiotics for cholangitis or endoscopic treatment for variceal bleeding. If complications cannot be managed medically, liver transplantation may be indicated. This mini-review will discuss the clinical manifestations and management of children with ARPKD liver disease.

  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. 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

  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

    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 men...

  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)

    Yzer, S.; 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. Mutations in MFSD8, encoding a lysosomal membrane protein, are associated with nonsyndromic autosomal recessive macular dystrophy

    NARCIS (Netherlands)

    Roosing, S.; Born, L.I. van den; Sangermano, R.; Banfi, S.; Koenekoop, R.K.; Zonneveld-Vrieling, M.N.; Klaver, C.C.; Lith-Verhoeven, J.J. van; Cremers, F.P.M.; Hollander, A.I. den; Hoyng, C.B.

    2015-01-01

    PURPOSE: This study aimed to identify the genetic defects in 2 families with autosomal recessive macular dystrophy with central cone involvement. DESIGN: Case series. PARTICIPANTS: Two families and a cohort of 244 individuals with various inherited maculopathies and cone disorders. METHODS:

  16. 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

    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...

  17. 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...

  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. 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

  20. The population genetics of human disease: The case of recessive, lethal mutations

    Science.gov (United States)

    Gao, Ziyue; Baker, Zachary; Diesel, José Francisco; Simons, Yuval B.; Haque, Imran S.; Pickrell, Joseph; Przeworski, Molly

    2017-01-01

    Do the frequencies of disease mutations in human populations reflect a simple balance between mutation and purifying selection? What other factors shape the prevalence of disease mutations? To begin to answer these questions, we focused on one of the simplest cases: recessive mutations that alone cause lethal diseases or complete sterility. To this end, we generated a hand-curated set of 417 Mendelian mutations in 32 genes reported to cause a recessive, lethal Mendelian disease. We then considered analytic models of mutation-selection balance in infinite and finite populations of constant sizes and simulations of purifying selection in a more realistic demographic setting, and tested how well these models fit allele frequencies estimated from 33,370 individuals of European ancestry. In doing so, we distinguished between CpG transitions, which occur at a substantially elevated rate, and three other mutation types. Intriguingly, the observed frequency for CpG transitions is slightly higher than expectation but close, whereas the frequencies observed for the three other mutation types are an order of magnitude higher than expected, with a bigger deviation from expectation seen for less mutable types. This discrepancy is even larger when subtle fitness effects in heterozygotes or lethal compound heterozygotes are taken into account. In principle, higher than expected frequencies of disease mutations could be due to widespread errors in reporting causal variants, compensation by other mutations, or balancing selection. It is unclear why these factors would have a greater impact on disease mutations that occur at lower rates, however. We argue instead that the unexpectedly high frequency of disease mutations and the relationship to the mutation rate likely reflect an ascertainment bias: of all the mutations that cause recessive lethal diseases, those that by chance have reached higher frequencies are more likely to have been identified and thus to have been included in

  1. The population genetics of human disease: The case of recessive, lethal mutations.

    Science.gov (United States)

    Amorim, Carlos Eduardo G; Gao, Ziyue; Baker, Zachary; Diesel, José Francisco; Simons, Yuval B; Haque, Imran S; Pickrell, Joseph; Przeworski, Molly

    2017-09-01

    Do the frequencies of disease mutations in human populations reflect a simple balance between mutation and purifying selection? What other factors shape the prevalence of disease mutations? To begin to answer these questions, we focused on one of the simplest cases: recessive mutations that alone cause lethal diseases or complete sterility. To this end, we generated a hand-curated set of 417 Mendelian mutations in 32 genes reported to cause a recessive, lethal Mendelian disease. We then considered analytic models of mutation-selection balance in infinite and finite populations of constant sizes and simulations of purifying selection in a more realistic demographic setting, and tested how well these models fit allele frequencies estimated from 33,370 individuals of European ancestry. In doing so, we distinguished between CpG transitions, which occur at a substantially elevated rate, and three other mutation types. Intriguingly, the observed frequency for CpG transitions is slightly higher than expectation but close, whereas the frequencies observed for the three other mutation types are an order of magnitude higher than expected, with a bigger deviation from expectation seen for less mutable types. This discrepancy is even larger when subtle fitness effects in heterozygotes or lethal compound heterozygotes are taken into account. In principle, higher than expected frequencies of disease mutations could be due to widespread errors in reporting causal variants, compensation by other mutations, or balancing selection. It is unclear why these factors would have a greater impact on disease mutations that occur at lower rates, however. We argue instead that the unexpectedly high frequency of disease mutations and the relationship to the mutation rate likely reflect an ascertainment bias: of all the mutations that cause recessive lethal diseases, those that by chance have reached higher frequencies are more likely to have been identified and thus to have been included in

  2. Appearance of autosomal recessive polycystic kidney disease in magnetic resonance imaging and RARE-MR-urography

    International Nuclear Information System (INIS)

    Kern, S.; Uhl, M.; Zimmerhackl, L.B.; Hildebrandt, F.; Ermisch-Omran, B.

    2000-01-01

    Purpose. To describe the appearance of autosomal recessive polycystic kidney disease (ARPKD) on MRI and RARE-MR urography.Materials and methods. Seven boys and one girl (aged 3 months to 14 years, median 2.5 years) were evaluated. Images were obtained with 0.23-T and 1.5-T MR systems using T1-weighted (T1-W) spin-echo, T2-weighted (T2-W) turbo-spin-echo and RARE-MR-urography sequences. Signal intensities, morphological appearance of the affected kidneys and, specifically, the picture of the urinary tract on RARE-MR-urography were evaluated.Results. All children showed kidney enlargement, reniform but humpy kidney shape, homogeneously grainy renal parenchyma, normal renal pelvis and normal calyces. Signal intensity was hyperintense in T2-W images in all cases. In six cases (n = 7), T1-W images were hypointense. On RARE-MR urography a hyperintense, linear radial pattern was seen in the cortex and medulla which represents the characteristic microcystic dilatation of collecting ducts in ARPKD. Three boys and the girl presented with a few circumscribed small subcapsular cysts.Conclusions. In order to confirm the diagnosis of ARPKD, RARE-MR urography seems to be a non-invasive imaging tool that shows directly the microcystic dilated water-filled collecting ducts. (orig.)

  3. 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.

  4. Autosomal recessive mental retardation syndrome with anterior maxillary protrusion and strabismus: MRAMS syndrome.

    Science.gov (United States)

    Basel-Vanagaite, Lina; Rainshtein, Limor; Inbar, Dov; Gothelf, Doron; Hennekam, Raoul; Straussberg, Rachel

    2007-08-01

    We report on a family in whom the combination of mental retardation (MR), anterior maxillary protrusion, and strabismus segregates. The healthy, consanguineous parents (first cousins) of Israeli-Arab descent had 11 children, 7 of whom (5 girls) were affected. They all had severe MR. Six of the seven had anterior maxillary protrusion with vertical maxillary excess, open bite, and prominent crowded teeth. None of the sibs with normal intelligence had jaw or dental anomalies. The child with MR but without a jaw anomaly was somewhat less severely retarded, had seizures and severe psychosis, which may point to his having a separate disorder. Biochemical and neurological studies, including brain MRI and standard cytogenetic studies, yielded normal results; fragile X was excluded, no subtelomeric rearrangements were detectable, and X-inactivation studies in the mother showed random inactivation. We have been unable to find a similar disorder in the literature, and suggest that this is a hitherto unreported autosomal recessive disorder, which we propose to name MRAMS (mental retardation, anterior maxillary protrusion, and strabismus). (c) 2007 Wiley-Liss, Inc.

  5. COL9A2 and COL9A3 mutations in canine autosomal recessive oculoskeletal dysplasia.

    Science.gov (United States)

    Goldstein, Orly; Guyon, Richard; Kukekova, Anna; Kuznetsova, Tatyana N; Pearce-Kelling, Susan E; Johnson, Jennifer; Aguirre, Gustavo D; Acland, Gregory M

    2010-08-01

    Oculoskeletal dysplasia segregates as an autosomal recessive trait in the Labrador retriever and Samoyed canine breeds, in which the causative loci have been termed drd1 and drd2, respectively. Affected dogs exhibit short-limbed dwarfism and severe ocular defects. The disease phenotype resembles human hereditary arthro-ophthalmopathies such as Stickler and Marshall syndromes, although these disorders are usually dominant. Linkage studies mapped drd1 to canine chromosome 24 and drd2 to canine chromosome 15. Positional candidate gene analysis then led to the identification of a 1-base insertional mutation in exon 1 of COL9A3 that cosegregates with drd1 and a 1,267-bp deletion mutation in the 5' end of COL9A2 that cosegregates with drd2. Both mutations affect the COL3 domain of the respective gene. Northern analysis showed that RNA expression of the respective genes was reduced in affected retinas. These models offer potential for studies such as protein-protein interactions between different members of the collagen gene family, regulation and expression of these genes in retina and cartilage, and even opportunities for gene therapy.

  6. RARE-MR-urography - a new diagnostic method in autosomal recessive polycystic kidney disease

    Energy Technology Data Exchange (ETDEWEB)

    Kern, S.; Uhl, M. [University Hospital Freiburg (Germany). Div. of Pediatric Radiology; Zimmerhackl, L.B.; Hildebrandt, F. [University Hospital Freiburg (Germany). Div. of Pediatric Nephrology

    1999-09-01

    Purpose: To describe the appearance of autosomal recessive polycystic kidney disease (ARPKD) by using a new diagnostic method: RARE-MR-urography. Material and Methods: Eight children were evaluated using MR images from 0.23 T and 1.5 T MR units, using T1-weighted spin-echo and T2-weighted turbo spin-echo sequences and RARE-MR-urography. Signal intensities, morphological appearance of the affected kidneys and, specifically, the picture of the urinary tract in RARE-MR-urography, were evaluated. Results: All children showed enlargement, reniform but humpy kidney shape, homogeneous-grainy renal parenchyma, normal renal pelvis and calyces. Although ARPKD is always associated with some degree of congenital hepatic fibrosis, there was no bile duct dilatation or liver fibrosis at the time of examination. Signal intensity was hyperintense in T2-weighted images in all cases. In 5 cases, T1-weighted images were hypointense. In RARE-MR-urography, hyperintense, linear, radial patterns in cortex and medulla were seen, which represent microcystic dilatation of collecting ducts and are therefore characteristic of ARPKD. Four patients presented with a few circumscribed small subcapsular cysts. Conclusion: RARE-MR-urography is a noninvasive method which demonstrates the pathognomonic water-filled cystic structures throughout the kidneys in ARPKD. (orig.)

  7. The ADAMTS18 gene is responsible for autosomal recessive early onset severe retinal dystrophy

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    Peluso Ivana

    2013-01-01

    Full Text Available Abstract Background Inherited retinal dystrophies, including Retinitis Pigmentosa and Leber Congenital Amaurosis among others, are a group of genetically heterogeneous disorders that lead to variable degrees of visual deficits. They can be caused by mutations in over 100 genes and there is evidence for the presence of as yet unidentified genes in a significant proportion of patients. We aimed at identifying a novel gene for an autosomal recessive form of early onset severe retinal dystrophy in a patient carrying no previously described mutations in known genes. Methods An integrated strategy including homozygosity mapping and whole exome sequencing was used to identify the responsible mutation. Functional tests were performed in the medaka fish (Oryzias latipes model organism to gain further insight into the pathogenic role of the ADAMTS18 gene in eye and central nervous system (CNS dysfunction. Results This study identified, in the analyzed patient, a homozygous missense mutation in the ADAMTS18 gene, which was recently linked to Knobloch syndrome, a rare developmental disorder that affects the eye and the occipital skull. In vivo gene knockdown performed in medaka fish confirmed both that the mutation has a pathogenic role and that the inactivation of this gene has a deleterious effect on photoreceptor cell function. Conclusion This study reveals that mutations in the ADAMTS18 gene can cause a broad phenotypic spectrum of eye disorders and contribute to shed further light on the complexity of retinal diseases.

  8. Risk Factors for Neurocognitive Functioning in Children with Autosomal Recessive Polycystic Kidney Disease

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    Stephen R. Hooper

    2017-05-01

    Full Text Available This mini review provides an overview of the issues and challenges inherent in autosomal recessive polycystic kidney disease (ARPKD, with a particular focus on the neurological factors and neurocognitive functioning of this population. ARPKD typically is discovered at the end of pregnancy or during the neonatal developmental period and occurs in approximately 1 in 20,000 live births. During the neonatal period, there is a relatively high risk of death, with many infants dying from respiratory failure. As the child ages, they experience progressive kidney disease and become increasingly vulnerable to liver disease, with many individuals eventually requiring dual organ transplants. This mini review provides a brief description of ARPKD and describes the various factors that place children with ARPKD at risk for neurological and neuropsychological impairment (e.g., a genetic condition leading to chronic kidney disease and eventual transplant; difficult-to-treat hypertension; eventual liver disease; possible dual transplantation of the kidneys and liver; chronic lung disease, including that these factors are present during a critical period of brain development. Further, the mini review discusses the available studies that have addressed the neurocognitive functioning in children with ARPKD. This paper concludes by providing the key clinical and research challenges that face the field of pediatric nephrology with respect to the clinical and scientific study of the neurocognitive functioning of children with ARPKD. Selected directions are offered in both the clinical and research arenas for this multiorgan chronic condition.

  9. CONSANGUINITY AND HOMOZYGOSITY AMONG TUNISIAN PATIENTS WITH AN AUTOSOMAL RECESSIVE DISORDER.

    Science.gov (United States)

    Kelmemi, Wided; Chelly, Imene; Kharrat, Maher; Chaabouni-Bouhamed, Habiba

    2015-11-01

    Consanguineous unions are a deeply rooted social practice among traditional societies. Despite their presumed social advantages, they can result in several health conditions. The aim of this study was: i) to compare consanguinity levels between Tunisian patients affected with autosomal recessive disorders (ARDs) and those with a chromosomal abnormality; and ii) to gain more insight into the mutational status of patients affected with ARDs. Data were collected from 290 files of patients affected by one of five ARDs confirmed by molecular analysis and 248 files of patients with confirmed Down syndrome. Information on the disease, mutation defining the disease, parents' relatedness and geographical origin was gathered. Consanguinity was found among 58% of the ARD patients and among 22% of Down syndrome patients, and a homozygous status was found in 90% of the patients born to related parents and in 70% of patients born to unrelated parents. Also, children from unrelated parents from the same geographical background were found to be more frequently affected by homozygous mutations than those from unrelated parents from different geographical backgrounds. The present study shows how marriage practices affect patterns of genetic variations and how they can lead to homogenization in the genetic pool.

  10. Missense mutations in the adhalin gene linked to autosomal recessive muscular dystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Roberds, S.L.; Anderson, R.D.; Lim, L.E. [Univ. of Iowa, Iowa City, IA (United States)] [and others

    1994-09-01

    Adhalin, the 50-kDa dystrophin-associated glycoprotein, is deficient in skeletal muscle of patients having severe childhood autosomal recessive muscular dystrophy (SCARMD). In several North African families, SCARMD has been linked to markers in the pericentromeric region of chromosome l3q, but SCARMD has been excluded from linkage to this locus in other families. To determine whether the adhalin gene might be involved in SCARMD, human adhalin cDNA and large portions of the adhalin gene were cloned. Adhalin is a transmembrane glycoprotein with an extracellular domain bearing limited homology to domains of entactin and nerve growth factor receptor, suggesting that adhalin may serve as a receptor for an extracellular matrix protein. The adhalin gene was mapped to chromosome 17q12-q21.33, excluding the gene from involvement in 13q-linked SCARMD. A polymorphic microsatellite was identified within intron 6 of the adhalin gene, and one allelic variant of this marker cosegregated with the disease phenotype in a large French family with a lod score of 3.61 at 0 recombination. Adhalin is undetectable in skeletal muscle from affected members of this family. Missense mutations were identified within the adhalin gene that might cause SCARMD in this family. Thus, genetic defects in at least two components, dystrophin and adhalin, of the dystrophin-glycoprotein complex can independently cause muscular dystrophies.

  11. WWOX and severe autosomal recessive epileptic encephalopathy: first case in the prenatal period.

    Science.gov (United States)

    Valduga, Mylène; Philippe, Christophe; Lambert, Laetitia; Bach-Segura, Pascale; Schmitt, Emmanuelle; Masutti, Jean Pierre; François, Bénédicte; Pinaud, Patrick; Vibert, Mireille; Jonveaux, Philippe

    2015-05-01

    WWOX has been recently implicated in autosomal recessive spinocerebellar ataxia type 12 (SCAR12) and severe early-onset epileptic encephalopathy (EOEE). By array comparative genomic hybridization, we identified a 0.6 Mb homozygous deletion in 16q23.1 in a fetus presenting with brain anomalies. His older sister who died at the age of 22 months from an EOEE was also homozygous for the copy number variations in 16q23.1. This deletion includes the first six exons of WWOX and results in a null genotype in homozygous patients. This family gives additional support for the implication of WWOX in severe EOEEs. We report for the first time prenatal ultrasound findings in a fetus with a WWOX-null genotype. Our study expands the range of brain abnormalities in WWOX-related EOEEs. This additional family confirms the genotype-phenotype correlation with WWOX-null alleles associated with the most severe form of WWOX-related epileptic encephalopathy with premature death.

  12. X-ray-induced recessive lethal mutations in adult and foetal female mice

    International Nuclear Information System (INIS)

    Luening, K.G.; Eiche, A.

    1982-01-01

    Tests of X-ray-induced recessive lethal mutations in adult and foetal mouse females were performed. The tests were based on family analysis which provided a possibility of making a distinction between pre-existing recessive lethal mutations and newly arisen (spontaneous + induced) ones. The way the tests were carried out provided material for the estimation of the frequency of spontaneous lethal mutations per genome. The two different estimates from this material, 0.72 and 0.91%, respectively, are similar and fall within the range previously suggested by Luening. The difference, though statistically non-significant, between data from irradiated mature and maturing oocytes in adult females and material from the unirradiated part, indicates a mutation rate of 13 x 10 -5 per rad per gamete according to one estimate and 8-12 x 10 -5 according to the other in comparison with 9 x 10 -5 from irradiated spermatogonia. In the limited data obtained after foetal irradiation, there is no indication of oogonia and developing oocytes being more sensitive to irradiation than oocytes in adult females fertilized within 6 weeks of treatment. (orig.)

  13. 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.

  14. Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS: typical clinical and neuroimaging features in a Brazilian family

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    J L Pedroso

    2011-01-01

    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. ARSACS has a high prevalence in northeastern Quebec, Canada. Several ARSACS cases have been reported outside Canada in recent decades. This is the first report of typical clinical and neuroimaging features in a Brazilian family with probable diagnosis of ARSACS.

  15. A novel deletion mutation in the TUSC3 gene in a consanguineous Pakistani family with autosomal recessive nonsyndromic intellectual disability

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    Ali Nadir

    2011-04-01

    Full Text Available Abstract Background Intellectual disability (ID is a serious disorder of the central nervous system with a prevalence of 1-3% in a general population. In the past decades, the research focus has been predominantly on X-linked ID (68 loci and 19 genes for non syndromic X linked ID while for autosomal recessive nonsyndromic ID (NSID only 30 loci and 6 genes have been reported to date. Methods Genome-wide homozygosity mapping with 500 K Nsp1 array (Affymetrix, CNV analysis, PCR based breakpoint mapping and DNA sequencing was performed to explore the genetic basis of autosomal recessive nonsyndromic ID in a large Pakistani family. Results Data analysis showed linkage at 8p23 locus with common homozygous region between SNPs rs6989820 and rs2237834, spanning a region of 12.494 Mb. The subsequent CNV analysis of the data revealed a homozygous deletion of 170.673 Kb which encompassed the TUSC3 gene. Conclusion We report a novel deletion mutation in TUSC3 gene which is the second gene after TRAPPC9 in which mutation has been identified in more than one family with autosomal recessive NSID. The study will aid in exploring the molecular pathway of cognition.

  16. Autosomal recessive MFN2-related Charcot-Marie-Tooth disease with diaphragmatic weakness: Case report and literature review.

    Science.gov (United States)

    Tan, Christopher A; Rabideau, Marina; Blevins, Amy; Westbrook, Marjorie Jody; Ekstein, Tali; Nykamp, Keith; Deucher, Anne; Harper, Amy; Demmer, Laurie

    2016-06-01

    Pathogenic variants in the mitofusin 2 gene (MFN2) are the most common cause of autosomal dominant Charcot-Marie-Tooth (CMT2) disease, which is typically characterized by axonal sensorimotor neuropathy. We report on a 7-month-old white female with hypotonia, motor delay, distal weakness, and motor/sensory axonal neuropathy in which next-generation sequencing analysis identified compound heterozygous pathogenic variants (c.2054_2069_1170del and c.392A>G) in MFN2. A review of the literature reveals that sporadic and familial cases of compound heterozygous or homozygous pathogenic MFN2 variants have been infrequently described, which indicates that MFN2 can also be inherited in a recessive manner. This case highlights several clinical findings not typically associated with MFN2 pathogenic variants, including young age of onset and rapidly progressing diaphragmatic paresis that necessitated tracheostomy and mechanical ventilation, and adds to the growing list of features identified in autosomal recessive MFN2-related CMT2. Our patient with MFN2-related CMT2 expands the clinical and mutational spectrum of individuals with autosomal recessive CMT2 and identifies a new clinical feature that warrants further observation. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  17. Comparative study of different sexis mutability: recessive sex-linked and dominant lethals in Drosophila melanogaster

    International Nuclear Information System (INIS)

    Vatti, K.V.; Dzhaparidze, L.A.; Mamon, L.A.

    1980-01-01

    The frequency of recessive sex-linked lethal mutations (RSLLM) and those realizing in embryogenesis of dominant lethals, which form in oo- and spermatogenesis of Drosophila and fly productivity under the effect of X-rays and N-nitroso-N methylourea (NMU), is studied. In the case of effect of both mutagens RSLLM form in spermatocytes with higher frequency as compared with oocytes. Dominant lethal mutations (DLM) during irradiation are also often registered in spermatocytes. NMU induces DLM in mitotic male cells with a very high frequency but is not effective during the effect on oocytes. When both mutagens affect males and X-rays affect females, the decrease of productivity is mainly conditioned by DLM. As NMU does not induce DLM in females realizing in embryogenesis but reduces productivity, a later lethal realization connected with their different nature is supposed. Differences in mole and female mutability found in the course of X-ray and NMU effect are discussed in connection with peculiarities of their mitotic cells and the nature of effect of mutagens applied [ru

  18. 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.

  19. Targeted next-generation sequencing of a 12.5 Mb homozygous region reveals ANO10 mutations in patients with autosomal-recessive cerebellar ataxia.

    NARCIS (Netherlands)

    Vermeer, S.; Hoischen, A.; Meijer, R.P.; Gilissen, C.F.H.A.; Neveling, K.; Wieskamp, N.A.W.; Brouwer, A.; Koenig, M.; Anheim, M.; Assoum, M.; Drouot, N.; Todorovic, S.; Milic-Rasic, V.; Lochmuller, H.; Stevanin, G.; Goizet, C.; David, A.; Durr, A.; Brice, A.; Kremer, B.; Warrenburg, B.P.C. van de; Schijvenaars, M.M.V.A.P.; Heister, A.; Kwint, M.P.; Arts, P.J.W.; Wijst, J.A.J. van der; Veltman, J.; Kamsteeg, E.J.; Scheffer, H.; Knoers, N.V.A.M.

    2010-01-01

    Autosomal-recessive cerebellar ataxias comprise a clinically and genetically heterogeneous group of neurodegenerative disorders. In contrast to their dominant counterparts, unraveling the molecular background of these ataxias has proven to be more complicated and the currently known mutations

  20. Targeted Next-Generation Sequencing of a 12.5 Mb Homozygous Region Reveals ANO10 Mutations in Patients with Autosomal-Recessive Cerebellar Ataxia

    NARCIS (Netherlands)

    Vermeer, Sascha; Hoischen, Alexander; Meijer, Rowdy P. P.; Gilissen, Christian; Neveling, Kornelia; Wieskamp, Nienke; de Brouwer, Arjan; Koenig, Michel; Anheim, Mathieu; Assoum, Mirna; Drouot, Nathalie; Todorovic, Slobodanka; Milic-Rasic, Vedrana; Lochmueller, Hanns; Stevanin, Giovanni; Goizet, Cyril; David, Albert; Durr, Alexandra; Brice, Alexis; Kremer, Berry; van de Warrenburg, Bart P. C.; Schijvenaars, Mascha M. V. A. P.; Heister, Angelien; Kwint, Michael; Arts, Peer; van der Wijst, Jenny; Veltman, Joris; Kamsteeg, Erik-Jan; Scheffer, Hans; Knoers, Nine

    2010-01-01

    Autosomal-recessive cerebellar ataxias comprise a clinically and genetically heterogeneous group of neurodegenerative disorders. In contrast to their dominant counterparts, unraveling the molecular background of these ataxias has proven to be more complicated and the currently known mutations

  1. Mutations in SULT2B1 Cause Autosomal-Recessive Congenital Ichthyosis in Humans.

    Science.gov (United States)

    Heinz, Lisa; Kim, Gwang-Jin; Marrakchi, Slaheddine; Christiansen, Julie; Turki, Hamida; Rauschendorf, Marc-Alexander; Lathrop, Mark; Hausser, Ingrid; Zimmer, Andreas D; Fischer, Judith

    2017-06-01

    Ichthyoses are a clinically and genetically heterogeneous group of genodermatoses associated with abnormal scaling of the skin over the whole body. Mutations in nine genes are known to cause non-syndromic forms of autosomal-recessive congenital ichthyosis (ARCI). However, not all genetic causes for ARCI have been discovered to date. Using whole-exome sequencing (WES) and multigene panel screening, we identified 6 ARCI-affected individuals from three unrelated families with mutations in Sulfotransferase family 2B member 1 (SULT2B1), showing their causative association with ARCI. Cytosolic sulfotransferases form a large family of enzymes that are involved in the synthesis and metabolism of several steroids in humans. We identified four distinct mutations including missense, nonsense, and splice site mutations. We demonstrated the loss of SULT2B1 expression at RNA and protein levels in keratinocytes from individuals with ARCI by functional analyses. Furthermore, we succeeded in reconstructing the morphologic skin alterations in a 3D organotypic tissue culture model with SULT2B1-deficient keratinocytes and fibroblasts. By thin layer chromatography (TLC) of extracts from these organotypic cultures, we could show the absence of cholesterol sulfate, the metabolite of SULT2B1, and an increased level of cholesterol, indicating a disturbed cholesterol metabolism of the skin upon loss-of-function mutation in SULT2B1. In conclusion, our study reveals an essential role for SULT2B1 in the proper development of healthy human skin. Mutation in SULT2B1 leads to an ARCI phenotype via increased proliferation of human keratinocytes, thickening of epithelial layers, and altered epidermal cholesterol metabolism. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  2. Biallelic Mutations in CRB1 Underlie Autosomal Recessive Familial Foveal Retinoschisis.

    Science.gov (United States)

    Vincent, Ajoy; Ng, Judith; Gerth-Kahlert, Christina; Tavares, Erika; Maynes, Jason T; Wright, Thomas; Tiwari, Amit; Tumber, Anupreet; Li, Shuning; Hanson, James V M; Bahr, Angela; MacDonald, Heather; Bähr, Luzy; Westall, Carol; Berger, Wolfgang; Cremers, Frans P M; den Hollander, Anneke I; Héon, Elise

    2016-05-01

    To identify the genetic cause of autosomal recessive familial foveal retinoschisis (FFR). A female sibship with FFR was identified (Family-A; 17 and 16 years, respectively); panel based genetic sequencing (132 genes) and comparative genome hybridization (142 genes) were performed. Whole-exome sequencing (WES) was performed on both siblings using the Illumina-HiSeq-2500 platform. A sporadic male (Family-B; 35 years) with FFR underwent WES using Illumina NextSeq500. All three affected subjects underwent detailed ophthalmologic evaluation including fundus photography, autofluorescence imaging, spectral-domain optical coherence tomography (SD-OCT), and full-field electroretinogram (ERG). Panel-based genetic testing identified two presumed disease causing variants in CRB1 (p.Gly123Cys and p.Cys948Tyr) in Family-A sibship; no deletion or duplication was detected. WES analysis in the sibship identified nine genes with two or more shared nonsynonymous rare coding sequence variants; CRB1 remained a strong candidate gene, and CRB1 variants segregated with the disease. WES in Family-B identified two presumed disease causing variants in CRB1 (p.Ile167_Gly169del and p.Arg764Cys) that segregated with the disease phenotype. Distance visual acuity was 20/40 or better in all three affected except for the left eye of the older subject (Family-B), which showed macular atrophy. Fundus evaluation showed spoke-wheel appearance at the macula in five eyes. The SD-OCT showed macular schitic changes in inner and outer nuclear layers in all cases. The ERG responses were normal in all subjects. This is the first report to implicate CRB1 as the underlying cause of FFR. This phenotype forms the mildest end of the spectrum of CRB1-related diseases.

  3. 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.

  4. Growth in children with autosomal recessive polycystic kidney disease in the CKiD cohort study

    Directory of Open Access Journals (Sweden)

    Erum Aftab Hartung

    2016-08-01

    Full Text Available Background: Previous studies have suggested that some children with autosomal recessive polycystic kidney disease (ARPKD have growth impairment out of proportion to their degree of chronic kidney disease (CKD. The objective of this study was to systematically compare growth parameters in children with ARPKD to those with other congenital causes of CKD in the Chronic Kidney Disease in Children (CKiD prospective cohort study. Methods: Height standard deviation scores (z-scores, proportion of children with severe short stature (z-score <-1.88, rates of growth hormone use, and annual change in height z-score were analyzed in children with ARPKD (n=22 compared to two matched control groups: children with aplastic/hypoplastic/dysplastic (A/H/D kidneys (n=44 and obstructive uropathy (OU (n=44. Differences in baseline characteristics were tested by Wilcoxon rank sum test or Fisher’s exact test. Matched differences in annual change in height z-score were tested by Wilcoxon signed rank test.Results: Median height z-score in children with ARPKD was -1.1 [interquartile range -1.5, -0.2]; 14% of the ARPKD group had height z-score <-1.88, and 18% were using growth hormone. There were no significant differences in median height z-score, proportion with height z-score <-1.88, growth hormone use, or annual change in height z-score between the ARPKD and control groups. Conclusions: Children with ARPKD and mild-to-moderate CKD in the CKiD cohort have a high prevalence of growth abnormalities, but these are similar to children with other congenital causes of CKD. This study does not support a disease-specific effect of ARPKD on growth, at least in the subset of children with mild-to-moderate CKD.

  5. Growth in Children with Autosomal Recessive Polycystic Kidney Disease in the CKiD Cohort Study.

    Science.gov (United States)

    Hartung, Erum A; Dell, Katherine M; Matheson, Matthew; Warady, Bradley A; Furth, Susan L

    2016-01-01

    Previous studies have suggested that some children with autosomal recessive polycystic kidney disease (ARPKD) have growth impairment out of proportion to their degree of chronic kidney disease (CKD). The objective of this study was to systematically compare growth parameters in children with ARPKD to those with other congenital causes of CKD in the chronic kidney disease in Children (CKiD) prospective cohort study. Height SD scores (z-scores), proportion of children with severe short stature (z-score growth hormone use, and annual change in height z-score were analyzed in children with ARPKD (n = 22) compared with two matched control groups: children with aplastic/hypoplastic/dysplastic kidneys (n = 44) and obstructive uropathy (OU) (n = 44). Differences in baseline characteristics were tested by Wilcoxon rank-sum test or Fisher's exact test. Matched differences in annual change in height z-score were tested by Wilcoxon signed-rank test. Median height z-score in children with ARPKD was -1.1 [interquartile range -1.5, -0.2]; 14% of the ARPKD group had height z-score growth hormone. There were no significant differences in median height z-score, proportion with height z-score growth hormone use, or annual change in height z-score between the ARPKD and control groups. Children with ARPKD and mild-to-moderate CKD in the CKiD cohort have a high prevalence of growth abnormalities, but these are similar to children with other congenital causes of CKD. This study does not support a disease-specific effect of ARPKD on growth, at least in the subset of children with mild-to-moderate CKD.

  6. 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.

  7. Biallelic SUN5 Mutations Cause Autosomal-Recessive Acephalic Spermatozoa Syndrome.

    Science.gov (United States)

    Zhu, Fuxi; Wang, Fengsong; Yang, Xiaoyu; Zhang, Jingjing; Wu, Huan; Zhang, Zhou; Zhang, Zhiguo; He, Xiaojin; Zhou, Ping; Wei, Zhaolian; Gecz, Jozef; Cao, Yunxia

    2016-10-06

    Acephalic spermatozoa syndrome is a rare and severe form of teratozoospermia characterized by a predominance of headless spermatozoa in the ejaculate. Family clustering and consanguinity suggest a genetic origin; however, causative mutations have yet to be identified. We performed whole-exome sequencing in two unrelated infertile men and subsequent variant filtering identified one homozygous (c.824C>T [p.Thr275Met]) and one compound heterozygous (c.1006C>T [p.Arg356Cys] and c.485T>A [p.Met162Lys]) SUN5 (also named TSARG4) variants. Sanger sequencing of SUN5 in 15 additional unrelated infertile men revealed four compound heterozygous (c.381delA [p.Val128Serfs ∗ 7] and c.824C>T [p.Thr275Met]; c.381delA [p.Val128Serfs ∗ 7] and c.781G>A [p.Val261Met]; c.216G>A [p.Trp72 ∗ ] and c.1043A>T [p.Asn348Ile]; c.425+1G>A/c.1043A>T [p.Asn348Ile]) and two homozygous (c.851C>G [p.Ser284 ∗ ]; c.350G>A [p.Gly114Arg]) variants in six individuals. These 10 SUN5 variants were found in 8 of 17 unrelated men, explaining the genetic defect in 47.06% of the affected individuals in our cohort. These variants were absent in 100 fertile population-matched control individuals. SUN5 variants lead to absent, significantly reduced, or truncated SUN5, and certain variants altered SUN5 distribution in the head-tail junction of the sperm. In summary, these results demonstrate that biallelic SUN5 mutations cause male infertility due to autosomal-recessive acephalic spermatozoa syndrome. Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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

    OpenAIRE

    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.

    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 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 t...

  9. The population genetics of human disease: The case of recessive, lethal mutations.

    Directory of Open Access Journals (Sweden)

    Carlos Eduardo G Amorim

    2017-09-01

    Full Text Available Do the frequencies of disease mutations in human populations reflect a simple balance between mutation and purifying selection? What other factors shape the prevalence of disease mutations? To begin to answer these questions, we focused on one of the simplest cases: recessive mutations that alone cause lethal diseases or complete sterility. To this end, we generated a hand-curated set of 417 Mendelian mutations in 32 genes reported to cause a recessive, lethal Mendelian disease. We then considered analytic models of mutation-selection balance in infinite and finite populations of constant sizes and simulations of purifying selection in a more realistic demographic setting, and tested how well these models fit allele frequencies estimated from 33,370 individuals of European ancestry. In doing so, we distinguished between CpG transitions, which occur at a substantially elevated rate, and three other mutation types. Intriguingly, the observed frequency for CpG transitions is slightly higher than expectation but close, whereas the frequencies observed for the three other mutation types are an order of magnitude higher than expected, with a bigger deviation from expectation seen for less mutable types. This discrepancy is even larger when subtle fitness effects in heterozygotes or lethal compound heterozygotes are taken into account. In principle, higher than expected frequencies of disease mutations could be due to widespread errors in reporting causal variants, compensation by other mutations, or balancing selection. It is unclear why these factors would have a greater impact on disease mutations that occur at lower rates, however. We argue instead that the unexpectedly high frequency of disease mutations and the relationship to the mutation rate likely reflect an ascertainment bias: of all the mutations that cause recessive lethal diseases, those that by chance have reached higher frequencies are more likely to have been identified and thus to

  10. Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica

    Directory of Open Access Journals (Sweden)

    Ariana Kariminejad

    2017-03-01

    Full Text Available Cutis laxa is a heterogeneous condition characterized by redundant, sagging, inelastic, and wrinkled skin. The inherited forms of this disease are rare and can have autosomal dominant, autosomal recessive, or X-linked inheritance. Three of the autosomal recessive cutis laxa syndromes, namely cutis laxa IIA (ARCL2A, cutis laxa IIB (ARCL2B, and geroderma osteodysplastica (GO, have very similar clinical features, complicating accurate diagnosis. Individuals with these conditions often present with cutis laxa, progeroid features, and hyperextensible joints. These conditions also share additional features, such as short stature, hypotonia, and congenital hip dislocation, but the severity and frequency of these findings are variable in each of these cutis laxa syndromes. The characteristic features for ARCL2A are abnormal isoelectric focusing and facial features, including downslanting palpebral fissures and a long philtrum. Rather, the clinical phenotype of ARCL2B includes severe wrinkling of the dorsum of the hands and feet, wormian bones, athetoid movements, lipodystrophy, cataract and corneal clouding, a thin triangular face, and a pinched nose. Normal cognition and osteopenia leading to pathological fractures, maxillary hypoplasia, and oblique furrowing from the outer canthus to the lateral border of the supraorbital ridge are discriminative features for GO. Here we present 10 Iranian patients who were initially diagnosed clinically using the respective features of each cutis laxa syndrome. Each patient’s clinical diagnosis was then confirmed with molecular investigation of the responsible gene. Review of the clinical features from the cases reported from the literature also supports our conclusions.

  11. 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

  12. A Naturally Occurring Canine Model of Autosomal Recessive Congenital Stationary Night Blindness.

    Directory of Open Access Journals (Sweden)

    Mineo Kondo

    Full Text Available Congenital stationary night blindness (CSNB is a non-progressive, clinically and genetically heterogeneous disease of impaired night vision. We report a naturally-occurring, stationary, autosomal recessive phenotype in beagle dogs with normal daylight vision but absent night vision. Affected dogs had normal retinas on clinical examination, but showed no detectable rod responses. They had "negative-type" mixed rod and cone responses in full-field ERGs. Their photopic long-flash ERGs had normal OFF-responses associated with severely reduced ON-responses. The phenotype is similar to the Schubert-Bornschein form of complete CSNB in humans. Homozygosity mapping ruled out most known CSNB candidates as well as CACNA2D4 and GNB3. Three remaining genes were excluded based on sequencing the open reading frame and intron-exon boundaries (RHO, NYX, causal to a different form of CSNB (RHO or X-chromosome (NYX, CACNA1F location. Among the genes expressed in the photoreceptors and their synaptic terminals, and mGluR6 cascade and modulators, reduced expression of GNAT1, CACNA2D4 and NYX was observed by qRT-PCR in both carrier (n = 2 and affected (n = 2 retinas whereas CACNA1F was down-regulated only in the affecteds. Retinal morphology revealed normal cellular layers and structure, and electron microscopy showed normal rod spherules and synaptic ribbons. No difference from normal was observed by immunohistochemistry (IHC for antibodies labeling rods, cones and their presynaptic terminals. None of the retinas showed any sign of stress. Selected proteins of mGluR6 cascade and its modulators were examined by IHC and showed that PKCα weakly labeled the rod bipolar somata in the affected, but intensely labeled axonal terminals that appeared thickened and irregular. Dendritic terminals of ON-bipolar cells showed increased Goα labeling. Both PKCα and Goα labeled the more prominent bipolar dendrites that extended into the OPL in affected but not normal retinas

  13. A common founder mutation of CERKL underlies autosomal recessive retinal degeneration with early macular involvement among Yemenite Jews.

    Science.gov (United States)

    Auslender, Noa; Sharon, Dror; Abbasi, Anan H; Garzozi, Hanna J; Banin, Eyal; Ben-Yosef, Tamar

    2007-12-01

    To investigate the genetic basis and clinical manifestations of a characteristic form of retinal degeneration in the Yemenite Jewish population. Haplotype analysis for all known genes and loci underlying autosomal recessive nonsyndromic retinal degeneration was performed in a Yemenite Jewish family segregating autosomal recessive severe retinal degeneration. The causative mutation was detected by direct sequencing of the underlying gene, and its prevalence in additional affected and unaffected Yemenite Jews was determined. Patients who were homozygous for this mutation underwent ophthalmic evaluation, including funduscopy, electroretinography, electro-oculography, perimetry, and color vision testing. In the studied Yemenite Jewish family, we found evidence for linkage to the CERKL gene. Direct sequencing revealed a novel homozygous splice-site mutation, c.238+1G>A. An in vitro splicing assay demonstrated that this mutation leads to incorrect splicing. c.238+1G>A was found to cause retinal degeneration in six additional Yemenite Jewish families. The carrier frequency of this mutation in the Yemenite Jewish population is 4.4%. All c.238+1G>A homozygotes manifest widespread progressive impairment of rod and cone function with early macular involvement. c.238+1G>A is the second reported mutation of CERKL and is a prevalent founder mutation that underlies approximately 33% of autosomal recessive retinal degeneration cases in the Yemenite Jewish population. It is associated with a characteristic retinal degeneration phenotype with early macular involvement, concomitant progression of rod and cone impairment, and characteristic fundus findings. The identification of this mutation and phenotype will facilitate molecular diagnosis, carrier screening, and genetic counseling in the Yemenite Jewish population.

  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...

  15. A Mutation in LIPN, Encoding Epidermal Lipase N, Causes a Late-Onset Form of Autosomal-Recessive Congenital Ichthyosis

    Science.gov (United States)

    Israeli, Shirli; Khamaysi, Ziyad; Fuchs-Telem, Dana; Nousbeck, Janna; Bergman, Reuven; Sarig, Ofer; Sprecher, Eli

    2011-01-01

    Autosomal-recessive congenital ichthyoses represent a large and heterogeneous group of disorders of epidermal cornification. Recent data suggest that most of these disorders might result from defective lipid transport and metabolism. In the present study, we describe a late-onset form of recessive ichthyosis in a large consanguineous pedigree. By using a combination of homozygosity mapping and positional candidate-gene screening, we identified a 2 bp deletion in LIPN that segregated with the disease phenotype throughout the family. LIPN encodes one of six acid lipases known to be involved in triglyceride metabolism in mammals . LIPN was found to be exclusively expressed in the epidermis and to be strongly induced during keratinocyte differentiation. PMID:21439540

  16. Whole Genome Sequencing Identifies Novel Compound Heterozygous Lysosomal Trafficking Regulator Gene Mutations Associated with Autosomal Recessive Chediak-Higashi Syndrome.

    Science.gov (United States)

    Jin, Yaqiong; Zhang, Li; Wang, Senfen; Chen, Feng; Gu, Yang; Hong, Enyu; Yu, Yongbo; Ni, Xin; Guo, Yongli; Shi, Tieliu; Xu, Zigang

    2017-02-01

    Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disease characterized by varying degrees of oculocutaneous albinism, recurrent infections, and a mild bleeding tendency, with late neurologic dysfunction. This syndrome is molecularly characterized by pathognomonic mutations in the LYST (lysosomal trafficking regulator). Using whole genome sequencing (WGS) we attempted to identify novel mutations of CHS based on a family of CHS with atypical symptoms. The two patients demonstrated a phenotypic constellation including partial oculocutaneous albinism, frequency upper respiratory infection or a marginal intelligence, without bleeding tendency and severe immunodeficiency. WGS revealed two compound LYST mutations including a maternally inherited chr1:235969126G > A (rs80338652) and a novel paternally inherited chr1: 235915327A > AT, associated with autosomal recessive CHS. These two variants fall in the coding regions of LYST, resulting in premature truncation of LYST due to R1104X/N2535KfsX2 induced incomplete translation. Notably, the heterozygous carriers (i.e. parents) were unaffected. Our finding also reveals decreased plasma serotonin levels in patients with CHS compared with unaffected individuals for the first time. The present study contributes to improved understanding of the causes of this disease and provides new ideas for possible treatments.

  17. Using next-generation sequencing as a genetic diagnostic tool in rare autosomal recessive neurologic Mendelian disorders.

    Science.gov (United States)

    Chen, Zhao; Wang, Jun-Ling; Tang, Bei-Sha; Sun, Zhan-Fang; Shi, Yu-Ting; Shen, Lu; Lei, Li-Fang; Wei, Xiao-Ming; Xiao, Jing-Jing; Hu, Zheng-Mao; Pan, Qian; Xia, Kun; Zhang, Qing-Yan; Dai, Mei-Zhi; Liu, Yu; Ashizawa, Tetsuo; Jiang, Hong

    2013-10-01

    Next-generation sequencing was used to investigate 9 rare Chinese pedigrees with rare autosomal recessive neurologic Mendelian disorders. Five probands with ataxia-telangectasia and 1 proband with chorea-acanthocytosis were analyzed by targeted gene sequencing. Whole-exome sequencing was used to investigate 3 affected individuals with Joubert syndrome, nemaline myopathy, or spastic ataxia Charlevoix-Saguenay type. A list of known and novel candidate variants was identified for each causative gene. All variants were genetically verified by Sanger sequencing or quantitative polymerase chain reaction with the strategy of disease segregation in related pedigrees and healthy controls. The advantages of using next-generation sequencing to diagnose rare autosomal recessive neurologic Mendelian disorders characterized by genetic and phenotypic heterogeneity are demonstrated. A genetic diagnostic strategy combining the use of targeted gene sequencing and whole-exome sequencing with the aid of next-generation sequencing platforms has shown great promise for improving the diagnosis of neurologic Mendelian disorders. Copyright © 2013 Elsevier Inc. All rights reserved.

  18. Autosomal recessive long QT syndrome, type 1 in eight families from Saudi Arabia

    NARCIS (Netherlands)

    Bdier, Amnah Y.; Al-Ghamdi, Saleh; Verma, Prashant K.; Dagriri, Khalid; Alshehri, Bandar; Jiman, Omamah A.; Ahmed, Sherif E.; Wilde, Arthur A. M.; Bhuiyan, Zahurul A.; Al-Aama, Jumana Y.

    2017-01-01

    One of the most common primary cardiac arrhythmia syndromes is autosomal dominant long QT syndrome, type 1 (LQT1), chiefly caused by mono-allelic mutations in the KCNQ1 gene. Bi-allelic mutations in the KCNQ1 gene are causal to Jervell and Lange-Nielsen syndrome (JLNS), characterized by severe and

  19. DOCK6 mutations are responsible for a distinct autosomal-recessive variant of Adams-Oliver syndrome associated with brain and eye anomalies.

    Science.gov (United States)

    Sukalo, Maja; Tilsen, Felix; Kayserili, Hülya; Müller, Dietmar; Tüysüz, Beyhan; Ruddy, Deborah M; Wakeling, Emma; Ørstavik, Karen Helene; Snape, Katie M; Trembath, Richard; De Smedt, Maryse; van der Aa, Nathalie; Skalej, Martin; Mundlos, Stefan; Wuyts, Wim; Southgate, Laura; Zenker, Martin

    2015-06-01

    Adams-Oliver syndrome (AOS) is characterized by the association of aplasia cutis congenita with terminal transverse limb defects, often accompanied by additional cardiovascular or neurological features. Both autosomal-dominant and autosomal-recessive disease transmission have been observed, with recent gene discoveries indicating extensive genetic heterogeneity. Mutations of the DOCK6 gene were first described in autosomal-recessive cases of AOS and only five DOCK6-related families have been reported to date. Recently, a second type of autosomal-recessive AOS has been attributed to EOGT mutations in three consanguineous families. Here, we describe the identification of 13 DOCK6 mutations, the majority of which are novel, across 10 unrelated individuals from a large cohort comprising 47 sporadic cases and 31 AOS pedigrees suggestive of autosomal-recessive inheritance. DOCK6 mutations were strongly associated with structural brain abnormalities, ocular anomalies, and intellectual disability, thus suggesting that DOCK6-linked disease represents a variant of AOS with a particularly poor prognosis. © 2015 WILEY PERIODICALS, INC.

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

    OpenAIRE

    Parisa Tahmasebi; Seyed Reza Kazemi Nezhad; Mohammad Amin Tabatabaiefar; Javad Mohammadi Asl; Nader Saki

    2016-01-01

    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. ...

  1. 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.

  2. 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

  3. 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.

  4. 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

  5. Familial Clustering of Unexplained Transient Respiratory Distress in 12 Newborns from Three Unrelated Families Suggests an Autosomal-Recessive Inheritance

    Directory of Open Access Journals (Sweden)

    Andrea Guala

    2007-01-01

    Full Text Available We report on 12 near-term babies from three families in which an unexplained transient respiratory distress was observed. No known risk factor was present in any family and no sequelae were recorded at follow-up. The most common causes of respiratory distress at birth are Neonatal Respiratory Distress Syndrome (NRD and Transient Tachypnea of the Newborn (TTN, and their cumulative incidence is estimated to be about 2%. Genetic factors have been identified in NRD (surfactant genes or suggested for TTN (genes affecting lung liquid clearance. Survivors from NRD may develop clinically relevant sequelae, while TTN does not cause any problem later in life. Our cases do not immediately fit NRD or TTN, while familial recurrence suggests the existence of a previously unreported subgroup on patients with respiratory distress for which autosomal-recessive inheritance is likely.

  6. An autosomal recessive DNASE1L3-related autoimmune disease with unusual clinical presentation mimicking systemic lupus erythematosus.

    Science.gov (United States)

    Carbonella, A; Mancano, G; Gremese, E; Alkuraya, F S; Patel, N; Gurrieri, F; Ferraccioli, G

    2017-06-01

    We describe the third family in the world, after Arabian and Turkish ones, displaying an autosomal recessive autoimmune disease (AID), mimicking systemic lupus erythematosus (SLE), with unusual manifestations due to a homozygous frame-shift variant in DNASE1L3. SLE is a complex AID characterized by multiple organ involvement. Genetic risk variants identified account for only 15% of SLE heritability. Rare Mendelian forms have been reported, including DNASE1L3-related SLE. Through specific genetic tests we identified a homozygous 2 bp-deletion c.289_290delAC (NM_004944.2) in DNASE1L3, predicting frameshift and premature truncation (p.Thr97Ilefs*2). The same mutation was previously reported in three sisters, born from consanguineous parents and affected with hypocomplementemic urticarial vasculitis syndrome (HUVS). As approximately 50% of individuals affected with HUVS develop SLE, it is still unclear whether it is a SLE sub-phenotype or a separate condition.

  7. Dominant and recessive effects of induced lethals in female mice by exposure to gamma-irradiation during the 10th to 14th day of intrauterine life

    International Nuclear Information System (INIS)

    Roennbaeck, C.

    1978-01-01

    The frequency of (dominant and) recessive lethal mutations induced by 160-rad chronic gamma-irradiation given with a dose rate of 0.03 rad/min during the 10th to 14th day of gestation has been studied in female CBA-mice. An increased rate of recessive lethal equivalents by about 10% has been noted. This increase corresponds to a mutation rate of 6.3 x 10 -4 mutation/rad/genome. There were not found any dominant mutations, nor any dominance effects from the induced recessive lethal equivalents. The hazards after irradiation during foetal development are discussed

  8. Neuromuscular blocking effects of cisatracurium and its antagonism with neostigmine in a canine model of autosomal-recessive centronuclear myopathy.

    Science.gov (United States)

    Martin-Flores, M; Paré, M D; Campoy, L; Gleed, R D

    2015-12-01

    Centronuclear myopathy (CNM) is a rare congenital condition associated with skeletal muscle weakness. Patients with CNM may have decreased acetylcholine receptor expression and a reduced number of releasable quanta. Such perturbations could affect the time-course of neuromuscular blocking agents (NMBAs) and their antagonism with cholinesterase inhibitors. As a result of the rarity of CNM, prospective data regarding NMBA use in this subpopulation is scarce. We evaluated the neuromuscular blocking effects of cisatracurium and its antagonism with neostigmine in a canine model of CNM. Six dogs with congenital autosomal-recessive CNM and six controls received cisatracurium 0.15 mg kg(-1) i.v. under general anaesthesia and intermittent positive pressure ventilation. Neuromuscular function was monitored with acceleromyography.When the second response (T2) to train-of-four (TOF) stimulation returned, neostigmine 0.04 mg kg(-1) (with glycopyrrolate) were administered i.v. The onset time, time to spontaneous return of T2, and the time to reach a TOF ratio ≥0.9 after neostigmine administration were recorded. Onset time was no different between groups. Median (interquartile range) time to return of T2 was 27 (24-31) min for control dogs and 26 (22-31) min for CNM dogs (P=0.93).After neostigmine administration, a TOF ratio ≥0.9 was reached in 12 (10-15) min and 17 (16-19) min in control and CNM, respectively (P=0.005). The spontaneous return of T2 was not different between groups. However, neostigmine-facilitated recovery was significantly slower in dogs with CNM. Canine autosomal-recessive CNM does not preclude the use of cisatracurium or its antagonism with neostigmine. © The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  9. 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.

  10. 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.

  11. Autosomal recessive POLR1D mutation with decrease of TCOF1 mRNA is responsible for Treacher Collins syndrome.

    Science.gov (United States)

    Schaefer, Elise; Collet, Corinne; Genevieve, David; Vincent, Marie; Lohmann, Dietmar R; Sanchez, Elodie; Bolender, Chantal; Eliot, Marie-Madeleine; Nürnberg, Gudrun; Passos-Bueno, Maria-Rita; Wieczorek, Dagmar; van Maldergem, Lionel; Doray, Bérénice

    2014-09-01

    Treacher Collins syndrome is a mandibulofacial dysostosis caused by mutations in genes involved in ribosome biogenesis and synthesis. TCOF1 mutations are observed in ~80% of the patients and are inherited in an autosomal dominant manner. Recently, two other genes have been reported in TCOF1, POLR1C, and POLR1D in two unrelated consanguineous families. The four affected children shared the same homozygous mutation in POLR1D (c.163C>G, p.Leu55Val). This mutation is localized in a region encoding the dimerization domain of the RNA polymerase. It is supposed that this mutation impairs RNA polymerase, resulting in a lower amount of mature dimeric ribosomes. A functional analysis of the transcripts of TCOF1 by real-time quantitative reverse transcription-polymerase chain reaction was performed in the first family, demonstrating a 50% reduction in the index case, compatible with this hypothesis. This is the first report of POLR1D mutation being responsible for an autosomal recessive inherited Treacher Collins syndrome. These results reinforce the concept of genetic heterogeneity of Treacher Collins syndrome and underline the importance of combining clinical expertise and familial molecular analyses for appropriate genetic counseling.

  12. Case report of intrafamilial variability in autosomal recessive centronuclear myopathy associated to a novel BIN1 stop mutation

    Directory of Open Access Journals (Sweden)

    Kurul Semra

    2010-12-01

    Full Text Available Abstract Centronuclear myopathies (CNM describe a group of rare muscle diseases typically presenting an abnormal positioning of nuclei in muscle fibers. To date, three genes are known to be associated to a classical CNM phenotype. The X-linked neonatal form (XLCNM is due to mutations in MTM1 and involves a severe and generalized muscle weakness at birth. The autosomal dominant form results from DNM2 mutations and has been described with early childhood and adult onset (ADCNM. Autosomal recessive centronuclear myopathy (ARCNM is less characterized and has recently been associated to mutations in BIN1, encoding amphiphysin 2. Here we present the first clinical description of intrafamilal variability in two first-degree cousins with a novel BIN1 stop mutation. In addition to skeletal muscle defects, both patients have mild mental retardation and the more severely affected male also displays abnormal ventilation and cardiac arrhythmia, thus expanding the phenotypic spectrum of BIN1-related CNM to non skeletal muscle defects. We provide an up-to-date review of all previous cases with ARCNM and BIN1 mutations.

  13. Investigating Seven Recently Identified Genes in 100 Iranian Families with Autosomal Recessive Non-syndromic Hearing Loss

    Directory of Open Access Journals (Sweden)

    Reihaneh Alikhani

    2015-09-01

    Full Text Available Objectives: Hearing loss (HL is the most common sensory disorder, and affects 1 in 1000 newborns. About 50% of HL is due to genetics and 70% of them are non-syndromic with a recessive pattern of inheritance. Up to now, more than 50 genes have been detected which are responsible for autosomal recessive non-syndromic hearing loss, (ARNSHL. In  Iran, HL is one of the most common disabilities due to consanguineous marriages. The aim was to investigate the prevalence of three new ARHL genes (GJB4, GJC3, and SLITRK6 reported in neighboring countries among Iranian families with ARNSHL. Methods: One hundred unrelated families with at least two affected siblings in consanguineous marriage, who were negative for GJB2 gene mutations, were selected. By using three STR markers for each gene, homozygosity mapping was performed. Results: Two families showed linkage to GJB4, six families were linked to GJC3 and only one family linked to SLITRK6. The samples of these families who showed linkage were sent for Sanger sequencing to detect the causative mutations. However, after analyzing the sequencing results, no mutation could be detected in either of the families. Molecular analysis for these nine families is underway in order to determine the pathogenic mutations using whole exome sequencing. Discussion: These data demonstrate a very low prevalence of mutation in these three genes (GJB4, GJC3, and SLITRK6 in the Iranian population, since no mutation was detected in our study group of 100 families.

  14. 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.

  15. 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

  16. 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

  17. 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

  18. 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...... 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...

  19. The role of mutant protein level in autosomal recessive catecholamine dependent polymorphic ventricular tachycardia (CPVT2)

    OpenAIRE

    Katz, Guy; Shainberg, Asher; Hochhauser, Edith; Kurtzwald-Josefson, Efrat; Issac, Ahuva; El-Ani, Dalia; Aravot, Dan; Afek, Arnon; Seidman, Jonathan G.; Seidman, Christine E.; Eldar, Michael; Arad, Michael

    2013-01-01

    Humans and genetically engineered mice with recessively inherited CPVT develop arrhythmia which may arise due to malfunction or degradation of calsequestrin (CASQ2). We investigated the relation between protein level and arrhythmia severity in CASQ2D307H/D307H (D307H), compared to CASQ2Δ/Δ (KO) and wild type (WT) mice. CASQ2 expression and Ca2+ transients were recorded in cardiomyocytes from neonatal or adult mice. Arrhythmia was studied in vivo using heart rhythm telemetry at rest, exercise ...

  20. Two sisters with clinical diagnosis of Wiskott-Aldrich Syndrome: Is the condition in the family autosomal recessive?

    Energy Technology Data Exchange (ETDEWEB)

    Kondoh, T.; Hayashi, K.; Matsumoto, T. [Nagasaki Univ. School of Medicine (Japan)] [and others

    1995-10-09

    We report two sisters in a family representing manifestations of Wiskott-Aldrich syndrome (WAS), an X-linked immunodeficiency disorder. An elder sister had suffered from recurrent infections, small thrombocytopenic petechiae, purpura, and eczema for 7 years. The younger sister had the same manifestations as the elder sister`s for a 2-year period, and died of intracranial bleeding at age 2 years. All the laboratory data of the two patients were compatible with WAS, although they were females. Sialophorin analysis with the selective radioactive labeling method of this protein revealed that in the elder sister a 115-KD band that should be specific for sialophorin was reduced in quantity, and instead an additional 135-KD fragment was present as a main band. Polymerase chain reaction (PCR) analysis of the sialophorin gene and single-strand conformation polymorphism (SSCP) analysis of the PCR product demonstrated that there were no detectable size-change nor electrophoretic mobility change in the DNA from both patients. The results indicated that their sialophorin gene structure might be normal. Studies on the mother-daughter transmission of X chromosome using a pERT84-MaeIII polymorphic marker mapped at Xp21 and HPRT gene polymorphism at Xq26 suggested that each sister had inherited a different X chromosome from the mother. Two explanations are plausible for the occurrence of the WAS in our patients: the WAS in the patients is attributable to an autosomal gene mutation which may regulate the sialophorin gene expression through the WAS gene, or, alternatively, the condition in this family is an autosomal recessive disorder separated etiologically from the X-linked WAS. 17 refs., 6 figs., 1 tab.

  1. 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.

  2. A screen for F1 hybrid male rescue reveals no major-effect hybrid lethality loci in the Drosophila melanogaster autosomal genome.

    Science.gov (United States)

    Cuykendall, Tawny N; Satyaki, P; Ji, Shuqing; Clay, Derek M; Edelman, Nathaniel B; Kimchy, Alexandra; Li, Ling-Hei; Nuzzo, Erin A; Parekh, Neil; Park, Suna; Barbash, Daniel A

    2014-10-27

    Hybrid sons between Drosophila melanogaster females and D. simulans males die as 3rd instar larvae. Two genes, D. melanogaster Hybrid male rescue (Hmr) on the X chromosome, and D. simulans Lethal hybrid rescue (Lhr) on chromosome II, interact to cause this lethality. Loss-of-function mutations in either gene suppress lethality, but several pieces of evidence suggest that additional factors are required for hybrid lethality. Here we screen the D. melanogaster autosomal genome by using the Bloomington Stock Center Deficiency kit to search for additional regions that can rescue hybrid male lethality. Our screen is designed to identify putative hybrid incompatibility (HI) genes similar to Hmr and Lhr which, when removed, are dominant suppressors of lethality. After screening 89% of the autosomal genome, we found no regions that rescue males to the adult stage. We did, however, identify several regions that rescue up to 13% of males to the pharate adult stage. This weak rescue suggests the presence of multiple minor-effect HI loci, but we were unable to map these loci to high resolution, presumably because weak rescue can be masked by genetic background effects. We attempted to test one candidate, the dosage compensation gene male specific lethal-3 (msl-3), by using RNA interference with short hairpin microRNA constructs targeted specifically against D. simulans msl-3 but failed to achieve knockdown, in part due to off-target effects. We conclude that the D. melanogaster autosomal genome likely does not contain additional major-effect HI loci. We also show that Hmr is insufficient to fully account for the lethality associated with the D. melanogaster X chromosome, suggesting that additional X-linked genes contribute to hybrid lethality. Copyright © 2014 Cuykendall et al.

  3. Autosomal recessive congenital ichthyosis: CERS3 mutations identified by a next generation sequencing panel targeting ichthyosis genes.

    Science.gov (United States)

    Youssefian, Leila; Vahidnezhad, Hassan; Saeidian, Amir Hossein; Sotoudeh, Soheila; Mahmoudi, Hamidreza; Daneshpazhooh, Maryam; Aghazadeh, Nessa; Adams, Rebecca; Ghanadan, Alireza; Zeinali, Sirous; Fortina, Paolo; Uitto, Jouni

    2017-11-01

    There are at least 38 mutant genes known to be associated with the ichthyosis phenotypes, and autosomal recessive congenital ichthyosis (ARCI) is a specific subgroup caused by mutations in 13 different genes. Mutations in some of these genes, such as CERS3 with only two previous reports, are rare. In this study, we identified mutations in candidate genes in consanguineous families with ARCI with a next generation sequencing (NGS) array that incorporates 38 ichthyosis associated genes. We applied this sequencing array to DNA from 140 ichthyosis families with high prevalence of consanguinity. Among these patients we identified six distinct, previously unreported mutations in CERS3 in six Iranian families. These mutations in each family co-segregated with the ichthyosis phenotype. The patients demonstrated collodion membrane at birth, acrogeria, generalized scaling, and hyperlinearity of the palms and soles. The presence of a significant percentage of CERS3 mutations in our cohort depicts a marked difference between the etiology of ichthyoses in genetically poorly characterized regions and well-characterized western populations. Also, it shows that rare alleles are more prevalent in the gene pool of consanguineous populations and emphasizes the importance of these population studies for better understanding of ichthyosis pathogenesis.

  4. Type I Transglutaminase Accumulation in the Endoplasmic Reticulum May Be an Underlying Cause of Autosomal Recessive Congenital Ichthyosis*

    Science.gov (United States)

    Jiang, Haibing; Jans, Ralph; Xu, Wen; Rorke, Ellen A.; Lin, Chen-Yong; Chen, Ya-Wen; Fang, Shengyun; Zhong, Yongwang; Eckert, Richard L.

    2010-01-01

    Type I transglutaminase (TG1) is an enzyme that is responsible for assembly of the keratinocyte cornified envelope. Although TG1 mutation is an underlying cause of autosomal recessive congenital ichthyosis, a debilitating skin disease, the pathogenic mechanism is not completely understood. In the present study we show that TG1 is an endoplasmic reticulum (ER) membrane-associated protein that is trafficked through the ER for ultimate delivery to the plasma membrane. Mutation severely attenuates this processing and a catalytically inactive point mutant, TG1-FLAG(C377A), accumulates in the endoplasmic reticulum and in aggresome-like structures where it is ubiquitinylated. This accumulation results from protein misfolding, as treatment with a chemical chaperone permits it to exit the endoplasmic reticulum and travel to the plasma membrane. ER accumulation is also observed for ichthyosis-associated TG1 mutants. Our findings suggest that misfolding of TG1 mutants leads to ubiquitinylation and accumulation in the ER and aggresomes, and that abnormal intracellular processing of TG1 mutants may be an underlying cause of ichthyosis. PMID:20663883

  5. Update on autosomal recessive congenital ichthyosis: mRNA analysis using hair samples is a powerful tool for genetic diagnosis.

    Science.gov (United States)

    Sugiura, Kazumitsu; Akiyama, Masashi

    2015-07-01

    Research on the molecular genetics and pathomechanisms of autosomal recessive congenital ichthyosis (ARCI) has advanced considerably and several causative genes and molecules underlying the disease have been identified. Three major ARCI phenotypes are harlequin ichthyosis (HI), lamellar ichthyosis (LI), and congenital ichthyosiform erythroderma (CIE). Skin barrier defects are involved in the pathogenesis of ARCI. In this review, the causative genes of ARCI and its phenotypes as well as recent advances in the field are summarized. The known causative molecules underlying ARCI include ABCA12, TGM1, ALOXE3, ALOX12B, NIPAL4, CYP4F22, PNPLA1, CERS3, and LIPN. It is important to examine genetic associations and to elucidate the pathomechanisms of ARCI to establish effective therapies and beneficial genetic counseling. Next-generation sequencing is a promising method that enables the detection of causative disease mutations, even in cases of unexpected concomitant genetic diseases. For genetic diagnosis, obtaining mRNA from hair follicle epithelial cells, which are analogous to keratinocytes in the interfollicular epidermis, is convenient and minimally invasive in patients with ARCI. We confirmed that our mRNA analysis method using hair follicle samples can be applied not only to keratinization disorders, but also to other genetic diseases in the dermatology field. Studies that suggest potential next-generation therapies using ARCI model mice are also reviewed. Copyright © 2015 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

  6. Localization of a gene for an autosomal recessive form of juvenile Parkinsonism to chromosome 6q25.2-27

    Energy Technology Data Exchange (ETDEWEB)

    Matsumine, Hiroto; Shimoda-Matsubayashi, Satoe; Nakagawa-Hattori, Yuko [Tokyo Metropolitan Ebara Hospital (Japan)] [and others

    1997-03-01

    An autosomal recessive form of juvenile Parkinsonism (AR-JP) (MIM 600116) is a levodopa-responsive Parkinsonism whose pathological finding is a highly selective degeneration of dopaminergic neurons in the zona compacta of the substantia nigra. By linkage analysis of diallelic polymorphism of the Mn-superoxide dismutase gene (SOD2), we found a family with AR-JP showing perfect segregation of the disease with the SOD2 locus. By extending the linkage analysis to 13 families with AR-JP, we discovered strong evidence for the localization of the AR-JP gene at chromosome 6q25.2-27, including the SOD2 locus, with the maximal cumulative pairwise LOD scores of 7.26 and 7.71 at D6S305 ({theta} = .03) and D6S253 ({theta} = .02), respectively. Observation of obligate recombination events, as well as multipoint linkage analysis, placed the AR-JP gene in a 17-cM interval between D6S437 and D6S264. Delineation of the AR-JP gene will be an important step toward our understanding of the molecular mechanism underlying selective degeneration of the nigral neurons. 38 refs., 4 figs., 1 tab.

  7. 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

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

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    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.

  9. COL9A2 and COL9A3 mutations in canine autosomal recessive Oculo-skeletal Dysplasia

    Science.gov (United States)

    Goldstein, Orly; Guyon, Richard; Kukekova, Anna; Pearce-Kelling, Sue; Johnson, Jennifer; Aguirre, Gustavo D.; Acland, Gregory M.

    2010-01-01

    Oculo-skeletal dysplasia segregates in two canine breeds, the Labrador retriever and samoyed, in which the causative loci have been termed drd1 and drd2, respectively. Affected dogs exhibit short-limbed dwarfism together with severe ocular defects, and this phenotype is inherited as an autosomal recessive trait in both breeds. The clinical and pathological appearance resembles human hereditary arthro-ophthalmopathies such as Stickler syndrome, or Marshall Syndrome, although these human disorders are usually dominant. Linkage studies in drd1-informative pedigrees mapped the locus to canine chromosome 24, and led to the identification of an insertional mutation in exon 1 of the gene COL9A3 that cosegregates with the disease. The drd2 locus was similarly mapped to canine chromosome 15 and shown to cosegregate with a 1,267 bp deletion mutation in the 5′ end of COL9A2. Both mutations affect the COL3 domain of the respective gene. Northern analysis showed reduced RNA expression in affected retina compared to normal. These models offer potential for studies such as protein-protein interactions between different members of the collagen gene family; regulation and expression of these genes in retina and cartilage, and even opportunities for gene therapy. PMID:20686772

  10. 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.

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

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    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.

  12. Autosomal recessive agammaglobulinemia due to defect in μ heavy chain caused by a novel mutation in the IGHM gene.

    Science.gov (United States)

    Silva, P; Justicia, A; Regueiro, A; Fariña, S; Couselo, J M; Loidi, L

    2017-09-01

    Agammaglobulinemia is a primary immunodeficiency disorder characterized by profoundly low or absent serum antibodies and low or absent circulating B cells. The most common form is X-linked agammaglobulinemia (XLA) caused by mutations in BTK gene. The remaining cases, clinically similar to XLA, are autosomal recessive agammaglobulinemia (ARA). Nearly 30% of ARA cases present mutations in the μ heavy constant region gene IGHM. Here, we present a 7-month-old patient, born from non-consanguineous parents, who is affected by ARA due to defect in the μ heavy chain. The genetic study showed that the patient is compound heterozygous for an IGHM gene deletion and the novel nonsense mutation X57331.1:g.275C>A (p.Tyr43*) (ClinVar Accession Number: SCV000537868.1). This finding allows for an adequate genetic counseling to the family and also broadens the spectrum of already described point mutations at this locus. The IGHM gene is very complex and it is likely that yet unidentified mutations appear in other patients.

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

    Science.gov (United States)

    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 from Germany and The Netherlands . 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. PMID:10958761

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

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    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.

  15. Studies on Drosophila radiosensitive strains. 7 Influence of maternal genotype on the rates of recessive and dominant lethal mutations induces by γ-rays in males

    International Nuclear Information System (INIS)

    Varentsova, E.P.

    1984-01-01

    Basc line males have been γ-irradiated and hybridized either with females of radiosensitive mutant rad (2)201sup(G1) of with females of control line Canton-S. Recessive sex linkage lethal mutations (RSLLM) and dominiant lethal mutations (DLM) have been considered. Mother genotype is shown to affect formation of mutations induced in males of tester line. The level of spontaneous and induced dominant lethalies was slightly higher after crotsing with females of radiosenssitive mutant as compared with control line. Differences are not disclosed by spontaneous level of recessive lethal mutations, but the effect of rad (2)201sup(G1) mutation on yield of recessive lethal mutations induces in males is revealed; dose dependence of frequency of arising this type of mutations differs from linear dependence described in literature

  16. 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...

  17. 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; Lesage, Suzanne; Tison, François; Vidailhet, Marie; Corvol, Jean-Christophe; Agid, Yves; Anheim, Mathieu; Bonnet, Anne-Marie; Borg, Michel; Broussolle, Emmanuel; Damier, Philippe; Destée, Alain; Dürr, Alexandra; Durif, Franck; Krack, Paul; Klebe, Stephan; Lohmann, Ebba; Martinez, Maria; Pollak, Pierre; Rascol, Olivier; Tranchant, Christine; Vérin, Marc; Viallet, François; Brice, Alexis; Lesage, Suzanne; Majounie, Elisa; Tison, François; Vidailhet, Marie; Corvol, Jean Christophe; Nalls, Michael A.; Hernandez, Dena G.; Gibbs, J. Raphael; Dürr, Alexandra; Arepalli, Sampath; Barker, Roger A.; Ben-Shlomo, Yoav; Berg, Daniela; Bettella, Francesco; Bhatia, Kailash; de Bie, Rob M.A.; Biffi, Alessandro; Bloem, Bastiaan R.; Bochdanovits, Zoltan; Bonin, Michael; Lesage, Suzanne; Tison, François; Vidailhet, Marie; Corvol, Jean-Christophe; Agid, Yves; Anheim, Mathieu; Bonnet, Anne-Marie; Borg, Michel; Broussolle, Emmanuel; Damier, Philippe; Destée, Alain; Dürr, Alexandra; Durif, Franck; Krack, Paul; Klebe, Stephan; Lohmann, Ebba; Martinez, Maria; Pollak, Pierre; Rascol, Olivier; Tranchant, Christine; Vérin, Marc; Bras, Jose M.; Brockmann, Kathrin; Brooks, Janet; Burn, David J.; Charlesworth, Gavin; Chen, Honglei; Chinnery, Patrick F.; Chong, Sean; Clarke, Carl E.; Cookson, Mark R.; Counsell, Carl; Damier, Philippe; Dartigues, Jean-François; Deloukas, Panos; Deuschl, Günther; Dexter, David T.; van Dijk, Karin D.; Dillman, Allissa; Dong, Jing; Durif, Frank; Edkins, Sarah; Escott-Price, Valentina; Evans, Jonathan R.; Foltynie, Thomas; Gao, Jianjun; Gardner, Michelle; Goate, Alison; Gray, Emma; Guerreiro, Rita; Harris, Clare; van Hilten, Jacobus J.; Hofman, Albert; Hollenbeck, Albert; Holmans, Peter; Holton, Janice; Hu, Michèle; Huang, Xuemei; Huber, Heiko; Hudson, Gavin; Hunt, Sarah E.; Huttenlocher, Johanna; Illig, Thomas; Jónsson, Pálmi V.; Kilarski, Laura L.; Jansen, Iris E.; Lambert, Jean-Charles; Langford, Cordelia; Lees, Andrew; Lichtner, Peter; Limousin, Patricia; Lopez, Grisel; Lorenz, Delia; Lubbe, Steven; Lungu, Codrin; Martinez, María; Mätzler, Walter; McNeill, Alisdair; Moorby, Catriona; Moore, Matthew; Morrison, Karen E.; Mudanohwo, Ese; O’Sullivan, Sean S.; Owen, Michael J.; Pearson, Justin; Perlmutter, Joel S.; Pétursson, Hjörvar; Plagnol, Vincent; Pollak, Pierre; Post, Bart; Potter, Simon; Ravina, Bernard; Revesz, Tamas; Riess, Olaf; Rivadeneira, Fernando; Rizzu, Patrizia; Ryten, Mina; Saad, Mohamad; Simón-Sánchez, Javier; Sawcer, Stephen; Schapira, Anthony; Scheffer, Hans; Schulte, Claudia; Sharma, Manu; Shaw, Karen; Sheerin, Una-Marie; Shoulson, Ira; Shulman, Joshua; Sidransky, Ellen; Spencer, Chris C.A.; Stefánsson, Hreinn; Stefánsson, Kári; Stockton, Joanna D.; Strange, Amy; Talbot, Kevin; Tanner, Carlie M.; Tashakkori-Ghanbaria, Avazeh; Trabzuni, Daniah; Traynor, Bryan J.; Uitterlinden, André G.; Velseboer, Daan; Walker, Robert; van de Warrenburg, Bart; Wickremaratchi, Mirdhu; Williams-Gray, Caroline H.; Winder-Rhodes, Sophie; Wurster, Isabel; Williams, Nigel; Morris, Huw R.; Heutink, Peter; Hardy, John; Wood, Nicholas W.; Gasser, Thomas; Singleton, Andrew B.; Brice, Alexis

    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 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. PMID:26942284

  18. Diagnostic exome sequencing for patients with a family history of consanguinity: over 38% of positive results are not autosomal recessive pattern.

    Science.gov (United States)

    Powis, Zöe; Farwell, Kelly D; Alamillo, Christina L; Tang, Sha

    2016-02-01

    Diagnostic exome sequencing (DES) is an effective tool for diagnosis in intractable cases where the underlying cause is thought be genetic. It is commonly assumed that patients with a family history of consanguinity will have increased detection rates for rare autosomal recessive Mendelian disorders through DES. Herein, we analyzed the diagnostic yield and relevant inheritance patterns within the DES cases with a reported consanguineous family history. Of the first 500 unselected cases referred for DES, 40 (8.0%) had a known consanguineous family history. Among the 40 cases, 13 (32.5%) received a definitive molecular diagnosis through DES and such positive rate is similar to that of families with no reported consanguinity (139/460, 30.2%, P=0.63). Although homozygous alterations likely related to consanguinity have been identified in eight positive cases, the other five (38.4%) causative mutations were unrelated to autosomal recessive inheritance. Our retrospective analysis demonstrated that individuals with known consanguinity were not more likely to have a positive DES result and a significant portion of the positive findings were not within an autosomal recessive gene. These results highlight that all applicable inheritance patterns should be considered for patients with a known family history of consanguinity.

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

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    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

  20. Mutations in SDR9C7 gene encoding an enzyme for vitamin A metabolism underlie autosomal recessive congenital ichthyosis.

    Science.gov (United States)

    Shigehara, Yohya; Okuda, Shujiro; Nemer, Georges; Chedraoui, Adele; Hayashi, Ryota; Bitar, Fadi; Nakai, Hiroyuki; Abbas, Ossama; Daou, Laetitia; Abe, Riichiro; Sleiman, Maria Bou; Kibbi, Abdul Ghani; Kurban, Mazen; Shimomura, Yutaka

    2016-10-15

    Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of hereditary skin disorder characterized by an aberrant cornification of the epidermis. ARCI is classified into a total of 11 subtypes (ARCI1-ARCI11) based on their causative genes or loci. Of these, the causative gene for only ARCI7 has not been identified, while it was previously mapped on chromosome 12p11.2-q13.1. In this study, we performed genetic analyses for three Lebanese families with ARCI, and successfully determined the linkage interval to 9.47 Mb region on chromosome 12q13.13-q14.1, which was unexpectedly outside of the ARCI7 locus. Whole-exome sequencing and the subsequent Sanger sequencing led to the identification of missense mutations in short chain dehydrogenase/reductase family 9C, member 7 (SDR9C7) gene on chromosome 12q13.3, i.e. two families shared an identical homozygous mutation c.599T > C (p.Ile200Thr) and one family had another homozygous mutation c.214C > T (p.Arg72Trp). In cultured cells, expression of both the mutant SDR9C7 proteins was markedly reduced as compared to wild-type protein, suggesting that the mutations severely affected a stability of the protein. In normal human skin, the SDR9C7 was abundantly expressed in granular and cornified layers of the epidermis. By contrast, in a patient’s skin, its expression in the cornified layer was significantly decreased. It has previously been reported that SDR9C7 is an enzyme to convert retinal into retinol. Therefore, our study not only adds a new gene responsible for ARCI, but also further suggests a potential role of vitamin A metabolism in terminal differentiation of the epidermis in humans.

  1. Homozygosity Mapping Reveals Mutations of GRXCR1 as a Cause of Autosomal-Recessive Nonsyndromic Hearing Impairment

    Science.gov (United States)

    Schraders, Margit; Lee, Kwanghyuk; Oostrik, Jaap; Huygen, Patrick L.M.; Ali, Ghazanfar; Hoefsloot, Lies H.; Veltman, Joris A.; Cremers, Frans P.M.; Basit, Sulman; Ansar, Muhammad; Cremers, Cor W.R.J.; Kunst, Henricus P.M.; Ahmad, Wasim; Admiraal, Ronald J.C.; Leal, Suzanne M.; Kremer, Hannie

    2010-01-01

    We identified overlapping homozygous regions within the DFNB25 locus in two Dutch and ten Pakistani families with sensorineural autosomal-recessive nonsyndromic hearing impairment (arNSHI). Only one of the families, W98-053, was not consanguineous, and its sibship pointed toward a reduced critical region of 0.9 Mb. This region contained the GRXCR1 gene, and the orthologous mouse gene was described to be mutated in the pirouette (pi) mutant with resulting hearing loss and circling behavior. Sequence analysis of the GRXCR1 gene in hearing-impaired family members revealed splice-site mutations in two Dutch families and a missense and nonsense mutation, respectively, in two Pakistani families. The splice-site mutations are predicted to cause frameshifts and premature stop codons. In family W98-053, this could be confirmed by cDNA analysis. GRXCR1 is predicted to contain a GRX-like domain. GRX domains are involved in reversible S-glutathionylation of proteins and thereby in the modulation of activity and/or localization of these proteins. The missense mutation is located in this domain, whereas the nonsense and splice-site mutations may result in complete or partial absence of the GRX-like domain or of the complete protein. Hearing loss in patients with GRXCR1 mutations is congenital and is moderate to profound. Progression of the hearing loss was observed in family W98-053. Vestibular dysfunction was observed in some but not all affected individuals. Quantitative analysis of GRXCR1 transcripts in fetal and adult human tissues revealed a preferential expression of the gene in fetal cochlea, which may explain the nonsyndromic nature of the hearing impairment. PMID:20137778

  2. 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.

  3. 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.

  4. 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

  5. Identification of a novel mutation in the PRCD gene causing autosomal recessive retinitis pigmentosa in a Turkish family.

    Science.gov (United States)

    Pach, Johanna; Kohl, Susanne; Gekeler, Florian; Zobor, Ditta

    2013-01-01

    Progressive rod-cone degeneration (PRCD) is a canine form of autosomal recessive photoreceptor degeneration and serves as an animal model for human retinitis pigmentosa (RP). To date, only two RP-causing mutations of the PRCD gene have been reported in humans. We found a novel mutation in PRCD (c.52C>T, p.R18X) in three siblings affected by RP and present detailed morphologic and functional parameters. A complete ophthalmological examination was performed including psychophysical tests (best-corrected visual acuity, Lanthony Panel D-15 color vision test, and visual field) and electrophysiology (ganzfeld and multifocal electroretinogram). Additionally, color and infrared fundus photography, autofluorescence, and spectral domain optical coherence tomography recordings were performed. Genomic DNA of the three affected individuals was analyzed with high-throughput sequencing for all RP-related genes in a diagnostic set-up. We identified a novel homozygous mutation in PRCD (c.52C>T, p.R18X) with diagnostic high-throughput panel sequencing. All three patients showed an advanced stage of retinitis pigmentosa with reduced visual acuity (mean: 20/80), small residual visual fields (mean for target III4e: 1134.35 deg²), and non-detectable electrophysiological responses. Myopia, posterior subcapsular cataract, bone spicule-like pigmentation, and attenuated arterioles were typical findings. Interestingly, bull's eye maculopathy due to patchy retinal pigment epithelium atrophy was also present in all patients. The mean central retinal thickness observed in optical coherence tomography was 148 µm. The identification of a third mutation in PRCD confirms its role in the pathogenesis of RP. Clinical findings were in line with the morphological changes observed in previous studies. Bull's eye maculopathy seems to be a hallmark of RP due to mutations in the PRCD gene.

  6. A new lethal sclerosing bone dysplasia

    International Nuclear Information System (INIS)

    Kingston, H.M.; Freeman, J.S.; Hall, C.M.

    1991-01-01

    A neonate is described with a lethal sclerosing bone dysplasia associated with prenatal fractures and craniofacial abnormalities including microcephaly, exophthalmos, hypoplastic nose and mid-face, small jaw and nodular hyperplasia of the gums. Parental consanguinity suggests that an autosomal recessive mutation is the likely aetiology. (orig.)

  7. Rhodopsin mutations are scarcely implicated in autosomal ...

    African Journals Online (AJOL)

    ... wide scale studies are needed to determine the genetic variations involved in RP and particularly in the autosomal recessive inheritance. KEYWORDS: Retinitis pigmentosa; Rhodopsin mutations; Autosomal recessive retinitispigmentosa; Autosomal dominant retinitis pigmentosa; Genetic counseling; Electroretinogram ...

  8. Unmasking an autosomal recessive disorder by a deletion in the DiGeorge/Velo-cardio-facial chromosome region (DGCR) in 22q11.2

    Energy Technology Data Exchange (ETDEWEB)

    Budarf, M.L.; Michaud, D.; Emanuel, B. [Children`s Hospital of Philadelphia, PA (United States)] [and others

    1994-09-01

    Unmasking an autosomal recessive disorder by constitutional hemizygosity is well documented for the embryonal tumors RB and WAGR, where the second hit is a somatic event. Few deletion-mediated recessive conditions have been reported in patients with germline mutations. The major platelet receptor for von Willebrand factor, Glycoprotein Ib (GpIb), is a complex of two plasma membrane glycoproteins, Ib{alpha} and Ib{beta}, covalently linked by disulfide bonds. Defects in this receptor have been associated with the rare congenital autosomal recessive bleeding disorder, Bernard-Soulier syndrome (BSS). BSS is characterized by prolonged bleeding times, thrombocytopenia and very large platelets. The GpIb{beta} gene has been cloned and we have mapped it within the DGCR. We have identified a patient with phenotypic features of both BSS and VCFS. The patient was referred for 22q11-deletion FISH studies because of a conventricular VSD and mild dysmorphia. FISH with the N25 DiGeorge cosmid demonstrated a deletion in 22q11.2. Western blot analysis of the patient`s platelet proteins demonstrates a complete absence of GpIb{beta}. We suggest that haploinsufficiency for the DGCR in this patient unmasks a mutation in the remaining GpIb{beta} allele, resulting in manifestations of BSS. This mechanism, haploinsufficiency coupled with a mutation of the {open_quotes}normal{close_quotes} chromosome, might explain some of the phenotypic variability seen amongst patients with 22q11.2 microdeletions. These results further suggest that patients with contiguous gene deletion syndromes are at increased risk for autosomal recessive disorders and that they provide the opportunity to {open_quotes}map{close_quotes}disease loci.

  9. 40 CFR 798.5275 - Sex-linked recessive lethal test in drosophila melanogaster.

    Science.gov (United States)

    2010-07-01

    ... homozygous or hemizygous condition. (3) Sex-Linked genes are present on the sex (X or Y) chromosomes. Sex... their brothers. In the F2 generation, each culture shall be scored for the absence of wild-type males. If a culture appears to have arisen from an F1 female carrying a lethal in the parental X-chromosome...

  10. Autosomal Recessive Inheritance

    Science.gov (United States)

    ... to sight-saving treatments and plays a key role in reducing visual impairment and blindness. NEI Home Contact Us A-Z Site Map NEI on Social Media Information in Spanish (Información en español) Website, Social ...

  11. 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.

  12. 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

  13. Analysis of dominant and recessive sex-linked lethal mutations induced by low radiation doses in genetically different strains of Drosophila melanogaster w and MS

    International Nuclear Information System (INIS)

    Aslanyan, M.M.; Kim, A.I.; Magomedova, M.A.; Fatkulbayanova, N.L.

    1994-01-01

    Frequencies of induced recessive sex-linked lethal mutations (RSLLM) and dominant lethal mutations (DLM) were analyzed in genetically different Drosophila melanogaster strains w and MS after their exposure to radiation on radioactive soil in laboratory conditions. The RSLLM test applied to males after their 14-day radiation exposure yielded controversial results. An analysis of induced and spontaneous DLM demonstrated an increase in the frequency of early embryonic lethal mutations in the experiment (radiation exposure) in comparison with the control (spontaneous mutation rate) in both strains examined

  14. 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.

  15. Targeted Next-Generation Sequencing of a 12.5 Mb Homozygous Region Reveals ANO10 Mutations in Patients with Autosomal-Recessive Cerebellar Ataxia

    Science.gov (United States)

    Vermeer, Sascha; Hoischen, Alexander; Meijer, Rowdy P.P.; Gilissen, Christian; Neveling, Kornelia; Wieskamp, Nienke; de Brouwer, Arjan; Koenig, Michel; Anheim, Mathieu; Assoum, Mirna; Drouot, Nathalie; Todorovic, Slobodanka; Milic-Rasic, Vedrana; Lochmüller, Hanns; Stevanin, Giovanni; Goizet, Cyril; David, Albert; Durr, Alexandra; Brice, Alexis; Kremer, Berry; van de Warrenburg, Bart P.C.; Schijvenaars, Mascha M.V.A.P.; Heister, Angelien; Kwint, Michael; Arts, Peer; van der Wijst, Jenny; Veltman, Joris; Kamsteeg, Erik-Jan; Scheffer, Hans; Knoers, Nine

    2010-01-01

    Autosomal-recessive cerebellar ataxias comprise a clinically and genetically heterogeneous group of neurodegenerative disorders. In contrast to their dominant counterparts, unraveling the molecular background of these ataxias has proven to be more complicated and the currently known mutations provide incomplete coverage for genotyping of patients. By combining SNP array-based linkage analysis and targeted resequencing of relevant sequences in the linkage interval with the use of next-generation sequencing technology, we identified a mutation in a gene and have shown its association with autosomal-recessive cerebellar ataxia. In a Dutch consanguineous family with three affected siblings a homozygous 12.5 Mb region on chromosome 3 was targeted by array-based sequence capture. Prioritization of all detected sequence variants led to four candidate genes, one of which contained a variant with a high base pair conservation score (phyloP score: 5.26). This variant was a leucine-to-arginine substitution in the DUF 590 domain of a 16K transmembrane protein, a putative calcium-activated chloride channel encoded by anoctamin 10 (ANO10). The analysis of ANO10 by Sanger sequencing revealed three additional mutations: a homozygous mutation (c.1150_1151del [p.Leu384fs]) in a Serbian family and a compound-heterozygous splice-site mutation (c.1476+1G>T) and a frameshift mutation (c.1604del [p.Leu535X]) in a French family. This illustrates the power of using initial homozygosity mapping with next-generation sequencing technology to identify genes involved in autosomal-recessive diseases. Moreover, identifying a putative calcium-dependent chloride channel involved in cerebellar ataxia adds another pathway to the list of pathophysiological mechanisms that may cause cerebellar ataxia. PMID:21092923

  16. 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.

  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...

  18. 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.

  19. CRTAP mutations in lethal and severe osteogenesis imperfecta: the importance of combining biochemical and molecular genetic analysis.

    NARCIS (Netherlands)

    Dijk, F.S. Van; Nesbitt, I.M.; Nikkels, P.G.J.; Dalton, A.; Bongers, E.M.H.F.; Kamp, J.M. van de; Hilhorst-Hofstee, Y.; Hollander, N.S. den; Lachmeijer, A.M.; Marcelis, C.L.M.; Tan-Sindhunata, G.M.; Rijn, R.R. van; Meijers-Heijboer, H.; Cobben, J.M.; Pals, G.

    2009-01-01

    Autosomal recessive lethal and severe osteogenesis imperfecta (OI) is caused by the deficiency of cartilage-associated protein (CRTAP) and prolyl-3-hydroxylase 1 (P3H1) because of CRTAP and LEPRE1 mutations. We analyzed five families in which 10 individuals had a clinical diagnosis of lethal and

  20. 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...

  1. Novel homozygous mutations in the EVC and EVC2 genes in two consanguineous families segregating autosomal recessive Ellis-van Creveld syndrome.

    Science.gov (United States)

    Aziz, Abdul; Raza, Syed I; Ali, Salman; Ahmad, Wasim

    2016-01-01

    Ellis-van Creveld syndrome (EVC) is a rare developmental disorder characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails, teeth, oral and cardiac abnormalities. It is caused by biallelic mutations in the EVC or EVC2 gene, separated by 2.6 kb of genomic sequence on chromosome 4p16. In the present study, we have investigated two consanguineous families of Pakistani origin, segregating EVC in autosomal recessive manner. Linkage in the families was established to chromosome 4p16. Subsequently, sequence analysis identified a novel nonsense mutation (p.Trp234*) in exon 8 of the EVC2 gene and 15 bp duplication in exon 14 of the EVC gene in the two families. This further expands the mutations in the EVC or EVC2 genes resulting in the EVC syndrome.

  2. 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...... refined the position of the disease locus (MCOP6) in an interval of 250 kb in chromosome 2q37.1 in two large Faroese families. We detected three different mutations in PRSS56. Patients of the Faroese families were either homozygous for c.926G>C (p.Trp309Ser) or compound heterozygous for c.926G>C and c.526...

  3. A Register-Based Study of Diseases With an Autosomal Recessive Origin in Small Children in Denmark According to Maternal Country of Origin

    DEFF Research Database (Denmark)

    Gundlund, Anna; Hansen, Anne Vinkel; Pedersen, Grete Skøtt

    2015-01-01

    BACKGROUND: Compared with children born of Danish mothers, the mortality of children, born and living in Denmark, is significantly increased in those with a mother from Afghanistan, Iraq, Pakistan, Somalia, and Turkey. Consanguinity has been suggested to account for part of this disparity. Since...... information on consanguinity is lacking, this suggestion is difficult to test. With an indirect approach, we addressed this question by comparing the risk of diseases with autosomal recessive inheritance in children born in Denmark of Danish-born women and of women born in these five countries, respectively...... ratios for the diseases in children of foreign-born women compared with children of Danish-born women. RESULTS: Compared with offspring of Danish-born women, the risk of a consanguinity-related disease was significantly increased in children of foreign-born women, although the absolute risk was low...

  4. 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.

  5. Autosomal recessive spastic tetraplegia caused by AP4M1 and AP4B1 gene mutation: expansion of the facial and neuroimaging features.

    Science.gov (United States)

    Tüysüz, Beyhan; Bilguvar, Kaya; Koçer, Naci; Yalçınkaya, Cengiz; Çağlayan, Okay; Gül, Ece; Sahin, Sezgin; Çomu, Sinan; Günel, Murat

    2014-07-01

    Adaptor protein complex-4 (AP4) is a component of intracellular transportation of proteins, which is thought to have a unique role in neurons. Recently, mutations affecting all four subunits of AP4 (AP4M1, AP4E1, AP4S1, and AP4B1) have been found to cause similar autosomal recessive phenotype consisting of tetraplegic cerebral palsy and intellectual disability. The aim of this study was analyzing AP4 genes in three new families with this phenotype, and discussing their clinical findings with an emphasis on neuroimaging and facial features. Using homozygosity mapping followed by whole-exome sequencing, we identified two novel homozygous mutations in AP4M1 and a homozygous deletion in AP4B1 in three pairs of siblings. Spastic tetraplegia, microcephaly, severe intellectual disability, limited speech, and stereotypic laughter were common findings in our patients. All patients also had similar facial features consisting of coarse and hypotonic face, bitemporal narrowing, bulbous nose with broad nasal ridge, and short philtrum which were not described in patients with AP4M1 and AP4B1 mutations previously. The patients presented here and previously with AP4M1, AP4B1, and AP4E1 mutations shared brain abnormalities including asymmetrical ventriculomegaly, thin splenium of the corpus callosum, and reduced white matter volume. The patients also had hippocampal globoid formation and thin hippocampus. In conclusion, disorders due to mutations in AP4 complex have similar neurological, facial, and cranial imaging findings. Thus, these four genes encoding AP4 subunits should be screened in patients with autosomal recessive spastic tetraplegic cerebral palsy, severe intellectual disability, and stereotypic laughter, especially with the described facial and cranial MRI features. © 2014 Wiley Periodicals, Inc.

  6. Does anonymous sperm donation increase the risk for unions between relatives and the incidence of autosomal recessive diseases due to consanguinity?

    Science.gov (United States)

    Serre, Jean-Louis; Leutenegger, Anne-Louise; Bernheim, Alain; Fellous, Marc; Rouen, Alexandre; Siffroi, Jean-Pierre

    2014-03-01

    In France gamete donation and notably sperm donation are anonymous. It has been claimed that anonymous artificial insemination by donor (AID) could highly contribute to an increase in the level of consanguinity and the incidence of autosomal recessive diseases, due to the unions between offspring of anonymous donors, unaware of their biological kinship, with the special case of unions between half-siblings. The actual incidence of consanguinity due to AID was compared with that resulting from the two other main sources of consanguinity and recessive diseases, i.e. voluntary unions between related individuals or inadvertent unions between the offspring of a common unknown male ancestor (false paternity). From these data, we estimated that expected unions in France between half sibs per year are 0.12 between offspring of sperm donors (1.2 every 10 years) and 0.5 between offspring of common male ancestors through false paternity (5 every 10 years). More generally, the inadvertent unions between false paternity offspring are roughly four times more frequent than those resulting from anonymous AID. We estimated that in the future, when AID has been in practice for several generations, out the 820 000 annual births in France, respectively, 6 and 25 births will be consanguineous through an unknown common ancestor related to anonymous AID and to a false paternity, both of which are negligible when compared with the 1256 children born from first-degree cousins. About 672 children per year are born with a recessive genetic disease due to the panmictic risk and additional affected cases due to consanguinity would be 34.54 for first-cousin offspring, 0.33 for offspring of individuals related due to false paternity and 0.079 for offspring of individuals related due to anonymous AID. Anonymous AID would therefore be responsible for 0.46% of consanguineous births and for 0.01% of recessive diseases. Therefore, the effect of anonymous AID on half-sibling unions, consanguinity and

  7. Confirmation of linkage and refinement of the RP28 locus for autosomal recessive retinitis pigmentosa on chromosome 2p14-p15 in an Indian family.

    Science.gov (United States)

    Kumar, Arun; Shetty, Jyoti; Kumar, Bharath; Blanton, Susan Halloran

    2004-06-15

    To report the linkage analysis of retinitis pigmentosa (RP) in an Indian family. Individuals were examined for symptoms of retinitis pigmentosa and their blood samples were withdrawn for genetic analysis. The disorder was tested for linkage to known 14 adRP and 22 arRP loci using microsatellite markers. Seventeen individuals including seven affecteds participated in the study. All affected individuals had typical RP. The age of onset of the disease ranged from 8-18 years. The disorder in this family segregated either as an autosomal recessive trait with pseudodominance or an autosomal dominant trait. Linkage to an autosomal recessive locus RP28 on chromosome 2p14-p15 was positive with a maximum two-point lod score of 3.96 at theta=0 for D2S380. All affected individuals were homozygous for alleles at D2S2320, D2S2397, D2S380, and D2S136. Recombination events placed the minimum critical region (MCR) for the RP28 gene in a 1.06 cM region between D2S2225 and D2S296. The present data confirmed linkage of arRP to the RP28 locus in a second Indian family. The RP28 locus was previously mapped to a 16 cM region between D2S1337 and D2S286 in a single Indian family. Haplotype analysis in this family has further narrowed the MCR for the RP28 locus to a 1.06 cM region between D2S2225 and D2S296. Of 15 genes reported in the MCR, 14 genes (KIAA0903, OTX1, MDH1, UGP2, VPS54, PELI1, HSPC159, FLJ20080, TRIP-Br2, SLC1A4, KIAA0582, RAB1A, ACTR2, and SPRED2) are either expressed in the eye or retina. Further study needs to be done to test which of these genes is mutated in patients with RP linked to the RP28 locus.

  8. PLEKHG5 deficiency leads to an intermediate form of autosomal-recessive Charcot–Marie–Tooth disease

    Science.gov (United States)

    Azzedine, Hamid; Zavadakova, Petra; Planté-Bordeneuve, Violaine; Vaz Pato, Maria; Pinto, Nuno; Bartesaghi, Luca; Zenker, Jennifer; Poirot, Olivier; Bernard-Marissal, Nathalie; Arnaud Gouttenoire, Estelle; Cartoni, Romain; Title, Alexandra; Venturini, Giulia; Médard, Jean-Jacques; Makowski, Edward; Schöls, Ludger; Claeys, Kristl G.; Stendel, Claudia; Roos, Andreas; Weis, Joachim; Dubourg, Odile; Leal Loureiro, José; Stevanin, Giovanni; Said, Gérard; Amato, Anthony; Baraban, Jay; LeGuern, Eric; Senderek, Jan; Rivolta, Carlo; Chrast, Roman

    2013-01-01

    Charcot–Marie–Tooth disease (CMT) comprises a clinically and genetically heterogeneous group of peripheral neuropathies characterized by progressive distal muscle weakness and atrophy, foot deformities and distal sensory loss. Following the analysis of two consanguineous families affected by a medium to late-onset recessive form of intermediate CMT, we identified overlapping regions of homozygosity on chromosome 1p36 with a combined maximum LOD score of 5.4. Molecular investigation of the genes from this region allowed identification of two homozygous mutations in PLEKHG5 that produce premature stop codons and are predicted to result in functional null alleles. Analysis of Plekhg5 in the mouse revealed that this gene is expressed in neurons and glial cells of the peripheral nervous system, and that knockout mice display reduced nerve conduction velocities that are comparable with those of affected individuals from both families. Interestingly, a homozygous PLEKHG5 missense mutation was previously reported in a recessive form of severe childhood onset lower motor neuron disease (LMND) leading to loss of the ability to walk and need for respiratory assistance. Together, these observations indicate that different mutations in PLEKHG5 lead to clinically diverse outcomes (intermediate CMT or LMND) affecting the function of neurons and glial cells. PMID:23777631

  9. The emergence of hepatic fibrosis and portal hypertension in infants and children with autosomal recessive polycystic kidney disease

    International Nuclear Information System (INIS)

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

    1988-01-01

    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. (orig.)

  10. Clinical and neuroimaging features of autosomal recessive spastic paraplegia 35 (SPG35): case reports, new mutations, and brief literature review.

    Science.gov (United States)

    Mari, Francesco; Berti, Beatrice; Romano, Alessandro; Baldacci, Jacopo; Rizzi, Riccardo; Grazia Alessandrì, M; Tessa, Alessandra; Procopio, Elena; Rubegni, Anna; Lourenḉo, Charles Marques; Simonati, Alessandro; Guerrini, Renzo; Santorelli, Filippo Maria

    2018-02-08

    Spastic paraplegia 35 (SPG35) is a recessive condition characterized by childhood onset, progressive course, complicated by dystonia, dysarthria, cognitive impairment, and epilepsy. Mutations in the FA2H gene have been described in several families, leading to the proposal of a single entity, named fatty acid hydrolase-associated neurodegeneration (FAHN). Several reports have described a polymorphic radiological picture with white matter lesions of various degrees and a distinct form of neurodegeneration with brain iron accumulation. While we reviewed the pertinent literature, we also report three new patients with SPG35, highlighting the possible absence of white matter lesions even after a long neuroimaging follow-up. Three-dimensional modeling of the mutated proteins was helpful to elucidate the role of the site of mutations and the correlation with the residual enzyme activity as determined in cultured skin fibroblasts.

  11. Genomewide clonal analysis of lethal mutations in the Drosophila melanogaster eye: comparison of the X chromosome and autosomes.

    Science.gov (United States)

    Call, Gerald B; Olson, John M; Chen, Jiong; Villarasa, Nikki; Ngo, Kathy T; Yabroff, Allison M; Cokus, Shawn; Pellegrini, Matteo; Bibikova, Elena; Bui, Chris; Cespedes, Albert; Chan, Cheryl; Chan, Stacy; Cheema, Amrita K; Chhabra, Akanksha; Chitsazzadeh, Vida; Do, Minh-Tu; Fang, Q Angela; Folick, Andrew; Goodstein, Gelsey L; Huang, Cheng R; Hung, Tony; Kim, Eunha; Kim, William; Kim, Yulee; Kohan, Emil; Kuoy, Edward; Kwak, Robert; Lee, Eric; Lee, JiEun; Lin, Henry; Liu, H-C Angela; Moroz, Tatiana; Prasad, Tharani; Prashad, Sacha L; Patananan, Alexander N; Rangel, Alma; Rosselli, Desiree; Sidhu, Sohrab; Sitz, Daniel; Taber, Chelsea E; Tan, Jingwen; Topp, Kasey; Tran, PhuongThao; Tran, Quynh-Minh; Unkovic, Mary; Wells, Maggie; Wickland, Jessica; Yackle, Kevin; Yavari, Amir; Zaretsky, Jesse M; Allen, Christopher M; Alli, Latifat; An, Ju; Anwar, Abbas; Arevalo, Sonia; Ayoub, Danny; Badal, Shawn S; Baghdanian, Armonde; Baghdanian, Arthur H; Baumann, Sara A; Becerra, Vivian N; Chan, Hei J; Chang, Aileen E; Cheng, Xibin A; Chin, Mabel; Chong, Fleurette; Crisostomo, Carlyn; Datta, Sanjit; Delosreyes, Angela; Diep, Francie; Ekanayake, Preethika; Engeln, Mark; Evers, Elizabeth; Farshidi, Farzin; Fischer, Katrina; Formanes, Arlene J; Gong, Jun; Gupta, Riju; Haas, Blake E; Hahm, Vicky; Hsieh, Michael; Hui, James Z; Iao, Mei L; Jin, Sophia D; Kim, Angela Y; Kim, Lydia S-H; King, Megan; Knudsen-Robbins, Chloe; Kohanchi, David; Kovshilovskaya, Bogdana; Ku, Amy; Kung, Raymond W; Landig, Mark E L; Latterman, Stephanie S; Lauw, Stephanie S; Lee, Daniel S; Lee, Joann S; Lei, Kai C; Leung, Lesley L; Lerner, Renata; Lin, Jian-ya; Lin, Kathleen; Lim, Bryon C; Lui, Crystal P Y; Liu, Tiffany Q; Luong, Vincent; Makshanoff, Jacob; Mei, An-Chi; Meza, Miguel; Mikhaeil, Yara A; Moarefi, Majid; Nguyen, Long H; Pai, Shekhar S; Pandya, Manish; Patel, Aadit R; Picard, Paul D; Safaee, Michael M; Salame, Carol; Sanchez, Christian; Sanchez, Nina; Seifert, Christina C; Shah, Abhishek; Shilgevorkyan, Oganes H; Singh, Inderroop; Soma, Vanessa; Song, Junia J; Srivastava, Neetika; StaAna, Jennifer L; Sun, Christie; Tan, Diane; Teruya, Alison S; Tikia, Robyn; Tran, Trinh; Travis, Emily G; Trinh, Jennifer D; Vo, Diane; Walsh, Thomas; Wong, Regan S; Wu, Katherine; Wu, Ya-Whey; Yang, Nkau X V; Yeranosian, Michael; Yu, James S; Zhou, Jennifer J; Zhu, Ran X; Abrams, Anna; Abramson, Amanda; Amado, Latiffe; Anderson, Jenny; Bashour, Keenan; Beyer, Elsa; Bookatz, Allen; Brewer, Sarah; Buu, Natalie; Calvillo, Stephanie; Cao, Joseph; Chan, Amy; Chan, Jenny; Chang, Aileen; Chang, Daniel; Chang, Yuli; Chen, YiBing; Choi, Joo; Chou, Jeyling; Dang, Peter; Datta, Sumit; Davarifar, Ardy; Deravanesian, Artemis; Desai, Poonam; Fabrikant, Jordan; Farnad, Shahbaz; Fu, Katherine; Garcia, Eddie; Garrone, Nick; Gasparyan, Srpouhi; Gayda, Phyllis; Go, Sherrylene; Goffstein, Chad; Gonzalez, Courtney; Guirguis, Mariam; Hassid, Ryan; Hermogeno, Brenda; Hong, Julie; Hong, Aria; Hovestreydt, Lindsay; Hu, Charles; Huff, Devon; Jamshidian, Farid; Jen, James; Kahen, Katrin; Kao, Linda; Kelley, Melissa; Kho, Thomas; Kim, Yein; Kim, Sarah; Kirkpatrick, Brian; Langenbacher, Adam; Laxamana, Santino; Lee, Janet; Lee, Chris; Lee, So-Youn; Lee, ToHang S; Lee, Toni; Lewis, Gemma; Lezcano, Sheila; Lin, Peter; Luu, Thanh; Luu, Julie; Marrs, Will; Marsh, Erin; Marshall, Jamie; Min, Sarah; Minasian, Tanya; Minye, Helena; Misra, Amit; Morimoto, Miles; Moshfegh, Yasaman; Murray, Jessica; Nguyen, Kha; Nguyen, Cynthia; Nodado, Ernesto; O'Donahue, Amanda; Onugha, Ndidi; Orjiakor, Nneka; Padhiar, Bhavin; Paul, Eric; Pavel-Dinu, Mara; Pavlenko, Alex; Paz, Edwin; Phaklides, Sarah; Pham, Lephong; Poulose, Preethi; Powell, Russell; Pusic, Aya; Ramola, Divi; Regalia, Kirsten; Ribbens, Meghann; Rifai, Bassel; Saakyan, Manyak; Saarikoski, Pamela; Segura, Miriam; Shadpour, Farnaz; Shemmassian, Aram; Singh, Ramnik; Singh, Vivek; Skinner, Emily; Solomin, Daniel; Soneji, Kosha; Spivey, Kristin; Stageberg, Erika; Stavchanskiy, Marina; Tekchandani, Leena; Thai, Leo; Thiyanaratnam, Jayantha; Tong, Maurine; Toor, Aneet; Tovar, Steve; Trangsrud, Kelly; Tsang, Wah-Yung; Uemura, Marc; Vollmer, Emily; Weiss, Emily; Wood, Damien; Wu, Joy; Wu, Sophia; Wu, Winston; Xu, Qing; Yamauchi, Yuki; Yarosh, Will; Yee, Laura; Yen, George; Banerjee, Utpal

    2007-10-01

    Using a large consortium of undergraduate students in an organized program at the University of California, Los Angeles (UCLA), we have undertaken a functional genomic screen in the Drosophila eye. In addition to the educational value of discovery-based learning, this article presents the first comprehensive genomewide analysis of essential genes involved in eye development. The data reveal the surprising result that the X chromosome has almost twice the frequency of essential genes involved in eye development as that found on the autosomes.

  12. Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis.

    Science.gov (United States)

    Raykova, Doroteya; Klar, Joakim; Azhar, Aysha; Khan, Tahir Naeem; Malik, Naveed Altaf; Iqbal, Muhammad; Tariq, Muhammad; Baig, Shahid Mahmood; Dahl, Niklas

    2014-01-01

    Pure hair and nail ectodermal dysplasia (PHNED) comprises a heterogeneous group of rare heritable disorders characterized by brittle hair, hypotrichosis, onychodystrophy and micronychia. Autosomal recessive (AR) PHNED has previously been associated with mutations in either KRT85 or HOXC13 on chromosome 12p11.1-q14.3. We investigated a consanguineous Pakistani family with AR PHNED linked to the keratin gene cluster on 12p11.1 but without detectable mutations in KRT85 and HOXC13. Whole exome sequencing of affected individuals revealed homozygosity for a rare c.821T>C variant (p.Phe274Ser) in the KRT74 gene that segregates AR PHNED in the family. The transition alters the highly conserved Phe274 residue in the coil 1B domain required for long-range dimerization of keratins, suggesting that the mutation compromises the stability of intermediate filaments. Immunohistochemical (IHC) analyses confirmed a strong keratin-74 expression in the nail matrix, the nail bed and the hyponychium of mouse distal digits, as well as in normal human hair follicles. Furthermore, hair follicles and epidermis of an affected family member stained negative for Keratin-74 suggesting a loss of function mechanism mediated by the Phe274Ser substitution. Our observations show for the first time that homozygosity for a KRT74 missense variant may be associated with AR PHNED. Heterozygous KRT74 mutations have previously been associated with autosomal dominant woolly hair/hypotrichosis simplex (ADWH). Thus, our findings expand the phenotypic spectrum associated with KRT74 mutations and imply that a subtype of AR PHNED is allelic with ADWH.

  13. Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis.

    Directory of Open Access Journals (Sweden)

    Doroteya Raykova

    Full Text Available Pure hair and nail ectodermal dysplasia (PHNED comprises a heterogeneous group of rare heritable disorders characterized by brittle hair, hypotrichosis, onychodystrophy and micronychia. Autosomal recessive (AR PHNED has previously been associated with mutations in either KRT85 or HOXC13 on chromosome 12p11.1-q14.3. We investigated a consanguineous Pakistani family with AR PHNED linked to the keratin gene cluster on 12p11.1 but without detectable mutations in KRT85 and HOXC13. Whole exome sequencing of affected individuals revealed homozygosity for a rare c.821T>C variant (p.Phe274Ser in the KRT74 gene that segregates AR PHNED in the family. The transition alters the highly conserved Phe274 residue in the coil 1B domain required for long-range dimerization of keratins, suggesting that the mutation compromises the stability of intermediate filaments. Immunohistochemical (IHC analyses confirmed a strong keratin-74 expression in the nail matrix, the nail bed and the hyponychium of mouse distal digits, as well as in normal human hair follicles. Furthermore, hair follicles and epidermis of an affected family member stained negative for Keratin-74 suggesting a loss of function mechanism mediated by the Phe274Ser substitution. Our observations show for the first time that homozygosity for a KRT74 missense variant may be associated with AR PHNED. Heterozygous KRT74 mutations have previously been associated with autosomal dominant woolly hair/hypotrichosis simplex (ADWH. Thus, our findings expand the phenotypic spectrum associated with KRT74 mutations and imply that a subtype of AR PHNED is allelic with ADWH.

  14. Study of radiosensitive Drosophila lines. XI. Induction of recessive sex-linked lethal mutations in females of the mutant line rad(2)201/sup G1/

    International Nuclear Information System (INIS)

    Varentsova, E.R.

    1986-01-01

    The authors have studied the frequency of occurrence of recessive sex-linked lethal mutations (RSLLM) after treatment of the females with γ-rays as a function of the dose (from 5 to 20 Gy) and oogenesis stage. They have shown that within the dose range used the oocytes of the 14th and 7th development stage are more sensitive in females of the mutant line than in those of the control. They detected significant differences in the frequency of occurrence of RSLLM between the 14th and 7th stages of development of oocytes for both Drosophila lines investigated

  15. Altered TGFβ signaling and cardiovascular manifestations in patients with autosomal recessive cutis laxa type I caused by fibulin-4 deficiency

    Science.gov (United States)

    Renard, Marjolijn; Holm, Tammy; Veith, Regan; Callewaert, Bert L; Adès, Lesley C; Baspinar, Osman; Pickart, Angela; Dasouki, Majed; Hoyer, Juliane; Rauch, Anita; Trapane, Pamela; Earing, Michael G; Coucke, Paul J; Sakai, Lynn Y; Dietz, Harry C; De Paepe, Anne M; Loeys, Bart L

    2010-01-01

    Fibulin-4 is a member of the fibulin family, a group of extracellular matrix proteins prominently expressed in medial layers of large veins and arteries. Involvement of the FBLN4 gene in cardiovascular pathology was shown in a murine model and in three patients affected with cutis laxa in association with systemic involvement. To elucidate the contribution of FBLN4 in human disease, we investigated two cohorts of patients. Direct sequencing of 17 patients with cutis laxa revealed no FBLN4 mutations. In a second group of 22 patients presenting with arterial tortuosity, stenosis and aneurysms, FBLN4 mutations were identified in three patients, two homozygous missense mutations (p.Glu126Lys and p.Ala397Thr) and compound heterozygosity for missense mutation p.Glu126Val and frameshift mutation c.577delC. Immunoblotting analysis showed a decreased amount of fibulin-4 protein in the fibroblast culture media of two patients, a finding sustained by diminished fibulin-4 in the extracellular matrix of the aortic wall on immunohistochemistry. pSmad2 and CTGF immunostaining of aortic and lung tissue revealed an increase in transforming growth factor (TGF)β signaling. This was confirmed by pSmad2 immunoblotting of fibroblast cultures. In conclusion, patients with recessive FBLN4 mutations are predominantly characterized by aortic aneurysms, arterial tortuosity and stenosis. This confirms the important role of fibulin-4 in vascular elastic fiber assembly. Furthermore, we provide the first evidence for the involvement of altered TGFβ signaling in the pathogenesis of FBLN4 mutations in humans. PMID:20389311

  16. Purkinje Cell Degeneration and Motor Coordination Deficits in a New Mouse Model of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

    Directory of Open Access Journals (Sweden)

    Man Ding

    2017-05-01

    Full Text Available Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS is an early-onset neurodegenerative disorder. In 2007, a novel locus, SAX2, which is located on chromosome 17p13 and contains 3 genes, ankyrin repeat and FYVE domain-containing 1 (ANKFY1, β-arrestin 2 (ARRB2 and kinesin family member 1C (KIF1C, was linked to ARSACS. We generated Ankfy1 heterozygous (Ankfy1/+ mice to establish an animal model and examine the pathophysiological basis of ARSACS. The transgenic mice displayed an abnormal gait with progressive motor and cerebellar nerve dysfunction that was highly reminiscent of ARSACS. These clinical features were accompanied by an early-onset and progressive loss of Purkinje cells, followed by gliosis. Additionally, the loss of Ankfy1 function resulted in an abnormal expression of neurotrophic factors (NTFs in the Ankfy1/+ mouse cerebellum. Moreover, Purkinje cells cultured from neonatal Ankfy1/+ mice exhibited a shorter dendritic length and decreased numbers of dendritic spines. Importantly, cerebellar Purkinje cells from Ankfy1/+ mice and cells transfected with a lentiviral Ankfy1 shRNA underwent apoptosis. We propose that transgenic Ankfy1/+ mice are a useful model for studying the pathogenesis of ARSACS and for exploring the molecular mechanisms involved in this neurodegenerative disease.

  17. Paris-Trousseau thrombocytopenia is phenocopied by the autosomal recessive inheritance of a DNA-binding domain mutation in FLI1.

    Science.gov (United States)

    Stevenson, William S; Rabbolini, David J; Beutler, Lucinda; Chen, Qiang; Gabrielli, Sara; Mackay, Joel P; Brighton, Timothy A; Ward, Christopher M; Morel-Kopp, Marie-Christine

    2015-10-22

    Hemizygous deletion of a variable region on chromosome 11q containing FLI1 causes an inherited platelet-related bleeding disorder in Paris-Trousseau thrombocytopenia and Jacobsen syndrome. These multisystem disorders are also characterized by heart anomalies, changes in facial structure, and intellectual disability. We have identified a consanguineous family with autosomal recessive inheritance of a bleeding disorder that mimics Paris-Trousseau thrombocytopenia but has no other features of the 11q23 deletion syndrome. Affected individuals in this family have moderate thrombocytopenia; absent collagen-induced platelet aggregation; and large, fused α-granules in 1% to 5% of circulating platelets. This phenotype was caused by a FLI1 homozygous c.970C>T-point mutation that predicts an arginine-to-tryptophan substitution in the conserved ETS DNA-binding domain of FLI1. This mutation caused a transcription defect at the promoter of known FLI1 target genes GP6, GP9, and ITGA2B, as measured by luciferase assay in HEK293 cells, and decreased the expression of these target proteins in affected members of the family as measured by Western blotting of platelet lysates. This kindred suggests abnormalities in FLI1 as causative of Paris-Trousseau thrombocytopenia and confirms the important role of FLI1 in normal platelet development. © 2015 by The American Society of Hematology.

  18. Summary of mutations underlying autosomal recessive congenital ichthyoses (ARCI) in Arabs with four novel mutations in ARCI-related genes from the United Arab Emirates.

    Science.gov (United States)

    Bastaki, Fatma; Mohamed, Madiha; Nair, Pratibha; Saif, Fatima; Mustafa, Ethar M; Bizzari, Sami; Al-Ali, Mahmoud T; Hamzeh, Abdul Rezzak

    2017-05-01

    Clinical and molecular heterogeneity is a prominent characteristic of congenital ichthyoses, with the involvement of numerous causative loci. Mutations in these loci feature in autosomal recessive congenital ichthyoses (ARCIs) quite variably, with certain genes/mutations being more frequently uncovered in particular populations. In this study, we used whole exome sequencing as well as direct Sanger sequencing to uncover four novel mutations in ARCI-related genes, which were found in families from the United Arab Emirates. In silico tools such as CADD and SIFT Indel were used to predict the functional consequences of these mutations. The here-presented mutations occurred in three genes (ALOX12B, TGM1, ABCA12), and these are a mixture of missense and indel variants with damaging functional consequences on their encoded proteins. This study presents an overview of the mutations that were found in ARCI-related genes in Arabs and discusses molecular and clinical details pertaining to the above-mentioned Emirati cases and their novel mutations with special emphasis on the resulting protein changes. © 2017 The International Society of Dermatology.

  19. Most mutations that cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16) destabilize the protein quality-control E3 ligase CHIP.

    Science.gov (United States)

    Kanack, Adam J; Newsom, Oliver J; Scaglione, Kenneth Matthew

    2018-02-23

    The accumulation of misfolded proteins promotes protein aggregation and neuronal death in many neurodegenerative diseases. To counteract misfolded protein accumulation, neurons have pathways that recognize and refold or degrade aggregation-prone proteins. One U-box-containing E3 ligase, C terminus of Hsc70-interacting protein (CHIP), plays a key role in this process, targeting misfolded proteins for proteasomal degradation. CHIP plays a protective role in mouse models of neurodegenerative disease, and in humans, mutations in CHIP cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16), a fatal neurodegenerative disease characterized by truncal and limb ataxia that results in gait instability. Here, we systematically analyzed CHIP mutations that cause SCAR16 and found that most SCAR16 mutations destabilize CHIP. This destabilization caused mutation-specific defects in CHIP activity, including increased formation of soluble oligomers, decreased interactions with chaperones, diminished substrate ubiquitination, and reduced steady-state levels in cells. Consistent with decreased CHIP stability promoting its dysfunction in SCAR16, most mutant proteins recovered activity when the assays were performed below the mutants' melting temperature. Together, our results have uncovered the molecular basis of genetic defects in CHIP function that cause SCAR16. Our insights suggest that compounds that improve the thermostability of genetic CHIP variants may be beneficial for treating patients with SCAR16. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

  20. 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.

  1. Novel Mutations and Mutation Combinations ofTMPRSS3Cause Various Phenotypes in One Chinese Family with Autosomal Recessive Hearing Impairment.

    Science.gov (United States)

    Gao, Xue; Yuan, Yong-Yi; Wang, Guo-Jian; Xu, Jin-Cao; Su, Yu; Lin, Xi; Dai, Pu

    2017-01-01

    Autosomal recessive hearing impairment with postlingual onset is rare. Exceptions are caused by mutations in the TMPRSS3 gene, which can lead to prelingual (DFNB10) as well as postlingual deafness (DFNB8). TMPRSS3 mutations can be classified as mild or severe, and the phenotype is dependent on the combination of TMPRSS3 mutations. The combination of two severe mutations leads to profound hearing impairment with a prelingual onset, whereas severe mutations in combination with milder TMPRSS3 mutations lead to a milder phenotype with postlingual onset. We characterized a Chinese family (number FH1523) with not only prelingual but also postlingual hearing impairment. Three mutations in TMPRSS3 , one novel mutation c.36delC [p.(Phe13Serfs⁎12)], and two previously reported pathogenic mutations, c.916G>A (p.Ala306Thr) and c.316C>T (p.Arg106Cys), were identified. Compound heterozygous mutations of p.(Phe13Serfs⁎12) and p.Ala306Thr manifest as prelingual, profound hearing impairment in the patient (IV: 1), whereas the combination of p.Arg106Cys and p.Ala306Thr manifests as postlingual, milder hearing impairment in the patient (II: 2, II: 3, II: 5), suggesting that p.Arg106Cys mutation has a milder effect than p.(Phe13Serfs⁎12). We concluded that different combinations of TMPRSS3 mutations led to different hearing impairment phenotypes (DFNB8/DFNB10) in this family.

  2. Quantitative magnetic resonance imaging (MRI) assessments of autosomal recessive polycystic kidney disease (ARPKD) progression and response to therapy in an animal model.

    Science.gov (United States)

    Erokwu, Bernadette O; Anderson, Christian E; Flask, Chris A; Dell, Katherine M

    2018-03-14

    Autosomal Recessive Polycystic Kidney Disease (ARPKD) is associated with significant mortality and morbidity and there are currently no disease-specific treatments available for ARPKD patients. One major limitation in establishing new therapies for ARPKD is a lack of sensitive measures of kidney disease progression. Magnetic Resonance Imaging (MRI) can provide multiple quantitative assessments of disease. We applied quantitative image analysis of high resolution (non-contrast) T2-weighted MRI techniques to study cystic kidney disease progression and response to therapy in the PCK rat model of ARPKD. Serial imaging over a 2 month period demonstrated that renal cystic burden (RCB, %)=[total cyst volume (TCV)/total kidney volume (TKV) × 100], TCV and, to a lesser extent, TKV, detected cystic kidney disease progression as well as the therapeutic effect of octreotide, a clinically-available medication shown previously to slow both kidney and liver disease progression in this model. All 3 MRI measures correlated significantly with histologic measures of renal cystic area, although the correlation of RCB and TCV was stronger than that of TKV. These preclinical MRI results provide a basis for applying these quantitative MRI techniques in clinical studies, to stage and measure progression in human ARPKD kidney disease.Pediatric Research accepted article preview online, 14 March 2018. doi:10.1038/pr.2018.24.

  3. Similar clinical, pathological, and genetic features in Chinese patients with autosomal recessive and dominant Charcot-Marie-Tooth disease type 2K.

    Science.gov (United States)

    Fu, Jun; Dai, Shixu; Lu, Yuanyuan; Wu, Rui; Wang, Zhaoxia; Yuan, Yun; Lv, He

    2017-08-01

    Mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) cause rare subtypes of Charcot-Marie-Tooth disease (CMT2K and CMT4A). CMT2K is an axonal neuropathy while CMT4A is a demyelinating type. In a series of 169 Chinese CMT patients (79 CMT1, 52 CMT2 and 38 unclassified), four unrelated patients (2.37%) were identified with GDAP1 mutations, including two with autosomal recessive CMT2K (AR-CMT2K) and two dominant CMT2K (AD-CMT2K). All patients had disease onset before 5 years of age, and presented with muscle weakness, atrophy, and mild sensory disturbance in distal limbs. Motor nerve conduction velocities of the median nerve were within normal ranges, and compound muscle action potential ranged from 1.5 to 3.8 mV. Sural nerve biopsy revealed loss of large myelinated fibers with regeneration clusters and a few onion bulbs. Electron microscopy showed mitochondrial aggregation in both axons and Schwann cells, and neurofilament accumulation in giant unmyelinated fibers. The p.H256R mutation was found in all patients with GDAP1 compound heterozygous mutations, suggesting that it might be a common mutation in Chinese patients. This study observed no difference in the disease onset, phenotype severity, electrophysiological findings, or pathological changes between AR-CMT2K and AD-CMT2K patients. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. 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...

  5. Beneficial effect of combined treatment with octreotide and pasireotide in PCK rats, an orthologous model of human autosomal recessive polycystic kidney disease.

    Directory of Open Access Journals (Sweden)

    Masanori Kugita

    Full Text Available Increased intracellular cyclic AMP (cAMP in renal tubular epithelia accelerates the progression of polycystic kidney disease (PKD. Thus, decreasing cAMP levels by an adenylyl cyclase inhibitory G protein activator is considered to be an effective approach in ameliorating PKD. In fact, pasireotide (PAS was effective in reducing disease progression in animal models of PKD. However, hyperglycemia caused by the administration of PAS is an adverse effect in its clinical use. Whereas, co-administration of octreotide (OCT with PAS did not increase serum glucose in normal rats. In the current study, we examined the efficacy of combined treatment with OCT and PAS in PCK rats, an autosomal recessive PKD model. Four-week-old PCK males were treated with the long-acting release type of OCT, PAS, or a combination of both (OCT/PAS for 12 weeks. After termination, serum and renal tissue were used for analyses. Kidney weight, kidney weight per body weight, renal cyst area, renal Ki67 expression, and serum urea nitrogen were significantly decreased either in the PAS or OCT/PAS group, compared with vehicle. Renal tissue cAMP content was significantly decreased by PAS or OCT/PAS treatment, but not OCT, compared with vehicle. As a marker of cellular mTOR signaling activity, renal phospho-S6 kinase expression was significantly decreased by OCT/PAS treatment compared with vehicle, OCT, or PAS. Serum glucose was significantly increased by PAS administration, whereas no difference was shown between vehicle and OCT/PAS, possibly because serum glucagon was decreased either by the treatment of OCT alone or co-application of OCT/PAS. In conclusion, since serum glucose levels are increased by the use of PAS, its combination with OCT may reduce the risk of hyperglycemia associated with PAS monotherapy against PKD progression.

  6. Interactions between FATP4 and ichthyin in epidermal lipid processing may provide clues to the pathogenesis of autosomal recessive congenital ichthyosis.

    Science.gov (United States)

    Li, Hao; Vahlquist, Anders; Törmä, Hans

    2013-03-01

    Autosomal recessive congenital ichthyosis (ARCI) is caused by mutations in ≥10 different genes, of which transglutaminase-1 (TGM1) predominates. A rare form is ichthyosis prematurity syndrome (IPS) caused by mutations in SLC27A4 encoding fatty acid transporter protein 4 (FATP4), believed to be an acyl-CoA synthetase activating long- and very-long-chain FA. Another ARCI is caused by mutations in NIPAL4, coding for ichthyin, which is proposed to be a magnesium transporter or a trans-membrane receptor. A possible interaction between FATP4 and ichthyin has not been studied before. To find common denominators in the pathogenesis of ARCI. FATP4 and ichthyin were analyzed by immunofluorescence and proximity ligation assay (PLA) in healthy and ARCI patient skin and in in vitro models of ARCI epidermis. Both proteins were expressed in the upper stratum granulosum of normal epidermis and PLA confirmed a close interaction between FATP4 and ichthyin. In IPS skin lacking FATP4 we found reduced ichthyin expression and this finding could be reproduced in organotypic epidermis with siRNA silenced SLC27A4. In contrast, increased FATP4 staining was found in patients with ichthyin (NIPAL4) mutations and in organotypic epidermis with silenced NIPAL4. In patients with TGM1 mutations, the expression of both FATP4 and ichthyin was increased, but the PLA signal was low probably indicating a malfunctioning protein interaction. Our study suggests that FATP4, ichthyin and TGM1 interact in lipid processing essential for maintaining the epidermal barrier function. It is also hypothesized that ichthyin serves as Mg(2+)-transporter for FATP4 in this process. Copyright © 2012 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

  7. 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.

  8. Autosomal recessive non-syndromic hearing loss is caused by novel compound heterozygous mutations in TMC1 from a Tibetan Chinese family.

    Science.gov (United States)

    Lin, Fangzhu; Li, Dejun; Wang, Ping; Fan, Dongyan; De, Ji; Zhu, Wei

    2014-12-01

    Hearing loss is the most common sensory disorder worldwide. Biallelic mutations in 42 different genes have been identified as associated with autosomal recessive non-syndromic hearing loss (ARNSHL). One of the common genes responsible for ARNSHL is TMC1. TMC1 mutations have been reported to cause non-syndromic hearing loss in a variety of populations. The current study is designed to investigate mutations prevalent among Chinese ethnic groups with ARNSHL. Targeted exome sequencing (TES) was employed to study the genetic causes of two siblings with ARNSHL in a Tibetan Chinese family. Variants identified by TES were further confirmed by Sanger sequencing. We identified two distinct variants in the TMC1 gene in two deaf siblings of one Tibetan Chinese family using TES. Both siblings inherited a paternal allele containing a deletion of c.1396_1398AAC (p.Asn466del) and a maternal allele containing an insertion of c.2210_2211insCT (p.Glu737HisfsX2). The former disrupts a highly conserved residue in the large intracellular loop domain adjacent to the fourth transmembrane domain, and the latter causes a truncation of a portion of the C-terminal domain. These variants were compound heterzygous and segregated with the hearing impairment in this family. The novel compound heterozygous mutant alleles of TMC1 identified in this study were responsible for the ARNSHL in this Tibetan Chinese family. Although compound heterozygous mutations in TMC1 occurring in different TMC1 domains have been previously described in Han Chinese; this result suggests that the TMC1 variants contributing to hereditary deafness in Chinese populations may be more complex than initially assumed and that sequence-based diagnostics will be required for a comprehensive evaluation of ARNSHL. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  9. An Empirical Biomarker-Based Calculator for Cystic Index in a Model of Autosomal Recessive Polycystic Kidney Disease-The Nieto-Narayan Formula.

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    Jake A Nieto

    Full Text Available Autosomal recessive polycystic kidney disease (ARPKD is associated with progressive enlargement of the kidneys fuelled by the formation and expansion of fluid-filled cysts. The disease is congenital and children that do not succumb to it during the neonatal period will, by age 10 years, more often than not, require nephrectomy+renal replacement therapy for management of both pain and renal insufficiency. Since increasing cystic index (CI; percent of kidney occupied by cysts drives both renal expansion and organ dysfunction, management of these patients, including decisions such as elective nephrectomy and prioritization on the transplant waitlist, could clearly benefit from serial determination of CI. So also, clinical trials in ARPKD evaluating the efficacy of novel drug candidates could benefit from serial determination of CI. Although ultrasound is currently the imaging modality of choice for diagnosis of ARPKD, its utilization for assessing disease progression is highly limited. Magnetic resonance imaging or computed tomography, although more reliable for determination of CI, are expensive, time-consuming and somewhat impractical in the pediatric population. Using a well-established mammalian model of ARPKD, we undertook a big data-like analysis of minimally- or non-invasive blood and urine biomarkers of renal injury/dysfunction to derive a family of equations for estimating CI. We then applied a signal averaging protocol to distill these equations to a single empirical formula for calculation of CI. Such a formula will eventually find use in identifying and monitoring patients at high risk for progressing to end-stage renal disease and aid in the conduct of clinical trials.

  10. The distribution of and complementation relationships between spontaneous X-linked recessive lethal mutations recovered from crossing long-term laboratory stocks of Drosophila melanogaster

    International Nuclear Information System (INIS)

    Schalet, A.P.

    1986-01-01

    Drosophila melanogaster males from a wild-type laboratory stock, were mated with virgin females of the M-6 stock, and 149 spontaneous independent non-mosaically transmitted, as well as 8 incidentally detected, mosaically transmitted, X-linked recessive lethal mutations were recovered from 95 704 F 2 cultures. 152 mutations were mapped over the entire length of the X-chromosome by complementation and/or crossover tests. Although there were far too few spontaneous mutations to make a meaningful comparison of relative mutability on a locus-by-locus basis, those loci displaying a relatively higher X-ray mutability, when taken as a group, tend to display a relatively higher spontaneous mutability, and those loci displaying a relatively lower X-ray mutability, when taken as a group, tend to display a relatively lower spontaneous mutability. (Auth.)

  11. Lethal/severe osteogenesis imperfecta in a large family: a novel homozygous LEPRE1 mutation and bone histological findings

    NARCIS (Netherlands)

    van Dijk, Fleur S.; Nikkels, Peter G. J.; den Hollander, Nicolette S.; Nesbitt, Isabel M.; van Rijn, Rick R.; Cobben, Jan M.; Pals, Gerard

    2011-01-01

    We report a large consanguineous Turkish family in which multiple individuals are affected with autosomal recessive lethal or severe osteogenesis imperfecta (OI) due to a novel homozygous LEPRE1 mutation. In one affected individual histological studies of bone tissue were performed, which may

  12. 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.

  13. 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

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    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

  14. Analysis of recessive sex-linked lethal mutations in genetically different strains of Drosophila melanogaster ms and w irradiated in the five-kilometer zone of the Chernobyl meltdown

    International Nuclear Information System (INIS)

    Aslanyan, M.M.; Kim, A.I.; Magomedova, M.A.; Fatkulbayanova, N.L.

    1994-01-01

    The frequency of induced and spontaneous recessive sex-linked lethal mutations (RSLLM) in Drosophila melanogaster strains w and ms was estimated after their chronic irradiation in the five-kilometer zone of the Chernobyl' meltdown. The mutagenic effect of relatively low radiation doses was analyzed. In an experiment conducted in 1990, a significant increase in the RSLLM frequency was recorded, while, in 1991, no significant difference between the experiment and control was found

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

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    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

  16. Mutations in SLC33A1 cause a lethal autosomal-recessive disorder with congenital cataracts, hearing loss, and low serum copper and ceruloplasmin

    DEFF Research Database (Denmark)

    Huppke, Peter; Brendel, Cornelia; Kalscheuer, Vera

    2012-01-01

    of the protein. We also showed that AT-1 knockdown in HepG2 cells leads to reduced ceruloplasmin secretion, indicating that the low copper in serum is due to reduced ceruloplasmin levels and is not a sign of copper deficiency. The severity of the phenotype implies an essential role of AT-1 in proper...... or compound heterozygous mutations for all affected subjects in SLC33A1 encoding a highly conserved acetylCoA transporter (AT-1) required for acetylation of multiple gangliosides and glycoproteins. The mutations were found to cause reduced or absent AT-1 expression and abnormal intracellular localization......, hearing loss, and severe developmental delay. Cerebral MRI showed pronounced cerebellar hypoplasia and hypomyelination. Homozygosity mapping was performed and displayed a region of commonality among three families at chromosome 3q25. Deep sequencing and conventional sequencing disclosed homozygous...

  17. Microcefalia primária autossômica recessiva em três famílias pernambucanas: aspectos clínicos e moleculares Autosomal recessive primary microcephaly in three families from Pernambuco: clinical and molecular aspects

    Directory of Open Access Journals (Sweden)

    Gabriela F. Leal

    2005-06-01

    Full Text Available OBJETIVOS: descrever os aspectos clínicos de três famílias pernambucanas com microcefalia primária autossômica recessiva e as análises de ligação em uma delas (família 2. MÉTODOS: três famílias consangüíneas pernambucanas, não relacionadas biologicamente, com microcefalia primária, foram estudadas. Os heredogramas e a história clínica dos afetados foram construídos com base em informações obtidas de seus pais e outros parentes. O exame físico foi realizado em todos os afetados, seus genitores e na quase totalidade dos irmãos normais dos afetados. O DNA genômico dos afetados da família 2 e de seus pais foi usado em reações de PCR (polimerase chain reaction com primers elaborados para amplificar marcadores microssatélites ligados aos locos já conhecidos de microcefalia primária autossômica recessiva. Os marcadores amplificados foram submetidos a eletroforese e seus alelos analisados. RESULTADOS: nas três famílias, os afetados apresentavam perímetro cefálico muito reduzido acompanhado de retardo mental e apenas uma paciente (da família 3 manifestava outras alterações neurológicas, mas sem dismorfias associadas. Estudos moleculares demonstraram que a microcefalia, na família 2, não apresentava ligação com nenhum dos locos associados à microcefalia primária autossômica recessiva já conhecidos. CONCLUSÕES: pelo menos mais um gene associado à microcefalia primária autossômica recessiva existe e aguarda identificação.OBJECTIVES: to describe the clinical findings in three families from Pernambuco with autosomal recessive primary microcephaly, and the linkage analysis in one of them (family 2. METHODS: three consanguineous families from Pernambuco, not related one to another and with primary microcephaly, were studied. The genealogical data and the clinical history of the affected individuals were obtained from their parents and other family members. All the affected subjects, almost all their normal

  18. 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.

  19. Case Report: Novel mutations in TBC1D24 are associated with autosomal dominant tonic-clonic and myoclonic epilepsy and recessive Parkinsonism, psychosis, and intellectual disability [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Erika Banuelos

    2017-04-01

    Full Text Available Mutations disrupting presynaptic protein TBC1D24 are associated with a variable neurological phenotype, including DOORS syndrome, myoclonic epilepsy, early-infantile epileptic encephalopathy, and non-syndromic hearing loss. In this report, we describe a family segregating autosomal dominant epilepsy, and a 37-year-old Caucasian female with a severe neurological phenotype including epilepsy, Parkinsonism, psychosis, visual and auditory hallucinations, gait ataxia and intellectual disability. Whole exome sequencing revealed two missense mutations in the TBC1D24 gene segregating within this family (c.1078C>T; p.Arg360Cys and c.404C>T; p.Pro135Leu. The female proband who presents with a severe neurological phenotype carries both of these mutations in a compound heterozygous state. The p.Pro135Leu variant, however, is present in the proband’s mother and sibling as well, and is consistent with an autosomal dominant pattern linked to tonic-clonic and myoclonic epilepsy. In conclusion, we describe a single family in which TBC1D24 mutations cause expanded dominant and recessive phenotypes. In addition, we discuss and highlight that some variants in TBC1D24 might cause a dominant susceptibility to epilepsy

  20. Meckel-Gruber syndrome: A rare and lethal anomaly with review of literature

    Science.gov (United States)

    Parelkar, Sandesh V.; Kapadnis, Satish P.; Sanghvi, Beejal V.; Joshi, Prashant B.; Mundada, Dinesh; Oak, Sanjay N.

    2013-01-01

    Meckel-Gruber syndrome is a rare autosomal recessive lethal malformation characterized by typical manifestations of occipital encephalocele, bilateral polycystic kidneys and post axial polydactyly. The worldwide incidence varies from 1 in 13,250 to 1 in 140,000 live births. Highest incidence was reported in Gujarati Indians. We report a rare case of Meckel-Gruber syndrome and review of literature. PMID:24082939

  1. 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.

  2. KCNQ1 mutations associated with Jervell and Lange-Nielsen syndrome and autosomal recessive Romano-Ward syndrome in India-expanding the spectrum of long QT syndrome type 1.

    Science.gov (United States)

    Vyas, Bijal; Puri, Ratna D; Namboodiri, Narayanan; Nair, Mohan; Sharma, Deepak; Movva, Sireesha; Saxena, Renu; Bohora, Shomu; Aggarwal, Neeraj; Vora, Amit; Kumar, Jatinder; Singh, Tarandeep; Verma, Ishwar C

    2016-06-01

    Long QT syndrome type 1 (LQT1) is the most common type of all Long QT syndromes (LQTS) and occurs due to mutations in KCNQ1. Biallelic mutations with deafness is called Jervell and Lange-Nielsen syndrome (JLNS) and without deafness is autosomal recessive Romano-Ward syndrome (AR RWS). In this prospective study, we report biallelic mutations in KCNQ1 in Indian patients with LQT1 syndrome. Forty patients with a clinical diagnosis of LQT1 syndrome were referred for molecular testing. Of these, 18 were excluded from the analysis as they did not fulfill the inclusion criteria of broad T wave ECG pattern of the study. Direct sequencing of KCNQ1 was performed in 22 unrelated probands, parents and at-risk family members. Mutations were identified in 17 patients, of which seven had heterozygous mutations and were excluded in this analysis. Biallelic mutations were identified in 10 patients. Five of 10 patients did not have deafness and were categorized as AR RWS, the rest being JLNS. Eight mutations identified in this study have not been reported in the literature and predicted to be pathogenic by in silico analysis. We hypothesize that the homozygous biallelic mutations identified in 67% of families was due to endogamous marriages in the absence of consanguinity. This study presents biallelic gene mutations in KCNQ1 in Asian Indian patients with AR JLNS and RWS. It adds to the scant worldwide literature of mutation studies in AR RWS. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  3. A founder mutation in LEPRE1 carried by 1.5% of West Africans and 0.4% of African Americans causes lethal recessive osteogenesis imperfecta.

    Science.gov (United States)

    Cabral, Wayne A; Barnes, Aileen M; Adeyemo, Adebowale; Cushing, Kelly; Chitayat, David; Porter, Forbes D; Panny, Susan R; Gulamali-Majid, Fizza; Tishkoff, Sarah A; Rebbeck, Timothy R; Gueye, Serigne M; Bailey-Wilson, Joan E; Brody, Lawrence C; Rotimi, Charles N; Marini, Joan C

    2012-05-01

    Deficiency of prolyl 3-hydroxylase 1, encoded by LEPRE1, causes recessive osteogenesis imperfecta (OI). We previously identified a LEPRE1 mutation exclusively in African Americans and contemporary West Africans. We hypothesized that this allele originated in West Africa and was introduced to the Americas with the Atlantic slave trade. We aimed to determine the frequency of carriers for this mutation among African Americans and West Africans, and the mutation origin and age. Genomic DNA was screened for the mutation using PCR and restriction digestion, and a custom TaqMan genomic single-nucleotide polymorphism assay. The mutation age was estimated using microsatellites and short tandem repeats spanning 4.2 Mb surrounding LEPRE1 in probands and carriers. Approximately 0.4% (95% confidence interval: 0.22-0.68%) of Mid-Atlantic African Americans carry this mutation, estimating recessive OI in 1/260,000 births in this population. In Nigeria and Ghana, 1.48% (95% confidence interval: 0.95-2.30%) of unrelated individuals are heterozygous carriers, predicting that 1/18,260 births will be affected with recessive OI, equal to the incidence of de novo dominant OI. The mutation was not detected in Africans from surrounding countries. All carriers shared a haplotype of 63-770 Kb, consistent with a single founder for this mutation. Using linkage disequilibrium analysis, the mutation was estimated to have originated between 650 and 900 years before present (1100-1350 CE). We identified a West African founder mutation for recessive OI in LEPRE1. Nearly 1.5% of Ghanians and Nigerians are carriers. The estimated age of this allele is consistent with introduction to North America via the Atlantic slave trade (1501-1867 CE).

  4. 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.

  5. Manifestation of x-radiation induced sex-linked recessive lethal mutation impairing the development of imaginal disks and gonads in Drosophila Melanogaster

    International Nuclear Information System (INIS)

    Abeleva, Eh.A.; Ivanov, A.I.

    1982-01-01

    A study was made of Drosophila melanogaster mutations impairing the development of imaginal disks. The state of gonads in these mutants was not studied. Using X-radiation a lethal mutation in X chromosome was obtained that induced degeneration of imaginal disks at the 3d stage of larva development. The gonads of the mutants at this stage of development vary in size. The transplantation tests showed that the mutation manifests itself in both the imaginal disks and the gonads

  6. Autosomal Recessive Myotonia Congenita, A Muscle ...

    African Journals Online (AJOL)

    Background: The muscle diseases are frequently encountered in medical clinics in Nigeria. In many cases however they are not optimally managed. The ion channel diseases, 'channelopathies', are a group of muscle disorders that share a lot of clinical similarity. Misdiagnosis can occur especially in resource poor settings ...

  7. Genetics Home Reference: autosomal recessive congenital methemoglobinemia

    Science.gov (United States)

    ... cell types. Each hemoglobin molecule contains four iron atoms, which are needed to carry oxygen. In normal ... direct-to-consumer genetic testing? What is precision medicine? What is newborn screening? New Pages Obstructive sleep ...

  8. Genetics Home Reference: autosomal recessive hypotrichosis

    Science.gov (United States)

    ... color than expected and is fragile and easily broken. Affected individuals often cannot grow hair longer than ... leading to woolly, fragile hair that is easily broken. A lack of these proteins in the epidermis ...

  9. Aspectos clínicos da doença renal policística autossômica recessiva DRPAR Clinical aspects of autosomal recessive polycystic kidney disease

    Directory of Open Access Journals (Sweden)

    Natasha Favoretto Dias

    2010-09-01

    Full Text Available INTRODUÇÃO: A Doença Renal Policística Autossômica Recessiva (DRPAR é uma causa importante de morbidade e mortalidade pediátricas, com um espectro variável de manifestações clínicas. MÉTODOS: A apresentação e evolução clínica de 25 pacientes (Pts foram analisadas através da revisão de prontuários, aplicando-se os formulários propostos por Guay-Woodford et al. As morbidades associadas à doença foram avaliadas quanto à frequência e à idade de manifestação. RESULTADOS: A idade média de diagnóstico foi de 61,45 meses (0 a 336,5 meses, com distribuição similar entre os sexos (52% dos pts do sexo feminino. Houve histórico familiar da doença em 20% dos casos (5/25, com dois casos de consanguinidade. Na análise inicial, diagnosticou-se hipertensão arterial (HAS em 56% dos Pts (14/25; doença renal crônica estágio > 2 (DRC > 2 em 24% (6/25; infecções do trato urinário (ITU em 40% (10/25 e hipertensão portal (HP em 32% dos casos (8/25. Das ultrassonografias abdominais iniciais, 80% demonstraram rins ecogênicos com cistos grosseiros e 64% detectaram fígado e vias biliares normais. Inibidores da ECA foram utilizados em 36% dos Pts, betabloqueadores em 20%, bloqueadores de canais de cálcio em 28% e diuréticos em 36% dos casos. Na análise final, após um tempo de acompanhamento médio de 152,2 meses (29,8 a 274,9 meses, HAS foi diagnosticada em 76% dos Pts, DRC > 2 em 44%, ITU em 52% e HP em 68%. CONCLUSÃO: As altas morbidade e mortalidade associadas à DRPAR justificam a construção de um banco de dados internacional, visando ao estabelecimento de um tratamento de suporte precoce.INTRODUCTION: Autosomal Recessive Polycystic Kidney Disease (ARPKD is an important pediatric cause of morbidity and mortality, with a variable clinical spectrum. METHODS: The clinical presentation and evolution of 25 patients (Pts were analyzed by clinical record review, according to the forms proposed by Guay-Woodford et al

  10. 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.

  11. 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.

  12. Non lethal Raine syndrome and differential diagnosis.

    Science.gov (United States)

    Elalaoui, Siham Chafai; Al-Sheqaih, Nada; Ratbi, Ilham; Urquhart, Jill E; O'Sullivan, James; Bhaskar, Sanjeev; Williams, Simon S; Elalloussi, Mustapha; Lyahyai, Jaber; Sbihi, Leila; Cherkaoui Jaouad, Imane; Sbihi, Abdelhafid; Newman, William G; Sefiani, Abdelaziz

    2016-11-01

    Raine syndrome is a rare autosomal recessive bone dysplasia characterized by characteristic facial features with exophthalmos and generalized osteosclerosis. Amelogenesis imperfecta, hearing loss, seizures, and intracerebral calcification are apparent in some affected individuals. Originally, Raine syndrome was originally reported as a lethal syndrome. However, recently a milder phenotype, compatible with life, has been described. Biallelic variants inFAM20C, encoding aGolgi casein kinase involved in biomineralisation, have been identified in affected individuals. We report here a consanguineous Moroccan family with two affected siblingsa girl aged 18 and a boy of 15years. Clinical features, including learning disability, seizures and amelogenesis imperfecta, initially suggested a diagnosis of Kohlschutter-Tonz syndrome. However,a novel homozygous FAM20Cvariantc.676T > A, p.(Trp226Arg) was identified in the affected siblings. Our report reinforces that Raine syndrome is compatible with life, and that mild hypophosphatemia and amelogenesis imperfecta are key features of the attenuated form. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  13. A Novel non-sense Mutation in Keratin 10 Causes a Familial Case of Recessive Epidermolytic Ichthyosis.

    Science.gov (United States)

    Gutierrez, Jeydith A; Hannoush, Zeina C; Vargas, Luis G; Momany, Allison; Garcia, Carmen C; Murray, Jeffrey C; Dunnwald, Martine

    2013-07-01

    Epidermolytic ichthyosis (EI) is a rare skin disorder characterized by generalized erythroderma and cutaneous blistering at birth, which is substituted by hyperkeratosis later in life. It is caused by autosomal dominant mutations in highly conserved regions of KRT1 and KRT10 . To date, only 4 mutations with autosomal recessive inheritance of EI have been described in consanguineous families. All of them affect the 2B domain of KRT10 . In the present study we describe four patients with EI (including one lethal case) born from unaffected parents in a consanguineous family of a native Venezuelan community. The objective of this study was to characterize the clinical, genetic and morphological aspects of the disease in this family, as well as understand its functional implications. Genomic DNA was sequenced for KRT10 and KRT1. Immunofluoresence for keratin expression was performed on cutaneous biopsies. After examination of cutaneous biopsies histology, our results showed hyperkeratosis and acantholysis with an expanded granular layer. Sequencing of KRT10 demonstrated a non-sense mutation (p.Tyr282Ter.) corresponding to the 1B domain of the protein in patients and a heterozygous pattern in other family members, resulting in complete absence of K10. The loss of K10 was compensated by upregulation of K14 and K17. In conclusion, this novel mutation in KRT10 is the first recessive genetic variation that is not located in the so called "hot spot" for recessive EI, suggesting that other areas of the gene are also susceptible for such mutations.

  14. Inactivation of Pink1 gene in vivo sensitizes dopamine-producing neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and can be rescued by autosomal recessive Parkinson disease genes, Parkin or DJ-1.

    Science.gov (United States)

    Haque, M Emdadul; Mount, Matthew P; Safarpour, Farzaneh; Abdel-Messih, Elizabeth; Callaghan, Steve; Mazerolle, Chantal; Kitada, Tohru; Slack, Ruth S; Wallace, Valerie; Shen, Jie; Anisman, Hymie; Park, David S

    2012-06-29

    Mutations in the mitochondrial PTEN-induced kinase 1 (Pink1) gene have been linked to Parkinson disease (PD). Recent reports including our own indicated that ectopic Pink1 expression is protective against toxic insult in vitro, suggesting a potential role for endogenous Pink1 in mediating survival. However, the role of endogenous Pink1 in survival, particularly in vivo, is unclear. To address this critical question, we examined whether down-regulation of Pink1 affects dopaminergic neuron loss following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the adult mouse. Two model systems were utilized: virally delivered shRNA-mediated knockdown of Pink1 and germ line-deficient mice. In both instances, loss of Pink1 generated significant sensitivity to damage induced by systemic MPTP treatment. This sensitivity was associated with greater loss of dopaminergic neurons in the Substantia Nigra pars compacta and terminal dopamine fiber density in the striatum region. Importantly, we also show that viral mediated expression of two other recessive PD-linked familial genes, DJ-1 and Parkin, can protect dopaminergic neurons even in the absence of Pink1. This evidence not only provides strong evidence for the role of endogenous Pink1 in neuronal survival, but also supports a role of DJ-1 and Parkin acting parallel or downstream of endogenous Pink1 to mediate survival in a mammalian in vivo context.

  15. Genetic analysis of the proximal region of chromosome 2 of Drosophila melanogaster. I. Detachment products of compound autosomes

    International Nuclear Information System (INIS)

    Hilliker, A.J.; Holm, D.G.

    1975-01-01

    To examine the genetic composition of proximal heterochromatin in chromosome 2, the detachment of compound second autosomes, for generating proximal deficiencies, appeared a promising method. Compound seconds were detached by gamma radiation. A fraction of the detachment products were recessive lethals owing to proximal deficiencies. Analysis by inter se complementation, pseudo-dominance tests with proximal mutations and allelism tests with known deficiencies provided evidence for at least two loci between the centromere and the light locus in 2L and one locus in 2R between the rolled locus and the centromere. The data further demonstrate that rolled, and probably light, are located within the proximal heterochromatin. Thus, functional genetic loci are found in heterochromatin, albeit at low density

  16. A novel nonsense mutation in keratin 10 causes a familial case of recessive epidermolytic ichthyosis

    Science.gov (United States)

    Gutierrez, Jeydith A; Hannoush, Zeina C; Vargas, Luis G; Momany, Allison; Garcia, Carmen C; Murray, Jeffrey C; Dunnwald, Martine

    2013-01-01

    Epidermolytic ichthyosis (EI) is a rare skin disorder characterized by generalized erythroderma and cutaneous blistering at birth, which is substituted by hyperkeratosis later in life. It is caused by autosomal dominant mutations in highly conserved regions of KRT1 and KRT10. To date, only four mutations with autosomal recessive inheritance of EI have been described in consanguineous families. All of them affect the 2B domain of KRT10. In the present study, we describe four patients with EI (including one lethal case) born from unaffected parents in a consanguineous family of a native Venezuelan community. The objective of this study was to characterize the clinical, genetic, and morphological aspects of the disease in this family, as well as understand its functional implications. Genomic DNA was sequenced for KRT10 and KRT1. Immunofluoresence for keratin expression was performed on cutaneous biopsies. After examination of cutaneous biopsies histology, our results showed hyperkeratosis and acantholysis with an expanded granular layer. Sequencing of KRT10 demonstrated a nonsense mutation (p.Tyr282Ter.) corresponding to the 1B domain of the protein in patients and a heterozygous pattern in other family members, resulting in complete absence of K10. The loss of K10 was compensated by upregulation of K14 and K17. In conclusion, this novel mutation in KRT10 is the first recessive genetic variation that is not located in the so called “hot spot” for recessive EI, suggesting that other areas of the gene are also susceptible for such mutations. PMID:23957016

  17. 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

  18. Autosomal Dominant Polycystic Kidney Disease

    Science.gov (United States)

    ... RePORT NIH Fact Sheets Home > Autosomal Dominant Polycystic Kidney Disease Small Text Medium Text Large Text Autosomal Dominant Polycystic Kidney Disease YESTERDAY Autosomal Dominant Polycystic Kidney Disease (ADPKD) resulted ...

  19. Lethal Epistaxis.

    Science.gov (United States)

    Byard, Roger W

    2016-09-01

    Epistaxis or nosebleed refers to bleeding from the nostrils, nasal cavity, or nasopharynx. Occasional cases may present with torrential lethal hemorrhage. Three cases are reported to demonstrate particular features: Case 1: A 51-year-old woman with lethal epistaxis with no obvious bleeding source; Case 2: A 77-year-old man with treated nasopharyngeal carcinoma who died from epistaxis arising from a markedly neovascularized tumor bed; Case 3: A 2-year-old boy with hemophilia B who died from epistaxis with airway obstruction in addition to gastrointestinal bleeding. Epistaxis may be associated with trauma, tumors, vascular malformations, bleeding diatheses, infections, pregnancy, endometriosis, and a variety of different drugs. Careful dissection of the nasal cavity is required to locate the site of hemorrhage and to identify any predisposing conditions. This may be guided by postmortem computerized tomographic angiography (PCTA). Despite careful dissection, however, a source of bleeding may never be identified. © 2016 American Academy of Forensic Sciences.

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

    African Journals Online (AJOL)

    Ichthyosis is a genetically and phenotypically heterogeneous disease that can be isolated and restricted to the skin manifestations or associated with extracutaneous symptoms. One of which is limb reduction defect known as CHILD syndrome; a rare inborn error of metabolism of cholesterol biosynthesis that is usually ...

  1. 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 ...

  2. 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 ...

  3. Elsahy-Waters Syndrome: Evidence for Autosomal Recessive Inheritance

    NARCIS (Netherlands)

    Castori, Marco; Cascone, Piero; Valiante, Michele; Laino, Luigi; Iannetti, Giorgio; Hennekam, Raoul C. M.; Grammatico, Paola

    2010-01-01

    Elsahy-Waters or branchioskeletogenital syndrome is a rare MCA/MR syndrome characterized by moderate mental retardation, hypospadias and characteristic craniofacial morphology, which includes brachycephaly, facial asymmetry, exotropia, hypertelorism/telechantus, broad nose, concave nasal ridge,

  4. A new variant of autosomal recessive exfoliative ichthyosis.

    Science.gov (United States)

    Zvulunov, A; Cagnano, E; Kachko, L; Shorer, Z; Elbedour, K; Stevens, H

    2002-01-01

    We report unusual congenital ichthyosiform dermatosis in 5 of 12 children in two related families of unaffected, consanguineous Bedouin parents. It appeared shortly after birth as a fine peeling of nonerythematous skin on palms and soles. Gradually it evolved into prominent, well-demarcated areas of peeling skin in moist and traumatized regions. The cutaneous manifestations share features of ichthyosis bullosa of Siemens (IBS) and peeling skin syndrome (PSS). Histologic examination revealed orthokeratosis, a thickened granular cell layer, and spongiosis without epidermolytic hyperkeratosis. On electron microscopy there was prominent intercellular edema and numerous aggregates of keratin filaments in basal keratinocytes. This combination of clinical, histologic, and ultrastructural features has not been previously reported in the heterogeneous group of congenital ichthyoses. We suggest that it represents a new variant of exfoliative ichthyosis.

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

    Indian Academy of Sciences (India)

    of Iran's Ministry of Health and Medical Education, writ- ten consent forms were obtained from participants. Physical examination of the affected individuals suggested a nonsyn- dromic HL pattern; no thyroid, ocular or cardiac symptoms were observed. Pure tone audiometry with air and bone con- duction was completed at ...

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

    Indian Academy of Sciences (India)

    Social Welfare and Rehabilitation Sciences, for genetic diag- nosis. According to the guidelines of the Ethic Committee .... (b) Pure tone air and bone conduction audiograms from left (blue) and right (red) ears of an affected individual in each family. (c) Sequence chromatographs of the mutated part of the ILDR1 gene in ...

  7. 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 ...

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

    Science.gov (United States)

    ... Blindness (Canada) ClinicalTrials.gov (1 link) ClinicalTrials.gov Scientific Articles on PubMed (1 link) PubMed OMIM (6 links) ... SN, Husnain T, Jiao X, MacDonald IM, Riazuddin S, Sieving PA, Katsanis N, Hejtmancik JF. ... article on PubMed Central Zeitz C, Jacobson SG, Hamel ...

  9. Completeness of catalogs of autosomal dominant, autosomal recessive, and X-linked phenotypes.

    Science.gov (United States)

    ten Kate, L P

    1992-06-01

    The completeness of McKusick's catalogs of Mendelian Inheritance in Man (MIM) as to the number of phenotypes included was studied by estimating the degree of concordance with the Dutch Gene Catalog of the Department of Medical Genetics of the University of Groningen, The Netherlands. On a total of 355 Mendelian phenotypes described in persons living in The Netherlands or originating from this country, there were nine disease entities which were not present in MIM. As judged from this comparison MIM attains 97.5% completeness (95% CI: 95.3-98.7%). Similar comparisons with data from other countries are needed before a final conclusion can be reached. Corresponding contributors in different countries or linguistic areas might further improve MIM's completeness.

  10. COMPLETENESS OF CATALOGS OF AUTOSOMAL DOMINANT, AUTOSOMAL RECESSIVE, AND X-LINKED PHENOTYPES

    NARCIS (Netherlands)

    TENKATE, LP

    1992-01-01

    The completeness of McKusick's catalogs of Mendelian Inheritance in Man (MIM) as to the number of phenotypes included was studied by estimating the degree of concordance with the Dutch Gene Catalog of the Department of Medical Genetics of the University of Groningen, The Netherlands. On a total of

  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 i...... in excess of both the classical recession predictors and the common factors. The strong importance of the sentiment variables is documented both in-sample and out-of-sample....

  13. Autosomal dominant polycystisk nyresygdom

    DEFF Research Database (Denmark)

    Naver, Signe Vinsand; Ørskov, Bjarne; Jensen, Anja Møller

    2017-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder which causes end stage renal disease. In Denmark, estimated 5,000 patients are living with the disease. Most of the patients are in regular contact with physicians due to the progression of kidney failure...

  14. Autosomal dominant cramping disease.

    Science.gov (United States)

    Ricker, K; Moxley, R T

    1990-07-01

    A family was studied in which four generations (16 of 41 members) suffered from painful recurrent muscle cramping. A clear pattern of autosomal dominant inheritance was noted. The cramping first developed during adolescence or early adulthood. Electromyographic analysis indicated a neurogenic origin. The cramps seemed to be due to dysfunction of the motor neurons. The mechanisms underlying this alteration are unclear and require further investigation.

  15. 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

  16. A novel homozygous variant in SERPINH1 associated with a severe, lethal presentation of osteogenesis imperfecta with hydranencephaly.

    Science.gov (United States)

    Marshall, Charlotte; Lopez, Jaime; Crookes, Laura; Pollitt, Rebecca C; Balasubramanian, Meena

    2016-12-20

    Osteogenesis imperfecta (OI) is a genetic disorder characterised by low bone mineral density resulting in fractures. 85-90% of patients with OI carry a variant in the type 1 collagen genes, COL1A1 and COL1A2, which follows an autosomal dominant pattern of inheritance. However, within the last two decades, there have been growing number of variants identified in genes that follow an autosomal recessive pattern of inheritance. Our proband is a child born in Mexico with multiple fractures of ribs, minimal calvarial mineralisation, platyspondyly, marked compression and deformed long bones. He also presented with significant hydranencephaly, requiring ventilatory support from birth, and died at 8days of age. A homozygous c.338_357delins22 variant in exon 2 of SERPINH1 was identified. This gene encodes heat shock protein 47, a collagen-specific chaperone which binds to the procollagen triple helix and is responsible for collagen stabilisation in the endoplasmic reticulum. There is minimal literature on the mechanism of action for variants in SERPINH1 resulting in osteogenesis imperfecta. Here we discuss this rare, previously unreported variant, and expand on the phenotypic presentation of this novel variant resulting in a severe, lethal phenotype of OI in association with hydranencephaly. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Defects of intergenomic communication: autosomal disorders that cause multiple deletions and depletion of mitochondrial DNA.

    Science.gov (United States)

    Hirano, M; Marti, R; Ferreiro-Barros, C; Vilà, M R; Tadesse, S; Nishigaki, Y; Nishino, I; Vu, T H

    2001-12-01

    Depletion and multiple deletions of mitochondrial DNA (mtDNA) have been associated with a growing number of autosomal diseases that have been classified as defects of intergenomic communication. MNGIE, an autosomal recessive disorder associated with mtDNA alterations is due to mutations in thymidine phosphorylase that may cause imbalance of the mitochondrial nucleotide pool. Subsequently, mutations in the mitochondrial proteins adenine nucleotide translocator 1, Twinkle, and polymerase gamma have been found to cause autosomal dominant progressive external ophthalmoplegia with multiple deletions of mtDNA. Uncovering the molecular bases of intergenomic communication defects will enhance our understanding of the mechanisms responsible for maintaining mtDNA integrity. Copyright 2001 Academic Press.

  18. More Recess Time, Please!

    Science.gov (United States)

    Chang, Rong; Coward, Fanni Liu

    2015-01-01

    Students in Shanghai, China, get much more recess time than their U.S. counterparts throughout their education. As U.S. education reform efforts seek ways of raising achievement, they have begun replacing recess with academic time. The lesson from Shanghai is that this may not be the best strategy. But whether the Shanghai system of more and…

  19. Starving for Recess

    Science.gov (United States)

    Patt, Mary Johnson

    2011-01-01

    Every weekday, millions of American schoolchildren throw away their half-eaten cafeteria lunches so that they can run outside to play. The traditional placement of lunch before recess, coupled with the recent decline in overall recess time to meet academic time constraints, forces children to choose between two essential needs: (1) food; and (2)…

  20. An autosomal locus causing autoimmune disease: Autoimmune polyglandular disease type I assigned to chromosome 21

    NARCIS (Netherlands)

    J. Aaltonen (Johanna); P. Björses (Petra); L.A. Sandkuijl (Lodewijk); J. Perheentupa (Jaakko); L. Peltonen (Leena Johanna)

    1994-01-01

    textabstractAutoimmune polyglandular disease type I (APECED) is an autosomal recessive autoimmune disease characterized by a variable combination of the failure of the endocrine glands. The pathogenesis of this unique autoimmune disease is unknown; unlike many other autoimmune diseases, APECED does

  1. X-linked lethal infantile spinal muscular atrophy: From clinical description to molecular mapping

    Energy Technology Data Exchange (ETDEWEB)

    Baumbach, L.; Schiavi, A. [Univ. of Miami, FL (United States)] [and others

    1994-09-01

    The proximal spinal muscular atrophies (PSMA), one of the most common forms of lower motor neuron disease in children, are characterized by progressive muscle weakness due to loss of anterior horn cells. All three autosomal recessive forms have been mapped to chromosome 5q11.2-11.3, implying an allelic association between these disorders. Recent evidence from our laboratories, as well as others, suggests that a distinct form of lethal neonatal spinal muscular atrophy, associated with early onset contractures, is determined by a gene on the X chromosome. We report our efforts in mapping this disease locus. Our original studies have focused on two unrelated multigenerational families with similar clinical presentations of severe hypotonia, muscle weakness, and a disease course similar to Werdnig Hoffman except for the additional finding of congenital or early onset contractures. Muscle biopsy and/or autopsy were indicative of anterior horn cell loss in affected males. Disease occurrence in each of the families was consistent with an X-linked recessive mode of inheritance. Subsequently, two additional families have been identified, as well as several sporadic male cases. Linkage analysis has been completed in one of these families using highly polymorphic repeats dispersed 10 cM on the X chromosome. Interpretation of results was achieved using an automated data acquisition program. Analysis of over 300 haplotypes generated using PCR-based DNA markers have identified two 16 cM regions on Xp with complete concordance to the disease phenotype. Our currents efforts are focused on the region surrounding the Kallman gene, in attempts to better define a candidate region, as well as analyze possible candidate genes within this region.

  2. Suppression of F1 Male-Specific Lethality in Caenorhabditis Hybrids by cbr-him-8

    Directory of Open Access Journals (Sweden)

    Vaishnavi Ragavapuram

    2016-03-01

    Full Text Available Haldane’s Rule and Darwin’s Corollary to Haldane’s Rule are the observations that heterogametic F1 hybrids are frequently less fit than their homogametic siblings, and that asymmetric results are often obtained from reciprocal hybrid crosses. In Caenorhabditis, Haldane’s Rule and Darwin’s Corollary have been observed in several hybrid crosses, including crosses of Caenorhabditis briggsae and C. nigoni. Fertile F1 females are obtained from reciprocal crosses. However, F1 males obtained from C. nigoni mothers are sterile and F1 males obtained from C. briggsae die during embryogenesis. We have identified cbr-him-8 as a recessive maternal-effect suppressor of F1 hybrid male-specific lethality in this combination of species. This result implicates epigenetic meiotic silencing in the suppression of F1 male-specific lethality. It is also shown that F1 males bearing a C. briggsae X chromosome are fertile. When crossed to C. briggsae hermaphrodites or F1 females derived from C. briggsae hermaphrodites, viable F2 and backcross (B2 progeny were obtained. Sibling males that possessed a C. nigoni X chromosome were sterile. Therefore, the sterility of F1 males bearing a C. nigoni X chromosome must result from dysgenic interactions between the X chromosome of C. nigoni and the autosomes of C. briggsae. The fertility of F1 males bearing a C. briggsae X chromosome provides an opportunity to identify C. nigoni loci that prevent spermatogenesis, and hence hermaphroditic reproduction, in diplo-X hybrids.

  3. Adeno-Associated Virus Serotype 8 Gene Transfer Rescues a Neonatal Lethal Murine Model of Propionic Acidemia

    Science.gov (United States)

    Chandler, Randy J.; Chandrasekaran, Suma; Carrillo-Carrasco, Nuria; Senac, Julien S.; Hofherr, Sean E.; Barry, Michael A.

    2011-01-01

    Abstract Propionic acidemia (PA) is an autosomal recessive disorder of metabolism caused by a deficiency of propionyl-coenzyme A carboxylase (PCC). Despite optimal dietary and cofactor therapy, PA patients still suffer from lethal metabolic instability and experience multisystemic complications. A murine model of PA (Pcca–/–) of animals that uniformly die within the first 48 hr of life was used to determine the efficacy of adeno-associated viral (AAV) gene transfer as a potential therapy for PA. An AAV serotype 8 (AAV8) vector was engineered to express the human PCCA cDNA and delivered to newborn mice via an intrahepatic injection. Greater than 64% of the Pcca–/– mice were rescued after AAV8-mediated gene transfer and survived until day of life 16 or beyond. Western analysis of liver extracts showed that PCC was completely absent from Pcca–/– mice but was restored to greater than wild-type levels after AAV gene therapy. The treated Pcca–/– mice also exhibited markedly reduced plasma levels of 2-methylcitrate compared with the untreated Pcca–/– mice, which indicates significant PCC enzymatic activity was provided by gene transfer. At the time of this report, the oldest treated Pcca–/– mice are over 6 months of age. In summary, AAV gene delivery of PCCA effectively rescues Pcca–/– mice from neonatal lethality and substantially ameliorates metabolic markers of the disease. These experiments demonstrate a gene transfer approach using AAV8 that might be used as a treatment for PA, a devastating and often lethal disorder desperately in need of new therapeutic options. PMID:20950151

  4. Towards a male-only release system for SIT with the Queensland fruit fly, Bactrocera tryoni, using a genetic sexing strain with a temperature-sensitive lethal mutation.

    Science.gov (United States)

    Meats, A; Maheswaran, P; Frommer, M; Sved, J

    2002-09-01

    Flies that are homozygous for the recessive autosomal mutation bent wings have a limited ability to fly and are less tolerant of high temperatures than normal flies in both the egg and puparial stages. The differences between the mutant and normal flies were found sufficient to be the basis of a genetic sexing strain. Genetic sexing strains were created using translocations of the autosome bearing the wild-type allele of bent wings (chromosome 2) to the Y chromosome, and crossing male flies carrying the translocation to mutant bent wings females. In the resulting strain, the females were homozygous for the bent wings mutation and the males were phenotypically normal for wing characters. Several translocations were recovered after irradiation, but only one translocation involving chromosome 2 was both stable and expressed in a stock that was vigorous enough for long-term viability. Unfortunately, all stocks containing the translocation showed high levels of temperature-dependent lethality, including, inexplicably, both males and females. Translocation stocks showing this effect included bent wings, another second chromosome mutation, white marks, and an otherwise normal stock. This phenomenon is probably rare, as it has not been reported before. It is likely that bent wings could be suitably used with another translocation.

  5. Bank profitability during recessions

    NARCIS (Netherlands)

    Bolt, Wilko; de Haan, Leo; Hoeberichts, Marco; van Oordt, Maarten R C; Swank, Job

    This paper contributes to the literature on the relation between bank profitability and economic activity. When allowing for stronger co-movement of bank profit with economic activity during deep recessions, we find a much larger impact of output growth on bank profitability than commonly found in

  6. The Recess Renaissance

    Science.gov (United States)

    Keeler, Rusty

    2015-01-01

    The author tells of his work around the country and world on transforming how schools do recess, free play, and outside time by transforming their outdoor spaces to match. Instead of a playground of fixed structures like traditional school grounds, newer spaces are filled with loose materials that children can use to build forts, dens, and tree…

  7. 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...

  8. 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.

  9. 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.

  10. Exclusion of the RET proto-oncogene as candidate for total colonic aganglionsis in the spotting lethal (sl) rat strain

    Energy Technology Data Exchange (ETDEWEB)

    Ceccherini, I.; Matera, I.; Devoto, M. [Istituto G. Gaslini, Genova (Italy)] [and others

    1994-09-01

    Causative germline mutations and deletions of the RET proto-oncogene have been demonstrated in a number of Hirschsprung disease (HSCR) patients showing either short- or long-segment intestinal aganglionosis, including both sporadic and familial cases with an autosomal dominant mode of inheritance. The spotting lethal (sl) rats show autosomal recessive recurrence of total colonic aganglionosis which resembles the long-segment HSCR type in humans with 100% mortality of the homozygotes at 4-5 weeks of age. Heterozygotes were backcrossed with DA rats and the F2 offspring was used to test the possible cosegregation of the aganglionosis and the RET proto-oncogene. A genomic DNA fragment of the rat RET gene was amplified using degenerated oligonucleotides, subcloned and sequenced. The coding portion of this DNA fragment (300bp) shares 93% and 81% of its amino acids with the murine and human RET proto-oncogene, respectively. An A{yields}G transition in the third nucleotide of the alanine codon corresponding to amino acid Glu90 of the human RET gene was identified in the sl but not in the wild type DA strain. This mutation creates a Bsp 1286I restriction site. Restriction analysis performed on 57 affected rats (mutated homozygotes) of the F2 generation revealed independent segregation between the rat colonic aganglionosis gene and RET, thus allowing the exclusion of the latter proto-oncogene as candidate for the mutation present in the sl rat strain. Several different candidate rat chromosomal regions are being analyzed in order to proceed with the mapping of the genetic defect in the sl rats.

  11. A strategy for generation and balancing of autosome: Y chromosome translocations.

    Science.gov (United States)

    Joshi, Sonal S; Cheong, Han; Meller, Victoria H

    2014-01-01

    We describe a method for generation and maintenance of translocations that move large autosomal segments onto the Y chromosome. Using this strategy we produced ( 2;Y) translocations that relocate between 1.5 and 4.8 Mb of the 2nd chromosome.. All translocations were easily balanced over a male-specific lethal 1 (msl-1) mutant chromosome. Both halves of the translocation carry visible markers, as well as P-element ends that enable molecular confirmation. Halves of these translocations can be separated to produce offspring with duplications and with lethal second chromosome deficiencies . Such large deficiencies are otherwise tedious to generate and maintain.

  12. A novel syndrome of lethal familial hyperekplexia associated with brain malformation

    Directory of Open Access Journals (Sweden)

    Seidahmed Mohammed

    2012-10-01

    Full Text Available Abstract Background Hyperekplexia (HPX is a rare non-epileptic disorder manifesting immediately after birth with exaggerated persistent startle reaction to unexpected auditory, somatosensory and visual stimuli, and non-habituating generalized flexor spasm in response to tapping of the nasal bridge (glabellar tap which forms its clinical hallmark. The course of the disease is usually benign with spontaneous amelioration with age. The disorder results from aberrant glycinergic neurotransmission, and several mutations were reported in the genes encoding glycine receptor (GlyR α1 and β subunits, glycine transporter GlyT2 as well as two other proteins involved in glycinergic neurotransmission gephyrin and collybistin. Methods The phenotype of six newborns, belonging to Saudi Arabian kindred with close consanguineous marriages, who presented with hyperekplexia associated with severe brain malformation, is described. DNA samples were available from two patients, and homozygosity scan to determine overlap with known hyperkplexia genes was performed. Results The kindred consisted of two brothers married to their cousin sisters, each with three affected children who presented antenatally with excessive fetal movements. Postnatally, they were found to have microcephaly, severe hyperekplexia and gross brain malformation characterized by severe simplified gyral pattern and cerebellar underdevelopment. The EEG was normal and they responded to clonazepam. All of the six patients died within six weeks. Laboratory investigations, including metabolic screen, were unremarkable. None of the known hyperkplexia genes were present within the overlapping regions of homozygosity between the two patients for whom DNA samples were available. Conclusions We present these cases as a novel syndrome of lethal familial autosomal recessive hyperekplexia associated with microcephaly and severe brain malformation.

  13. 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.)

  14. 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.

  15. Recessive epidermolytic ichthyosis results from loss of keratin 10 expression, regardless of the mutation location.

    Science.gov (United States)

    Vodo, D; Sarig, O; Peled, A; Samuelov, L; Malchin, N; Grafi-Cohen, M; Sprecher, E

    2018-03-01

    Epidermolytic ichthyosis (EI) is a rare skin disorder caused by mutations in the genes KRT1 and KRT10, and is usually inherited in an autosomal dominant fashion. Only five recessive mutations causing EI have been described, all of which are located in the central region of the KRT10 gene. In the current study, we aimed to identify the genetic defect underlying EI in a 12-year-old patient. Direct sequencing of the patient's genomic DNA revealed a novel homozygous nonsense mutation residing within the proximal part KRT10 first exon. The mutation was found to co-segregate with the disease phenotype in an autosomal recessive fashion. Using real-time quantitative PCR, we found an almost two-fold decrease in KRT10 expression in the patient's skin compared with the skin of healthy controls. Western blot analysis showed complete absence of keratin 10 protein in the patient's skin, suggesting early protein degradation. © 2017 British Association of Dermatologists.

  16. 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.

  17. Crises and the recent recession

    OpenAIRE

    Tatom, John

    2010-01-01

    The United States economy has suffered over the past four years from crises in mortgage foreclosures and in financial markets, as well as a long recession that some have referred to as the Great Recession. The links between these events, or more broadly the causes, extent and effects of these developments, are sources of continuing controversy and uncertainty. This paper attempts to disentangle the links between the mortgage foreclosure crisis, the financial crisis, a possible banking crisis ...

  18. 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 ...

  19. 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

  20. Disruption of NBS1 gene leads to early embryonic lethality in homozygous null mice and induces specific cancer in heterozygous mice

    Energy Technology Data Exchange (ETDEWEB)

    Kurimasa, Akihiro; Burma, Sandeep; Henrie, Melinda; Ouyang, Honghai; Osaki, Mitsuhiko; Ito, Hisao; Nagasawa, Hatsumi; Little, John B.; Oshimura, Mitsuo; Li, Gloria C.; Chen, David J.

    2002-04-15

    Nijmegen breakage syndrome (NBS) is a rare autosomal recessive chromosome instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition, with cellular features similar to that of ataxia telangiectasia (AT). NBS results from mutations in the mammalian gene Nbs1 that codes for a 95-kDa protein called nibrin, NBS1, or p95. To establish an animal model for NBS, we attempted to generate NBS1 knockout mice. However, NBS1 gene knockouts were lethal at an early embryonic stage. NBS1 homozygous(-/-) blastocyst cells cultured in vitro showed retarded growth and subsequently underwent growth arrest within 5 days of culture. Apoptosis, assayed by TUNEL staining, was observed in NBSI homozygous(-/-) blastocyst cells cultured for four days. NBSI heterozygous(+/-) mice were normal, and exhibited no specific phenotype for at least one year. However, fibroblast cells from NBSI heterozygous(+/-) mice displayed an enhanced frequency of spontaneous transformation to anchorage-independent growth as compared to NBS1 wild-type(+/+) cells. Furthermore, heterozygous(+/-) mice exhibited a high incidence of hepatocellular carcinoma after one year compared to wild-type mice, even though no significant differences in the incidence of other tumors such as lung adenocarcinoma and lymphoma were observed. Taken together, these results strongly suggest that NBS1 heterozygosity and reduced NBSI expression induces formation of specific tumors in mice.

  1. Homozygosity for a Missense Mutation in SERPINH1, which Encodes the Collagen Chaperone Protein HSP47, Results in Severe Recessive Osteogenesis Imperfecta

    OpenAIRE

    Christiansen, Helena E.; Schwarze, Ulrike; Pyott, Shawna M.; AlSwaid, Abdulrahman; Al Balwi, Mohammed; Alrasheed, Shatha; Pepin, Melanie G.; Weis, Mary Ann; Eyre, David R.; Byers, Peter H.

    2010-01-01

    Osteogenesis imperfecta (OI) is characterized by bone fragility and fractures that may be accompanied by bone deformity, dentinogenesis imperfecta, short stature, and shortened life span. About 90% of individuals with OI have dominant mutations in the type I collagen genes COL1A1 and COL1A2. Recessive forms of OI resulting from mutations in collagen-modifying enzymes and chaperones CRTAP, LEPRE1, PPIB, and FKBP10 have recently been identified. We have identified an autosomal-recessive missens...

  2. Deletion of exon 20 of the Familial Dysautonomia gene Ikbkap in mice causes developmental delay, cardiovascular defects, and early embryonic lethality.

    Directory of Open Access Journals (Sweden)

    Paula Dietrich

    Full Text Available Familial Dysautonomia (FD is an autosomal recessive disorder that affects 1/3,600 live births in the Ashkenazi Jewish population, and leads to death before the age of 40. The disease is characterized by abnormal development and progressive degeneration of the sensory and autonomic nervous system. A single base pair substitution in intron 20 of the Ikbkap gene accounts for 98% of FD cases, and results in the expression of low levels of the full-length mRNA with simultaneous expression of an aberrantly spliced mRNA in which exon 20 is missing. To date, there is no animal model for the disease, and the essential cellular functions of IKAP--the protein encoded by Ikbkap--remain unknown. To better understand the normal function of IKAP and in an effort to generate a mouse model for FD, we have targeted the mouse Ikbkap gene by homologous recombination. We created two distinct alleles that result in either loss of Ikbkap expression, or expression of an mRNA lacking only exon 20. Homozygosity for either mutation leads to developmental delay, cardiovascular and brain malformations, accompanied with early embryonic lethality. Our analyses indicate that IKAP is essential for expression of specific genes involved in cardiac morphogenesis, and that cardiac failure is the likely cause of abnormal vascular development and embryonic lethality. Our results also indicate that deletion of exon 20 abolishes gene function. This implies that the truncated IKAP protein expressed in FD patients does not retain any significant biological function.

  3. 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...

  4. Exome sequencing identifies truncating mutations in human SERPINF1 in autosomal-recessive osteogenesis imperfecta

    NARCIS (Netherlands)

    Becker, J.; Semler, O.; Gilissen, C.F.H.A.; Li, Y.; Bolz, H.J.; Giunta, C.; Bergmann, C.; Rohrbach, M.; Koerber, F.; Zimmermann, K.; Vries, P.F. de; Wirth, B.; Schoenau, E.; Wollnik, B.; Veltman, J.A.; Hoischen, A.; Netzer, C.

    2011-01-01

    Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder characterized by bone fragility and susceptibility to fractures after minimal trauma. After mutations in all known OI genes had been excluded by Sanger sequencing, we applied next-generation sequencing to analyze the exome of a single

  5. Exome sequencing identifies truncating mutations in human SERPINF1 in autosomal-recessive osteogenesis imperfecta.

    Science.gov (United States)

    Becker, Jutta; Semler, Oliver; Gilissen, Christian; Li, Yun; Bolz, Hanno Jörn; Giunta, Cecilia; Bergmann, Carsten; Rohrbach, Marianne; Koerber, Friederike; Zimmermann, Katharina; de Vries, Petra; Wirth, Brunhilde; Schoenau, Eckhard; Wollnik, Bernd; Veltman, Joris A; Hoischen, Alexander; Netzer, Christian

    2011-03-11

    Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder characterized by bone fragility and susceptibility to fractures after minimal trauma. After mutations in all known OI genes had been excluded by Sanger sequencing, we applied next-generation sequencing to analyze the exome of a single individual who has a severe form of the disease and whose parents are second cousins. A total of 26,922 variations from the human reference genome sequence were subjected to several filtering steps. In addition, we extracted the genotypes of all dbSNP130-annotated SNPs from the exome sequencing data and used these 299,494 genotypes as markers for the genome-wide identification of homozygous regions. A single homozygous truncating mutation, affecting SERPINF1 on chromosome 17p13.3, that was embedded into a homozygous stretch of 2.99 Mb remained. The mutation was also homozygous in the affected brother of the index patient. Subsequently, we identified homozygosity for two different truncating SERPINF1 mutations in two unrelated patients with OI and parental consanguinity. All four individuals with SERPINF1 mutations have severe OI. Fractures of long bones and severe vertebral compression fractures with resulting deformities were observed as early as the first year of life in these individuals. Collagen analyses with cultured dermal fibroblasts displayed no evidence for impaired collagen folding, posttranslational modification, or secretion. SERPINF1 encodes pigment epithelium-derived factor (PEDF), a secreted glycoprotein of the serpin superfamily. PEDF is a multifunctional protein and one of the strongest inhibitors of angiogenesis currently known in humans. Our data provide genetic evidence for PEDF involvement in human bone homeostasis. Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  6. Exome Sequencing Identifies Truncating Mutations in Human SERPINF1 in Autosomal-Recessive Osteogenesis Imperfecta

    OpenAIRE

    Becker, Jutta; Semler, Oliver; Gilissen, Christian; Li, Yun; Bolz, Hanno Jörn; Giunta, Cecilia; Bergmann, Carsten; Rohrbach, Marianne; Koerber, Friederike; Zimmermann, Katharina; de Vries, Petra; Wirth, Brunhilde; Schoenau, Eckhard; Wollnik, Bernd; Veltman, Joris A.

    2011-01-01

    Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder characterized by bone fragility and susceptibility to fractures after minimal trauma. After mutations in all known OI genes had been excluded by Sanger sequencing, we applied next-generation sequencing to analyze the exome of a single individual who has a severe form of the disease and whose parents are second cousins. A total of 26,922 variations from the human reference genome sequence were subjected to several filtering steps...

  7. Autosomal recessive ichthyosis with limb reduction defect: A simple association and not CHILD syndrome

    Directory of Open Access Journals (Sweden)

    Rabah M. Shawky

    2016-07-01

    Full Text Available Ichthyosis is a genetically and phenotypically heterogeneous disease that can be isolated and restricted to the skin manifestations or associated with extracutaneous symptoms. One of which is limb reduction defect known as CHILD syndrome; a rare inborn error of metabolism of cholesterol biosynthesis that is usually restricted to one side of the body. Here we describe an Egyptian child with generalized lamellar ichthyosis and limb reduction defect. Most probably this is a simple association and not a rare case of CHILD syndrome with bilateral skin involvement.

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

    Science.gov (United States)

    ... the first signs of the disorder. About half of affected individuals have a stroke or similar episode before age 40. As the disease progresses, most people with CARASIL also develop mood and personality changes, a decline in thinking ability (dementia), memory ...

  9. Autosomal recessive truncating MAB21L1 mutation associated with a syndromic scrotal agenesis.

    Science.gov (United States)

    Bruel, A-L; Masurel-Paulet, A; Rivière, J-B; Duffourd, Y; Lehalle, D; Bensignor, C; Huet, F; Borgnon, J; Roucher, F; Kuentz, P; Deleuze, J-F; Thauvin-Robinet, C; Faivre, L; Thevenon, J

    2017-02-01

    We report on a boy with a rare malformative association of scrotum agenesis, ophthalmological anomalies, cerebellar malformation, facial dysmorphism and global development delay. The reported patient was carrying a homozygous frameshift in MAB21L1 detected by whole-exome sequencing, considered as the most likely disease-causing variant. Mab21l1 knockout mice present a strikingly similar malformative association of ophthalmological malformations of the anterior chamber and preputial glands hypoplasia. We hypothesize that MAB21L1 haploinsufficiency cause a previously undescribed syndrome with scrotal agenesis, ophthalmological anomalies, facial dysmorphism and gross psychomotor delay as remarkable hallmarks. Four cases from the literature were reported with features suggestive of a similar and recognizable clinical entity. We hypothesize that MAB21L1 should be the culprit gene in these patients. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. Vici Syndrome: A Rare Autosomal Recessive Syndrome with Brain Anomalies, Cardiomyopathy, and Severe Intellectual Disability

    Directory of Open Access Journals (Sweden)

    R. Curtis Rogers

    2011-01-01

    Full Text Available Purpose. The objective of this study was to present and describe two additional patients diagnosed with Vici syndrome. Methods. Clinical, laboratory, and imaging findings of the two siblings are discussed in detail. The two patients' descriptions are compared with the other eleven patients reported in the literature. We also presented detailed autopsy results on the male sibling, which demonstrated cytoplasmic vacuoles of the cardiomyocytes and confirmed the clinical findings. Results. The patients reported here include the 13th and 14th patients reported with Vici syndrome. The summary of findings present in these patients includes postnatal growth retardation, developmental delay, bilateral cataracts, agenesis of the corpus callosum, cerebellar anomalies, gyral abnormalities, seizures, hypotonia, and cardiomyopathy. Conclusion. Vici syndrome should be suspected in any child with agenesis of the corpus callosum and one of the following findings: cardiomyopathy, cataracts, immune deficiency, or cutaneous hypopigmentation.

  11. Polymicrogyria and myoclonic epilepsy in autosomal recessive cutis laxa type 2A.

    Science.gov (United States)

    Cohen, Rony; Halevy, Ayelet; Aharoni, Sharon; Kraus, Dror; Konen, Osnat; Basel-Vanagaite, Lina; Goldberg-Stern, Hadassa; Straussberg, Rachel

    2016-10-01

    Cutis laxa syndromes are rare inherited disorders of skin and connective tissue metabolism associated with variable systemic involvement. The main clinical manifestation is loose, wrinkled, redundant, inelastic skin, hypotonia, typical facies including short nose and down-slanting palpebral fissures, and varying degrees of developmental delay. The aim of this report is to describe two siblings diagnosed with a moderate form of ATP6V0A2-related cutis laxa with polymicrogyria (cobblestone-like brain dysgenesis). One of the patients has myoclonic epilepsy which may have contributed to his more severe clinical presentation. The literature on cutis laxa syndromes is reviewed.

  12. 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

    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. (C) 2014 Wiley Periodicals, Inc....

  13. Autosomal recessive mental retardation syndrome with anterior maxillary protrusion and strabismus: MRAMS syndrome

    NARCIS (Netherlands)

    Basel-Vanagaite, Lina; Rainshtein, Limor; Inbar, Dov; Gothelf, Doron; Hennekam, Raoul; Straussberg, Rachel

    2007-01-01

    We report on a family in whom the combination of mental retardation (MR), anterior maxillary protrusion, and strabismus segregates. The healthy, consanguineous parents (first cousins) of Israeli-Arab descent had 11 children, 7 of whom (5 girls) were affected. They all had severe MR. Six of the seven

  14. 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.

  15. Libyan Boy with Autosomal Recessive Trait (P 22-phox Defect) of ...

    African Journals Online (AJOL)

    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 ...

  16. 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.

  17. Genetics Home Reference: autosomal recessive spastic ataxia of Charlevoix-Saguenay

    Science.gov (United States)

    ... 12 months and 18 months, as toddlers are learning to walk. The signs and symptoms worsen over ... links) Health Topic: Degenerative Nerve Diseases Health Topic: Movement Disorders Health Topic: Neurologic Diseases Genetic and Rare Diseases ...

  18. 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

  19. 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.)

  20. 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

  1. 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

  2. PTRHD1 (C2orf79) mutations lead to autosomal-recessive intellectual disability and parkinsonism.

    Science.gov (United States)

    Khodadadi, Hamidreza; Azcona, Luis J; Aghamollaii, Vajiheh; Omrani, Mir Davood; Garshasbi, Masoud; Taghavi, Shaghayegh; Tafakhori, Abbas; Shahidi, Gholam Ali; Jamshidi, Javad; Darvish, Hossein; Paisán-Ruiz, Coro

    2017-02-01

    Atypical parkinsonism is a neurodegenerative disease that includes diverse neurological and psychiatric manifestations. We aimed to identify the disease-cauisng mutations in a consanguineous family featuring intellectual disability and parkinsonism. Full phenotypic characterization, followed by genome-wide single-nucleotide polymorphism genotyping and whole-genome sequencing, was carried out in all available family members. The chromosome, 2p23.3, was identified as the disease-associated locus, and a homozygous PTRHD1 mutation (c.157C>T) was then established as the disease-causing mutation. The pathogenicity of this PTRHD1 mutation was supported by its segregation with the disease status, its location in a functional domain of the encoding protein, as well as its absence in public databases and ethnicity-matched control chromosomes. Given the role of 2p23 locus in patients with intellectual disability and the previously reported PTRHD1 mutation (c.155G>A) in patients with parkinsonism and cognitive dysfunction, we concluded that the PTRHD1 mutation identified in this study is likely to be responsible for the phenotypic features of the family under consideration. © 2016 International Parkinson and Movement Disorder Society. © 2016 International Parkinson and Movement Disorder Society.

  3. 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

    3-methylglutaconic aciduria (3-MGA-uria) is a nonspecific finding associated with mitochondrial dysfunction, including defects of oxidative phosphorylation. 3-MGA-uria is classified into five groups, of which one, type IV, is genetically heterogeneous. Here we report five children with a form...... 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...

  4. Craniofacial anomalies, humero-radial synostosis, rhizomelic limb shortness: previously unrecognized autosomal recessive syndrome.

    Science.gov (United States)

    Al-Hassnan, Zuhair N; Teebi, Ahmad S

    2007-03-15

    Humero-radial synostosis (HRS) is a rare skeletal anomaly that might be seen in some craniosynostosis syndromes, notably Antley-Bixler syndrome, and in other disorders in association with skeletal anomalies. Here we report on two daughters of first cousin Saudi parents with syndromic HRS. Both patients had distinctive craniofacial features including cranium bifidum occultum, hypertelorism, epicanthus inversus, capillary hemangiomata, and malformed ears. Musculoskeletal examination revealed rhizomelic shortness with normal hands and feet. Skeletal survey showed bilateral HRS with no evidence of craniosynostosis. The craniofacial manifestations in these two patients do not match any of the syndromes known to be associated with HRS. We consider that the constellation is unique and apparently represents a previously unrecognized syndrome. (c) 2007 Wiley-Liss, Inc.

  5. A homozygous missense mutation in the IRBP gene (RBP3) associated with autosomal recessive retinitis pigmentosa.

    NARCIS (Netherlands)

    Hollander, A.I. den; McGee, T.L.; Ziviello, C.; Banfi, S.; Dryja, T.P.; Gonzalez-Fernandez, F.; Ghosh, D.; Berson, E.L.

    2009-01-01

    PURPOSE: Interphotoreceptor retinoid-binding protein (IRBP) has been considered essential for normal rod and cone function, as it mediates the transport of retinoids between the photoreceptors and the retinal pigment epithelium. This study was performed to determine whether mutations in the IRBP

  6. GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability.

    Science.gov (United States)

    Lodder, Elisabeth M; De Nittis, Pasquelena; Koopman, Charlotte D; Wiszniewski, Wojciech; Moura de Souza, Carolina Fischinger; Lahrouchi, Najim; Guex, Nicolas; Napolioni, Valerio; Tessadori, Federico; Beekman, Leander; Nannenberg, Eline A; Boualla, Lamiae; Blom, Nico A; de Graaff, Wim; Kamermans, Maarten; Cocciadiferro, Dario; Malerba, Natascia; Mandriani, Barbara; Akdemir, Zeynep Hande Coban; Fish, Richard J; Eldomery, Mohammad K; Ratbi, Ilham; Wilde, Arthur A M; de Boer, Teun; Simonds, William F; Neerman-Arbez, Marguerite; Sutton, V Reid; Kok, Fernando; Lupski, James R; Reymond, Alexandre; Bezzina, Connie R; Bakkers, Jeroen; Merla, Giuseppe

    2016-09-01

    GNB5 encodes the G protein β subunit 5 and is involved in inhibitory G protein signaling. Here, we report mutations in GNB5 that are associated with heart-rate disturbance, eye disease, intellectual disability, gastric problems, hypotonia, and seizures in nine individuals from six families. We observed an association between the nature of the variants and clinical severity; individuals with loss-of-function alleles had more severe symptoms, including substantial developmental delay, speech defects, severe hypotonia, pathological gastro-esophageal reflux, retinal disease, and sinus-node dysfunction, whereas related heterozygotes harboring missense variants presented with a clinically milder phenotype. Zebrafish gnb5 knockouts recapitulated the phenotypic spectrum of affected individuals, including cardiac, neurological, and ophthalmological abnormalities, supporting a direct role of GNB5 in the control of heart rate, hypotonia, and vision. Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  7. Histopathological effects of lethal and sub-lethal concentrations of ...

    African Journals Online (AJOL)

    The histopathological effects of lethal and sub-lethal concentrations of glyphosate on African catfish Clarias gariepinus were investigated. C. gariepinus juveniles were assessed in a static renewal bioassay for 96 hours (acute toxicity) and 28 days (chronic toxicity) using varying concentrations (0.0 mg/l 20.0 mg/l, 30.0 mg/l, ...

  8. Barriers for recess physical activity

    DEFF Research Database (Denmark)

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

    2014-01-01

    . This was verified by a thematic analysis of transcripts from the open discussions and go-along interviews. RESULTS: The most frequently identified barriers for both boys and girls were weather, conflicts, lack of space, lack of play facilities and a newly-found barrier, use of electronic devices. While boys......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...

  9. 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.

  10. Suicide Lethality: A Concept Analysis.

    Science.gov (United States)

    DeBastiani, Summer; De Santis, Joseph P

    2018-02-01

    Suicide is a significant health problem internationally. Those who complete suicide may have different behaviors and risk factors than those who attempt a non-fatal suicide. The purpose of this article is to analyze the concept of suicide lethality and propose a clear definition of the concept through the identification of antecedents, attributes, and consequences. A literature search for articles published in the English language between 1970 and 2016 was conducted using MEDLINE, the Cochrane Library, Pubmed, Psychlit, Ovid, PsycINFO, and Proquest. The bibliographies of all included studies were also reviewed to identify additional relevant citations. A concept analysis was conducted on the literature findings using six stages of Walker and Avant's method. The concept analysis differentiated between suicide, lethality, suicidal behavior, and suicide lethality. Presence of a suicide plan or a written suicide note was not found to be associated with the majority of completed suicides included in the definition of suicide lethality. There are a few scales that measure the lethality of a suicide attempt, but none that attempt to measure the concept of suicide lethality as described in this analysis. Clarifying the concept of suicide lethality encourages awareness of the possibility of different suicidal behaviors associated with different suicide outcomes and will inform the development of future nursing interventions. A clearer definition of the concept of suicide lethality will guide clinical practice, research, and policy development aimed at suicide prevention.

  11. Genetics Home Reference: autosomal dominant hypocalcemia

    Science.gov (United States)

    ... low levels of a hormone called parathyroid hormone (hypoparathyroidism). This hormone is involved in the regulation of ... Other Names for This Condition ADH autosomal dominant hypoparathyroidism familial hypercalciuric hypocalcemia familial hypocalcemia Related Information How ...

  12. Autosomal Dominant Polycystic Kidney Disease, incidental finding ...

    African Journals Online (AJOL)

    N.J. Gildenhuys

    2016-06-30

    Jun 30, 2016 ... Abbreviations: ADPKD, Autosomal Dominant Polycystic Kidney Disease; UPJ, congenital ureteropelvic junction obstruction; HK, horseshoe kidney;. RCC, renal cell carcinoma; MVA, motor vehicle accident; PVA, pedestrian vehicle accident; GH, gross haematuria; AP, abdominal pain; FP, flank pain;.

  13. 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...

  14. Present Day Recession Effects on Human Resources

    OpenAIRE

    Bujor Anca Liliana

    2012-01-01

    Specific characteristic for recession situation are: instability, anxiety, unpredictable attitude and behavior accentuation of knowledge, cognitive filters and erroneous interpretation of social, economic or existential realities. In this paper, for knowing this recession from the perspective of human resources, I started from determining some objectives such as: Knowledge of present recession peculiarities, of its area and depth, learning recession effects, its impact upon human resources, i...

  15. Recessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal epilepsy, developmental delay and teeth hypoplasia

    DEFF Research Database (Denmark)

    Hardies, Katia; de Kovel, Carolien G F; Weckhuysen, Sarah

    2015-01-01

    The epileptic encephalopathies are a clinically and aetiologically heterogeneous subgroup of epilepsy syndromes. Most epileptic encephalopathies have a genetic cause and patients are often found to carry a heterozygous de novo mutation in one of the genes associated with the disease entity....... Occasionally recessive mutations are identified: a recent publication described a distinct neonatal epileptic encephalopathy (MIM 615905) caused by autosomal recessive mutations in the SLC13A5 gene. Here, we report eight additional patients belonging to four different families with autosomal recessive...... their energy status and neurotransmitter production. The effect of all seven identified mutations (two premature stops and five amino acid substitutions) was studied in vitro, using immunocytochemistry, selective western blot and mass spectrometry. We hereby demonstrate that cells expressing mutant sodium...

  16. 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.

  17. Novel harmful recessive haplotypes identified for fertility traits in Nordic Holstein cattle

    DEFF Research Database (Denmark)

    Sahana, Goutam; Nielsen, Ulrik Sander; Aamand, Gert Pedersen

    2013-01-01

    Using genomic data, lethal recessives may be discovered from haplotypes that are common in the population but never occur in the homozygote state in live animals. This approach only requires genotype data from phenotypically normal (i.e. live) individuals and not from the affected embryos that die....... A total of 7,937 Nordic Holstein animals were genotyped with BovineSNP50 BeadChip and haplotypes including 25 consecutive markers were constructed and tested for absence of homozygotes states. We have identified 17 homozygote deficient haplotypes which could be loosely clustered into eight genomic regions...... carrier-by-carrier mattings in practical animal breeding. Further, identification of causative genes/polymorphisms responsible for lethal effects will lead to accurate testing of the individuals carrying a lethal allele...

  18. 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.

  19. Chromosomal localization of autosomal mutations in Drosophila ...

    Indian Academy of Sciences (India)

    Unknown

    1Drosophila Stock Centre, Department of Studies in Zoology, University of Mysore,. Manasagangotri, Mysore 570 006, ... of genetic markers. In the present study, we have exploited the differences in karyotypic composition between these two subspecies, and their cross-fertility, in order to localize some autosomal genes.

  20. Progress on Autosomal Dominant Polycystic Kidney Disease ...

    African Journals Online (AJOL)

    Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is the most common life threatening hereditary disease of the kidney. It is a systemic disease characterized by multiple, bilateral renal cysts that result in massive renal enlargement and progressive functional impairment. This review discusses the current ...

  1. Cleidocranial Dysplasia with Autosomal Dominant Inheritance Pattern

    African Journals Online (AJOL)

    Cleidocranial dysplasia (CCD) is an autosomal dominant disease with a wide range of expression, characterized by clavicular hypoplasia, retarded cranial ossification, delayed bone and teeth development, supernumerary teeth, stomatognathic, craniofacial and skeletal abnormalities. This paper presents a case of CCD in ...

  2. Autosomal dominant non-epidermolytic palmoplantar hyperkeratosis ...

    African Journals Online (AJOL)

    PROF. EZECHUKWU

    2013-08-12

    Aug 12, 2013 ... Abstract. Palmoplantar kerato- derma (PPK) is a hereditary cuta- neous 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 Paedi- atric Outpatient ...

  3. 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...

  4. Autosomal Dominant Polycystic Kidney Disease, incidental finding ...

    African Journals Online (AJOL)

    Introduction: Pre-existing renal lesions predispose kidneys to effects of otherwise insignificant blunt trauma, and may uncommonly present as an incidental finding in the workup of a suspected renal injury. Observation: This is a case report of a 28-year-old male diagnosed incidentally with Autosomal Dominant Polycystic ...

  5. 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.

  6. 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....

  7. The etiology and prevalence of gingival recession.

    Science.gov (United States)

    Kassab, Moawia M; Cohen, Robert E

    2003-02-01

    Gingival recession in its localized or generalized form is an undesirable condition resulting in root exposure. The result often is not esthetic and may lead to sensitivity and root caries. Exposed root surfaces also are prone to abrasion. The purpose of this article is to describe the prevalence, etiology and factors associated with gingival recession. The authors reviewed cross-sectional epidemiologic studies of gingival recession and found that they correlated the prevalence of recession to trauma, sex, malpositioned teeth, inflammation and tobacco consumption. The recent surveys they reviewed revealed that 88 percent of people 65 years of age and older and 50 percent of people 18 to 64 years of age have one or more sites with recession. The presence and extent of gingival recession also increased with age. More than 50 percent of the population has one or more sites with gingival recession of 1 mm or more. The prevalence of gingival recession was found in patients with both good and poor oral hygiene. It has been proposed that recession is multifactorial, with one type being associated with anatomical factors and another type with physiological or pathological factors. Recession has been found more frequently on buccal surfaces than on other aspects of the teeth. Dentists should be knowledgeable about the etiology, prevalence and associating factors of gingival recession, as well as treatment options, so that appropriate treatment modalities can be offered to patients. Treatments for gingival recession include gingival grafting, guided tissue regeneration and orthodontic therapy. Such treatments typically result in esthetic improvement, elimination of sensitivity and a decreased risk of developing root caries.

  8. Genetics Home Reference: autosomal dominant nocturnal frontal lobe epilepsy

    Science.gov (United States)

    ... Health Conditions ADNFLE Autosomal dominant nocturnal frontal lobe epilepsy Printable PDF Open All Close All Enable Javascript ... collapse boxes. Description Autosomal dominant nocturnal frontal lobe epilepsy ( ADNFLE ) is an uncommon form of epilepsy that ...

  9. Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment

    DEFF Research Database (Denmark)

    Rendtorff, Nanna D; Lodahl, Marianne; Boulahbel, Houda

    2011-01-01

    Optic atrophy (OA) and sensorineural hearing loss (SNHL) are key abnormalities in several syndromes, including the recessively inherited Wolfram syndrome, caused by mutations in WFS1. In contrast, the association of autosomal dominant OA and SNHL without other phenotypic abnormalities is rare...... that patients who are heterozygous for WFS1 missense mutations should be carefully clinically examined for OA and other manifestations of Wolfram syndrome....

  10. Identification of a cryptic lethal mutation in the mouse t(w73) haplotype.

    Science.gov (United States)

    Howell, Gareth R; Bergstrom, Rebecca A; Munroe, Robert J; Masse, Jessica; Schimenti, John C

    2004-12-01

    t haplotypes are naturally occurring, variant forms of the t complex on mouse chromosome 17, characterized by the presence of four inversions with respect to wild-type. They harbour mutations causing male sterility, male transmission ratio distortion (TRD) and embryonic lethality. Mice carrying t haplotypes have been found throughout the world, and genetic studies of the lethal mutations have identified at least 16 complementation groups. The embryonic lethal phenotypes of many t haplotypes have been characterized in detail, and are thought to be the consequence of homozygosity for single gene mutations. However, the existence of additional mutations in genes that function at later stages of development would be obscured. Here we investigated the possibility of multiple mutations in t haplotypes by screening the t(w73) haplotype for the presence of novel mutations. Since genetic analysis of t haplotype mutations is hindered by recombination suppression due to the inversions, deletion complexes covering the proximal two-thirds of the t complex were used to uncover the presence of any new lethal alleles. This analysis revealed a novel mutation between D17Jcs41 and D17Mit100, causing mice carrying both t(w73) and selected deletions to die at birth, prior to feeding. The finding of a new, cryptic lethal mutation in t haplotypes is an indication that these recombinationally isolated chromosomes, which already contain at least one lethal mutation that prevents homozygosity, may serve as sinks for the accumulation of additional recessive mutations.

  11. MIDLINE LETHAL GRANULOMA COMPLICATING PREGNANCY ...

    African Journals Online (AJOL)

    Kateee

    East African Medical Journal Vol. 80. No. 7 July 2003. MIDLINE LETHAL GRANULOMA COMPLICATING PREGNANCY: CASE REPORT. B.D.O. Saheeb, BDS, FWACS, FICS, FDS, RCS (Edin) Senior Lecturer/Consultant, and M.A. Ojo, BDS, MMed Sc, Dip Maxfac Rad, Associate Professor/Consultant. Department of oral ...

  12. [The "lethal white foal" syndrome].

    Science.gov (United States)

    Blendinger, C; Müller, G; Bostedt, H

    1994-06-01

    The lethal white foal syndrome (congenital intestinal aganglionosis) was diagnosed by history, clinical signs and pathological findings in a female foal, born in March 1992, that was an offspring of two overo-spotted paint horses. The syndrome is a congenital innervation defect of the gastrointestinal tract. A literature review of this condition, relatively unknown in Germany, is given.

  13. Mutagenic Potential of Nitroguanidine in the Drosophila melanogaster Sex-Linked Recessive Lethal Test

    Science.gov (United States)

    1988-07-01

    Raj K. Guipta, Lillie D. Witcher , Vilmar O.M. Villa, Don W. Korte, Jr. 13a. TYPE OF REPORT 13b. TIME COVERED 14 DATE OF REPORT (Year, Month, Day) 15...MAJI, [*s,’u Stu,.dy Eirctor- Rj AJ(""MsGUPTA’ P-hDIEate i MAJ MSC PDDt Principal investigator E-~ D. WITCHER , BS/Date SGT, USA V Biological Scienceus...337-351. 15. Harbell JW, Witcher LD, Sebastian SE, Korte DW. Studies on the mutagenic potential of nitroguanidine and nitrosoguanidine. 1987 JANNAF

  14. Immunological loss-of-function due to genetic gain-of-function in humans: autosomal dominance of the third kind.

    Science.gov (United States)

    Boisson, Bertrand; Quartier, Pierre; Casanova, Jean-Laurent

    2015-02-01

    All the human primary immunodeficiencies (PIDs) recognized as such in the 1950s were Mendelian traits and, whether autosomal or X-linked, displayed recessive inheritance. The first autosomal dominant (AD) PID, hereditary angioedema, was recognized in 1963. However, since the first identification of autosomal recessive (AR), X-linked recessive (XR) and AD PID-causing genes in 1985 (ADA; severe combined immunodeficiency), 1986 (CYBB, chronic granulomatous disease) and 1989 (SERPING1; hereditary angioedema), respectively, the number of genetically defined AD PIDs has increased more rapidly than that of any other type of PID. AD PIDs now account for 61 of the 260 known conditions (23%). All known AR PIDs are caused by alleles with some loss-of-function (LOF). A single XR PID is caused by gain-of-function (GOF) mutations (WASP-related neutropenia, 2001). In contrast, only 44 of 61 AD defects are caused by LOF alleles, which exert dominance by haploinsufficiency or negative dominance. Since 2003, up to 17 AD disorders of the third kind, due to GOF alleles, have been described. Remarkably, six of the 17 genes concerned also harbor monoallelic (STAT3), biallelic (C3, CFB, CARD11, PIK3R1) or both monoallelic and biallelic (STAT1) LOF alleles in patients with other clinical phenotypes. Most heterozygous GOF alleles result in auto-inflammation, auto-immunity, or both, with a wide range of immunological and clinical forms. Some also underlie infections and, fewer, allergies, by impairing or enhancing immunity to non-self. Malignancies are also rare. The enormous diversity of immunological and clinical phenotypes is thought provoking and mirrors the diversity and pleiotropy of the underlying genotypes. These experiments of nature provide a unique insight into the quantitative regulation of human immunity. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. Familial muscle cramps with autosomal dominant transmission.

    Science.gov (United States)

    Van den Bergh, P; Bulcke, J A; Dom, R

    1980-01-01

    A family is described with generalized muscle cramps inherited as an autosomal dominant trait and with maximal expression during adolescence. The age of onset varies between 10 and 15 years. Muscle enzymes are elevated with a peak level between 15 and 25 years. The complaints seem to disappear after the age of 25 years. EMG and muscle biopsies suggest a neurogenic origin of the cramps.

  16. Timing of the uv mutagenesis in yeast: a pedigree analysis of induced recessive mutation

    International Nuclear Information System (INIS)

    James, A.P.; Kilbey, B.J.

    1977-01-01

    The mechanism of uv-induced mutation in eukaryotes was studied in individual yeast cells by a procedure that combined pedigree analysis and tetrad analysis. The technique involved the induction of recessive lethals and semilethals in G1 diploid cells. Induced frequencies were 25 and 61% at survival levels of 90 and 77%, respectively. No evidence of gross chromosome aberrations was detected. Recessive mutations that affect only one strand or that affect both strands of the DNA molecule are induced much at random among a population of cells, and both types can occur within the same cell. However, the data confirm that two-strand mutations are in the majority after a low level of irradiation. The simplest explanation involves a mechanism whereby most mutations are fixed in both strands prior to the first round of post-irradiation DNA replication. The recessive mutational consequences of irradiation are exhausted at the conclusion of the first post-irradiation cell division, although dominant-lethal sectoring continues at a high level through the second post-irradiation division. It is concluded that pyrimidine dimers that persist to the second round of DNA replication are rare or ineffective

  17. A recessive Mendelian model to predict carrier probabilities of DFNB1 for nonsyndromic deafness.

    Science.gov (United States)

    González, Juan R; Wang, Wenyi; Ballana, Ester; Estivill, Xavier

    2006-11-01

    Mutations in the DFNB1 locus, where two connexin genes are located (GJB2 and GJB6), account for half of congenital cases of nonsyndromic autosomal recessive deafness. Because of the high frequency of DFNB1 gene mutations and the availability of genetic diagnostic tests involving these genes, they are the best candidates to develop a risk prediction model of being hearing impaired. People undergoing genetic counseling are normally interested in knowing the probability of having a hearing impaired child given his/her family history. To address this, a Mendelian model that predicts the probability of being a carrier of DFNB1 mutations, using family history of deafness, has been developed. This probability will be useful as additional information to decide whether or not a genetic test should be performed. This model incorporates Mendelian mode of inheritance, the age of onset of the disease, and the current age of hearing family members. The carrier probabilities are obtained using Bayes' theorem, in which mutation prevalence is used as the prior distribution. We have validated our model by using information from 305 families affected with congenital or progressive nonsyndromic deafness, in which genetic analysis of GJB2 and GJB6 had already been performed. This model works well, especially in homozygous carriers, showing a high discriminative power. This indicates that our proposed model can be useful in the context of clinical counseling of autosomal recessive disorders. (c) 2006 Wiley-Liss, Inc.

  18. A strong loss-of-function mutation in RAN1 results in constitution activation of the ethylene response pathway as well as a rosette-lethal phenotype

    Science.gov (United States)

    Keith Woeste; Joseph J. Kieber

    2000-01-01

    A recessive mutation was identified that constitutively activated the ethylene response pathway in Arabidopsis and resuited in a rosette-lethal phenotype. Positional cloning of the gene corresponding to this mutation revealed that it was allelic to responsive to antagonist1 (ran1), a mutation that causes seedlings to respond in a positive manner to what is normally a...

  19. Recessive Cancer Genes Engage in Negative Genetic Interactions with Their Functional Paralogs

    Directory of Open Access Journals (Sweden)

    Matteo D’Antonio

    2013-12-01

    Full Text Available Cancer genetic heterogeneity offers a wide repertoire of molecular determinants to be screened as therapeutic targets. Here, we identify potential anticancer targets by exploiting negative genetic interactions between genes with driver loss-of-function mutations (recessive cancer genes and their functionally redundant paralogs. We identify recessive genes with additional copies and experimentally test our predictions on three paralogous pairs. We confirm digenic negative interactions between two cancer genes (SMARCA4 and CDH1 and their corresponding paralogs (SMARCA2 and CDH3. Furthermore, we identify a trigenic negative interaction between the cancer gene DNMT3A, its functional paralog DNMT3B, and a third gene, DNMT1, which encodes the only other human DNA-methylase domain. Although our study does not exclude other causes of synthetic lethality, it suggests that functionally redundant paralogs of cancer genes could be targets in anticancer therapy.

  20. 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.

  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. Children's Physical Activity Behavior during School Recess

    DEFF Research Database (Denmark)

    Pawlowski, Charlotte Skau; Andersen, Henriette Bondo; Troelsen, Jens

    2016-01-01

    Schoolyards are recognized as important settings for physical activity interventions during recess. However, varying results have been reported. This pilot study was conducted to gain in-depth knowledge of children's physical activity behavior during recess using a mixed-methods approach combining...... 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...... preferred the schoolyard over the field to avoid the competitive soccer games on the field whereas boys dominated the field playing soccer. Using a mixed-methods approach to investigate children's physical activity behavior during recess helped gain in-depth knowledge that can aid development of future...

  6. 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.

  7. Shadow of trouble : the effect of pre-recession characteristics on the severity of recession impact

    OpenAIRE

    Knudsen, Eirik Sjåholm

    2011-01-01

    The recent financial crisis has heightened the need to understand why some firms are more severely affected by recessions than others and how different firm and industry characteristics affect firms’ vulnerability to such shocks. To study these questions empirically, we complement secondary financial data with primary data from an extensive questionnaire about the effects of the recent recession distributed to 5000 Norwegian CEOs in late 2010. We find that high pre-recession operating profit...

  8. 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...

  9. 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...

  10. Gingival Recession in Orthodontics: A Review

    OpenAIRE

    Shah, Aakash; Shah, Purvesh; Goje, Santosh Kumar; Shah, Romil; Modi, Bhumi

    2017-01-01

    By clinical definition, gingival recession refers to the exposure of the root surface by an apical shift in the position of the gingiva. Recession is important because it can lead to poor esthetics, tooth hypersensitivity, loss of periodontal support, difficulties in maintenance of oral hygiene, and increased susceptibility to caries. Although its etiology is not fully understood, periodontal disease and mechanical trauma are considered the primary factors in the pathogenesis of gingival rece...

  11. A Traffic Jam Theory of Recessions

    OpenAIRE

    Jennifer La'O

    2013-01-01

    I construct a dynamic economy in which agents are interconnected: the output produced by one agent is the consumption good of another. I show that this economy can generate recessions which resemble traffic jams. At the micro level, each individual agent waits for his own income to increase before he increases his spending. However, his spending behavior affects the income of another agent. Thus, the spending behavior of agents during recessions resembles the stop-and-go behavior of vehicles ...

  12. Electroshock weapons can be lethal!

    Science.gov (United States)

    Lundquist, Marjorie

    2008-03-01

    Electroshock weapons (EWs)-stun guns, tasers, riot shields-are electroconductive devices designed to safely incapacitate healthy men neuromuscularly, so they are called nonlethal or less-lethal. EW firms seeking large nonmilitary markets targeted law enforcement and corrections personnel, who began using EWs in prisons/jails and on public patrol in 1980 in the USA. This shifted the EW-shocked population from healthy soldiers to a heterogeneous mix of both sexes, ages 6-92, in a wide variety of health conditions! An EW operates by disrupting normal physiological processes, producing transient effects in healthy people. But if a person's health is sufficiently compromised, the margin of safety can be lost, resulting in death or permanent health problems. 325 people have died after EW shock since 1980. Did the EW cause these deaths? Evidence indicates that EWs do play a causal role in most such deaths. EWs can be lethal for people in diabetic shock^1 (hypoglycemia), which may be why Robert Dziekanski-a Polish immigrant to Canada-died so quickly after he was tasered at Vancouver Airport: not having eaten for over 10 hours, he likely was severely hypoglycemic. The EW death rate in North America is 30 times higher than need be, because EW users have not been properly trained to use EWs on a heterogeneous population safely! ^1J. Clinical Engineering 30(3):111(2005).

  13. A Simulation Study of Recessed Type Hydrostatic Journal Bearing

    Directory of Open Access Journals (Sweden)

    Wong Shih-Ming

    2016-01-01

    Full Text Available In this paper, a simulation model is established to study effects of the bearing system parameters on bearing performance. The static performance (such as load capacity, stiffness and flow about various dimensions of multi-recess type hydrostatic journal bearings with constant-resistant restrictor compensation was investigated. The parameters studied includes length/diameter ratio, number of recess, recess length ratio, recess width ratio, initial ratio between recess pressure to supply pressure, and eccentricity.

  14. 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.

  15. Detrimental effects of an autosomal selfish genetic element on sperm competitiveness in house mice.

    Science.gov (United States)

    Sutter, Andreas; Lindholm, Anna K

    2015-07-22

    Female multiple mating (polyandry) is widespread across many animal taxa and indirect genetic benefits are a major evolutionary force favouring polyandry. An incentive for polyandry arises when multiple mating leads to sperm competition that disadvantages sperm from genetically inferior mates. A reduction in genetic quality is associated with costly selfish genetic elements (SGEs), and studies in invertebrates have shown that males bearing sex ratio distorting SGEs are worse sperm competitors than wild-type males.We used a vertebrate model species to test whether females can avoid an autosomal SGE, the t haplotype, through polyandry. The t haplotype inhouse mice exhibits strong drive in t heterozygous males by affecting spermatogenesis and is associated with homozygous in utero lethality. We used controlled matings to test the effect of the t haplotype on sperm competitiveness. Regardless of mating order, t heterozygous males sired only 11% of zygotes when competing against wild-type males, suggesting a very strong effect of the t haplotype on sperm quality. We provide, to our knowledge,the first substantial evidence that polyandry ameliorates the harmful effects of an autosomal SGE arising through genetic incompatibility. We discuss potential mechanisms in our study species and the broader implications for the benefits of polyandry.

  16. Novel SOX9 Gene Mutation in Campomelic Dysplasia with Autosomal Sex Reversal

    Directory of Open Access Journals (Sweden)

    Hui-Pin Hsiao

    2006-01-01

    Full Text Available Campomelic dysplasia (CD; OMIM #114290 is an autosomal dominant, frequently lethal dysplasia syndrome whose primary features include angular bowing and shortening of the limbs, and sex reversal in the majority of affected XY individuals. Most CD cases have heterozygous de novo mutations in the coding region of the transcription factor gene SOX9 (SRY-related high-mobility group [HMG] box 9 in chromosome 17q. Here, we report a novel mutation of SOX9 in a female neonate with CD with autosomal sex reversal. Respiratory distress and cyanosis were noted at birth, and endotracheal intubation with mechanical ventilation was performed due to respiratory failure. The presenting phenotypes included dysmorphic face with macrocephaly prominent forehead, low nasal bridge, cleft palate and micrognathia. Skeletal deformities characteristic of CD were observed, including narrow thoracic cage, hypoplastic scapulae, scoliosis and short limbs with anterolateral femoral and tibial bowing. The karyotype was 46,XY despite female external genitalia. SOX9 gene analysis revealed frameshift mutation (at nucleotide position 1095G →AT in the open reading frame, resulting in a frameshift with 211 new amino acids.

  17. 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 s...... 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....... shows that our tests have power to reject unpredictability in both expansions and recessions. To judge the economic significance of the results we compute utility gains for a meanvariance investor who takes the predictability patterns into account and show that utility gains are positive in expansions...... 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...

  18. Effect of lethal and sub-lethal concentrations of tobacco (Nicotiana ...

    African Journals Online (AJOL)

    Lethal and sub-lethal bioassays on Clarias gariepinus were conducted to evaluate the toxicity of tobacco (Nicotiana tobaccum) leaf dust on weight gain and haematological indices of Clarias gariepinus (mean weight 10.5±0.70g) in glass aquaria with aeration system. The concentrations used during the lethal exposure are: ...

  19. accessions resistants to lethal yellowing disease

    African Journals Online (AJOL)

    Administrator

    2007-02-19

    Feb 19, 2007 ... One of the problems faced in coconut cultivation is the lethal yellowing disease. Experimental trials, conducted in endemic region, showed that the Vanuatu Tall and Sri-Lanka Green Dwarf genotypes were tolerant while the West African Tall appeared susceptible to the lethal yellowing disease. Genetic.

  20. 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...

  1. High Resolution Ultrasonography for Assessment of Renal Cysts in the PCK Rat Model of Autosomal Recessive Polycystic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Sarika Kapoor

    2016-03-01

    Full Text Available Background/Aims: The PCK rat model of polycystic kidney disease is characterized by the progressive development of renal medullary cysts. Here, we evaluated the suitability of high resolution ultrasonography (HRU to assess the kidney and cyst volume in PCK rats, testing three different ultrasound image analysis methods, and correlating them with kidneys weights and histological examinations. Methods: After inducing anesthesia, PCK rats (n=18 were subjected to HRU to visualize the kidneys, to perform numeric and volumetric measurements of the kidney and any cysts observed, and to generate 3-dimensional images of the cysts within the kidney parenchyma. Results: HRU provided superior information in comparison to microscopic analysis of stained kidney sections. HRU-based kidney volumes correlated strongly with kidney weights (R2=0.809; PConclusion: HRU represents a useful diagnostic tool for kidney and cyst volume measurements in PCK rats. Sequential HRU examinations may be useful to study the effect of drugs on cyst growth without the need to euthanize experimental animals.

  2. Novel missense loss-of-function mutations of WNT1 in an autosomal recessive Osteogenesis imperfecta patient.

    Science.gov (United States)

    Won, Joon Yeon; Jang, Woo Young; Lee, Hye-Ran; Park, Seon Young; Kim, Woo-Young; Park, Jong Hoon; Kim, Yonghwan; Cho, Tae-Joon

    2017-08-01

    Osteogenesis imperfecta (OI) is a heritable skeletal disorder characterized by bone fragility and low bone mass. Recently, loss-of-function mutations of WNT1 have been reported to be causative in OI or osteoporosis. We report an OI patient with novel compound heterozygous WNT1 missense mutations, p.Glu123Asp and p.Cys153Gly. Both mutations are found in the exon 3, and the p.Glu123Asp is the most proximal N-terminus missense mutation among the reported WNT1 missense mutations in OI patients. In vitro functional analysis reveals that while expression of wildtype WNT1 stimulates canonical WNT1-mediated β-catenin signaling, that of individual WNT1 mutant fails to do so, indicative of the pathogenic nature of the WNT1 variants. Although the pathogenic mechanism of WNT1 defects in OI has yet to be uncovered, these findings further contribute to the implications and importance of functional relevance of WNT1 in skeletal disorders. Copyright © 2017. Published by Elsevier Masson SAS.

  3. 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

    was shown by diagnostic restriction enzyme digest, and marker analysis of another aphakia family from Madagascar carrying the same mutation excluded the presence of a founder mutation. Clinical re-examination of the family was not possible due to the escalating security concerns and internal displacement...

  4. Biallelic Mutations in GNB3 Cause a Unique Form of Autosomal-Recessive Congenital Stationary Night Blindness.

    Science.gov (United States)

    Vincent, Ajoy; Audo, Isabelle; Tavares, Erika; Maynes, Jason T; Tumber, Anupreet; Wright, Thomas; Li, Shuning; Michiels, Christelle; Condroyer, Christel; MacDonald, Heather; Verdet, Robert; Sahel, José-Alain; Hamel, Christian P; Zeitz, Christina; Héon, Elise

    2016-05-05

    Congenital stationary night blindness (CSNB) is a heterogeneous group of non-progressive inherited retinal disorders with characteristic electroretinogram (ERG) abnormalities. Riggs and Schubert-Bornschein are subtypes of CSNB and demonstrate distinct ERG features. Riggs CSNB demonstrates selective rod photoreceptor dysfunction and occurs due to mutations in genes encoding proteins involved in rod phototransduction cascade; night blindness is the only symptom and eye examination is otherwise normal. Schubert-Bornschein CSNB is a consequence of impaired signal transmission between the photoreceptors and bipolar cells. Schubert-Bornschein CSNB is subdivided into complete CSNB with an ON bipolar signaling defect and incomplete CSNB with both ON and OFF pathway involvement. Both subtypes are associated with variable degrees of night blindness or photophobia, reduced visual acuity, high myopia, and nystagmus. Whole-exome sequencing of a family screened negative for mutations in genes associated with CSNB identified biallelic mutations in the guanine nucleotide-binding protein subunit beta-3 gene (GNB3). Two siblings were compound heterozygous for a deletion (c.170_172delAGA [p.Lys57del]) and a nonsense mutation (c.1017G>A [p.Trp339(∗)]). The maternal aunt was homozygous for the nonsense mutation (c.1017G>A [p.Trp339(∗)]). Mutational analysis of GNB3 in a cohort of 58 subjects with CSNB identified a sporadic case individual with a homozygous GNB3 mutation (c.200C>T [p.Ser67Phe]). GNB3 encodes the β subunit of G protein heterotrimer (Gαβγ) and is known to modulate ON bipolar cell signaling and cone transducin function in mice. Affected human subjects showed an unusual CSNB phenotype with variable degrees of ON bipolar dysfunction and reduced cone sensitivity. This unique retinal disorder with dual anomaly in visual processing expands our knowledge about retinal signaling. Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  5. 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.

  6. Canine Disorder Mirrors Human Disease: Exonic Deletion in HES7 Causes Autosomal Recessive Spondylocostal Dysostosis in Miniature Schnauzer Dogs

    OpenAIRE

    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 ...

  7. Relative frequency of GJB2 gene mutations in autosomal recessive non-syndromic hearing loss (ARNSHL patients in Lorestan population

    Directory of Open Access Journals (Sweden)

    mitra Sapahvand

    2007-01-01

    Conclusion: Unexpectedly, in this research just 17 percent of cases are covered. In this study 510 insCGAA mutation was seen. This is a new mutation which is not reported in other studied populations in the world. Hence, this research shows that – at least in our studied population- the effect of other genes that could cause non-syndromic hearing loss is possible and should be studied

  8. Transcription-terminating mutation in telethonin causing autosomal recessive muscular dystrophy type 2G in a European patient.

    Science.gov (United States)

    Olivé, Montse; Shatunov, Alexey; Gonzalez, Laura; Carmona, Olga; Moreno, Dolores; Quereda, Lidia Gonzalez; Martinez-Matos, J A; Goldfarb, Lev G; Ferrer, Isidro

    2008-12-01

    A 27-year-old woman of Moldavian origin presented at the age of 15 with progressive proximal limb weakness and painful cramps in her calf muscles. Clinical examination revealed prominent muscle weakness in proximal muscles of the lower extremities and distal anterior compartment of legs, and mild weakness in shoulder girdle muscles. In addition, she had marked calf hypertrophy, muscle atrophy involving the anterior and posterior compartments of the thighs, and the distal anterior compartment of legs, as well as mild scapular winging and hyperlordosis. A muscle biopsy taken from the biceps brachii showed mild dystrophic changes, absent vacuoles, and abundant lobulated fibers. Immunofluorescence and Western blot assays demonstrated complete telethonin deficiency. Molecular analysis revealed a homozygous Trp25X mutation in the telethonin (TCAP) gene resulting in termination of transcription at an early point. Four families from Brazil with telethonin deficiency have previously been reported and classified as LGMD2G, but the actual frequency of this disease is unknown. With this current identification of a case outside the Brazilian population, telethonin mutation-associated LGMD should be considered worldwide.

  9. 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.

  10. Loss of ZMPSTE24 (FACE-1) causes autosomal recessive restrictive dermopathy and accumulation of Lamin A precursors

    NARCIS (Netherlands)

    Navarro, Claire L.; Cadiñanos, Juan; de Sandre-Giovannoli, Annachiara; Bernard, Rafaëlle; Courrier, Sébastien; Boccaccio, Irène; Boyer, Amandine; Kleijer, Wim J.; Wagner, Anja; Giuliano, Fabienne; Beemer, Frits A.; Freije, Jose M.; Cau, Pierre; Hennekam, Raoul C. M.; López-Otín, Carlos; Badens, Catherine; Lévy, Nicolas

    2005-01-01

    Restrictive dermopathy (RD) is characterized by intrauterine growth retardation, tight and rigid skin with prominent superficial vessels, bone mineralization defects, dysplastic clavicles, arthrogryposis and early neonatal death. In two patients affected with RD, we recently reported two different

  11. 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

    families. Rescue experiments with the altered proteins in PGAP2-deficient Chinese hamster ovary cell lines showed less expression of cell-surface GPI-anchored proteins DAF and CD59 than of the wild-type protein, substantiating the pathogenicity of the identified alterations. Furthermore, we observed a full...

  12. 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...... of core activities in response to a recessionary shock. Further, we find a negative interaction effect between reductions in access to credit and reductions in demand on insourcing of core activities, but no such effect on outsourcing of core activities. We argue that this finding may highlight a possible...

  13. 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.

  14. Molecular analysis of two mouse dilute locus deletion mutations: Spontaneous dilute lethal20J and radiation-induced dilute prenatal lethal Aa2 alleles

    International Nuclear Information System (INIS)

    Strobel, M.C.; Seperack, P.K.; Copeland, N.G.; Jenkins, N.A.

    1990-01-01

    The dilute (d) coat color locus of mouse chromosome 9 has been identified by more than 200 spontaneous and mutagen-induced recessive mutations. With the advent of molecular probes for this locus, the molecular lesion associated with different dilute alleles can be recognized and precisely defined. In this study, two dilute mutations, dilute-lethal20J (dl20J) and dilute prenatal lethal Aa2, have been examined. Using a dilute locus genomic probe in Southern blot analysis, we detected unique restriction fragments in dl20J and Aa2 DNA. Subsequent analysis of these fragments showed that they represented deletion breakpoint fusion fragments. DNA sequence analysis of each mutation-associated deletion breakpoint fusion fragment suggests that both genomic deletions were generated by nonhomologous recombination events. The spontaneous dl20J mutation is caused by an interstitial deletion that removes a single coding exon of the dilute gene. The correlation between this discrete deletion and the expression of all dilute-associated phenotypes in dl20J homozygotes defines the dl20J mutation as a functional null allele of the dilute gene. The radiation-induced Aa2 allele is a multilocus deletion that, by complementation analysis, affects both the dilute locus and the proximal prenatal lethal-3 (pl-3) functional unit. Molecular analysis of the Aa2 deletion breakpoint fusion fragment has provided access to a previously undefined gene proximal to d. Initial characterization of this new gene suggests that it may represent the genetically defined pl-3 functional unit

  15. Autosomal dominant polycystic kidney disease in children

    Science.gov (United States)

    Cadnapaphornchai, Melissa A.

    2015-01-01

    Purpose of review Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, affecting one in 500 individuals. The cardinal manifestation of ADPKD is progressive cystic dilatation of renal tubules with kidney enlargement and progression to end-stage renal disease in approximately half of cases by 60 years of age. Although previously considered a condition of adults, it is clear that children and young adults are subject to the complications of ADPKD. Recent findings It has been increasingly recognized that interventions early in life are necessary in order to confer the best long-term outcome in this common condition. Therefore, it is imperative for pediatricians to recognize the manifestations and complications of this disease. Until recently ADPKD management focused on general principles of chronic kidney disease. However, several recent clinical trials in children and adults with ADPKD have focused on disease-specific therapies. Summary This review will highlight the clinical manifestations, diagnosis, and appropriate management of ADPKD in childhood and will review recent relevant clinical trials in children and adults with this condition. PMID:25635587

  16. 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

  17. 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.

  18. Autosomal dominant polycystic kidney disease in children.

    Science.gov (United States)

    Cadnapaphornchai, Melissa A

    2015-04-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, affecting one in 500 individuals. The cardinal manifestation of ADPKD is progressive cystic dilatation of renal tubules with kidney enlargement and progression to end-stage renal disease in approximately half of cases by 60 years of age. Although previously considered a condition of adults, it is clear that children and young adults are subject to the complications of ADPKD. It has been increasingly recognized that interventions early in life are necessary in order to confer the best long-term outcome in this common condition. Therefore, it is imperative for pediatricians to recognize the manifestations and complications of this disease. Until recently ADPKD management focused on general principles of chronic kidney disease. However, several recent clinical trials in children and adults with ADPKD have focused on disease-specific therapies. This review will highlight the clinical manifestations, diagnosis, and appropriate management of ADPKD in childhood and will review recent relevant clinical trials in children and adults with this condition.

  19. Cantu syndrome in a woman and her two daughters: Further confirmation of autosomal dominant inheritance and review of the cardiac manifestations.

    Science.gov (United States)

    Grange, Dorothy K; Lorch, Steven M; Cole, Patricia L; Singh, Gautam K

    2006-08-01

    Cantu syndrome, or hypertrichosis-osteodysplasia-cardiomegaly syndrome, is a rare disorder of unknown etiology, associated with hypertrichosis, characteristic facial features, skeletal abnormalities, cardiomegaly, and occasional pericardial effusions. Although autosomal recessive inheritance was originally proposed, a man with three affected children has been reported, making autosomal dominant inheritance likely. We report on a woman and her two daughters with Cantu syndrome, further confirming dominant inheritance. All three of our patients have cardiac involvement, and symptomatic pericardial effusions requiring surgical intervention occurred in the mother and one of her daughters. Chromosome microarray analysis was normal in one of the girls. The etiology of the cardiomegaly and pericardial effusions in Cantu syndrome is unknown. We review all previously reported cases of Cantu syndrome and the associated cardiac manifestations. Copyright 2006 Wiley-Liss, Inc.

  20. Are recessions good for workplace safety?

    NARCIS (Netherlands)

    Boone, J.; van Ours, J.

    2006-01-01

    Empirical evidence shows that in recessions the rate of workplace accidents goes down. This paper presents a theory and an empirical investigation to explain this phenomenon. The theory is based on the idea that reporting an accident affects the reputation of a worker and raises the probability that

  1. 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…

  2. 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

  3. 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…

  4. Weathering the Recession in College Health

    Science.gov (United States)

    Christmas, William A.

    2010-01-01

    The current global recession has increased personal stress levels throughout our society. With dwindling resources, institutions of higher learning are especially prone to budgetary cutbacks during such periods. Based on 22 years of experience as a health service director, the author offers some personal insights in the hope that they will help…

  5. Recessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal epilepsy, developmental delay and teeth hypoplasia.

    Science.gov (United States)

    Hardies, Katia; de Kovel, Carolien G F; Weckhuysen, Sarah; Asselbergh, Bob; Geuens, Thomas; Deconinck, Tine; Azmi, Abdelkrim; May, Patrick; Brilstra, Eva; Becker, Felicitas; Barisic, Nina; Craiu, Dana; Braun, Kees P J; Lal, Dennis; Thiele, Holger; Schubert, Julian; Weber, Yvonne; van 't Slot, Ruben; Nürnberg, Peter; Balling, Rudi; Timmerman, Vincent; Lerche, Holger; Maudsley, Stuart; Helbig, Ingo; Suls, Arvid; Koeleman, Bobby P C; De Jonghe, Peter

    2015-11-01

    The epileptic encephalopathies are a clinically and aetiologically heterogeneous subgroup of epilepsy syndromes. Most epileptic encephalopathies have a genetic cause and patients are often found to carry a heterozygous de novo mutation in one of the genes associated with the disease entity. Occasionally recessive mutations are identified: a recent publication described a distinct neonatal epileptic encephalopathy (MIM 615905) caused by autosomal recessive mutations in the SLC13A5 gene. Here, we report eight additional patients belonging to four different families with autosomal recessive mutations in SLC13A5. SLC13A5 encodes a high affinity sodium-dependent citrate transporter, which is expressed in the brain. Neurons are considered incapable of de novo synthesis of tricarboxylic acid cycle intermediates; therefore they rely on the uptake of intermediates, such as citrate, to maintain their energy status and neurotransmitter production. The effect of all seven identified mutations (two premature stops and five amino acid substitutions) was studied in vitro, using immunocytochemistry, selective western blot and mass spectrometry. We hereby demonstrate that cells expressing mutant sodium-dependent citrate transporter have a complete loss of citrate uptake due to various cellular loss-of-function mechanisms. In addition, we provide independent proof of the involvement of autosomal recessive SLC13A5 mutations in the development of neonatal epileptic encephalopathies, and highlight teeth hypoplasia as a possible indicator for SLC13A5 screening. All three patients who tried the ketogenic diet responded well to this treatment, and future studies will allow us to ascertain whether this is a recurrent feature in this severe disorder. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  6. Factors influencing circadian rhythms in acetaminophen lethality.

    Science.gov (United States)

    Schnell, R C; Bozigian, H P; Davies, M H; Merrick, B A; Park, K S; McMillan, D A

    1984-01-01

    Experiments were conducted to examine the effects of changes in lighting schedules and food consumption on circadian rhythms in acetaminophen lethality and hepatic glutathione levels in male mice. Under a normal lighting schedule (light: 06.00-18.00 h), male mice exhibited a circadian rhythm in acetaminophen lethality (peak: 18.00 h; nadir: 06.00, 10.00 h) and an inverse rhythm in hepatic glutathione concentrations (peak: 06.00, 10.00 h; nadir: 18.00 h). Under a reversed lighting schedule (light: 18.00-06.00 h) the glutathione rhythm was reversed and the rhythm in acetaminophen lethality was altered showing greater sensitivity to the drug. Under continuous light, there was a shift in the acetaminophen lethality and the hepatic glutathione rhythms. Under continuous dark, both rhythms were abolished. Under a normal lighting regimen, hepatic glutathione levels were closely correlated with food consumption; i.e., both were increased during the dark phase and decreased during the light phase. Fasting the mice for 12 h abolished the rhythms in acetaminophen lethality and hepatic glutathione levels; moreover, the lethality was increased and the hepatic glutathione levels were decreased. These experiments show that both lighting schedules and feeding can alter the circadian rhythms in acetaminophen lethality and hepatic glutathione levels in male mice.

  7. 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.

  8. Genomewide Clonal Analysis of Lethal Mutations in the Drosophila melanogaster Eye: Comparison of the X Chromosome and Autosomes

    OpenAIRE

    Call, Gerald B.; Olson, John M.; Chen, Jiong; Villarasa, Nikki; Ngo, Kathy T.; Yabroff, Allison M.; Cokus, Shawn; Pellegrini, Matteo; Bibikova, Elena; Bui, Chris; Cespedes, Albert; Chan, Cheryl; Chan, Stacy; Cheema, Amrita K.; Chhabra, Akanksha

    2007-01-01

    Using a large consortium of undergraduate students in an organized program at the University of California, Los Angeles (UCLA), we have undertaken a functional genomic screen in the Drosophila eye. In addition to the educational value of discovery-based learning, this article presents the first comprehensive genomewide analysis of essential genes involved in eye development. The data reveal the surprising result that the X chromosome has almost twice the frequency of essential genes involved ...

  9. Differential expression of the lethal gene Luteus-Pa in cacao of the Parinari series.

    Science.gov (United States)

    Rehem, B C; Almeida, A-A F; Figueiredo, G S F; Gesteira, A S; Santos, S C; Corrêa, R X; Yamada, M M; Valle, R R

    2016-02-22

    The recessive lethal character Luteus-Pa is found in cacao (Theobroma cacao) genotypes of the Parinari series (Pa) and is characterized by expression of leaf chlorosis and seedling death. Several genotypes of the Pa series are bearers of the gene responsible for the expression of the Luteus-Pa character, which can be used as a tool for determining relationships between genotypes of this group. To evaluate this phenomenon, we analyzed the differential expression of genes between mutant seedlings and wild-type hybrid Pa 30 x 169 seedlings, with the aim of elucidating the possible lethal mechanisms of the homozygous recessive character Luteus-Pa. Plant material was harvested from leaves of wild and mutant seedlings at different periods to construct a subtractive library and perform quantitative analysis using real-time PCR. The 649 sequences obtained from the subtractive library had an average length of 500 bp, forming 409 contigs. The probable proteins encoded were grouped into 10 functional categories. Data from ESTs identified genes associated with Rubisco, peroxidases, and other proteins and enzymes related to carbon assimilation, respiration, and photosystem 2. Mutant seedlings were characterized by synthesizing defective PsbO and PsbA proteins, which were overexpressed from 15 to 20 days after seedling emergence.

  10. 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

  11. X Chromosome and Autosome Dosage Responses in Drosophila melanogaster Heads

    Science.gov (United States)

    Chen, Zhen-Xia; Oliver, Brian

    2015-01-01

    X chromosome dosage compensation is required for male viability in Drosophila. Dosage compensation relative to autosomes is two-fold, but this is likely to be due to a combination of homeostatic gene-by-gene regulation and chromosome-wide regulation. We have baseline values for gene-by-gene dosage compensation on autosomes, but not for the X chromosome. Given the evolutionary history of sex chromosomes, these baseline values could differ. We used a series of deficiencies on the X and autosomes, along with mutations in the sex-determination gene transformer-2, to carefully measure the sex-independent X-chromosome response to gene dosage in adult heads by RNA sequencing. We observed modest and indistinguishable dosage compensation for both X chromosome and autosome genes, suggesting that the X chromosome is neither inherently more robust nor sensitive to dosage change. PMID:25850426

  12. Autosomal dominant HMSN with proximal involvement: new Brazilian cases

    OpenAIRE

    Patroclo,Cristiane Borges; Lino,Angelina Maria Martins; Marchiori,Paulo Eurípides; Brotto,Mário Wilson Iervolino; Hirata,Maria Teresa Alves

    2009-01-01

    We report four Brazilian siblings with Autosomal Dominant Hereditary Motor Sensory Neuropathy with Proximal Dominant Involvement (HMSN-P), a rare form of HMSN, that was characterized by proximal dominant muscle weakness and atrophy onset after the age of 30 years, fasciculation, arreflexia and sensory disturbances with autosomal dominant inheritance. Electrophysiological study and sural nerve biopsy were in the accordance with axonal sensory motor polyneuropathy and laboratorial analysis disc...

  13. Formulating the spring discharge-function for the recession period ...

    Indian Academy of Sciences (India)

    Prediction of spring water availability during the recession period is the key to its proper management. The spring discharge-rate can be forecasted by studying its behaviour for the past recession periods. Expressing recession curve in mathematical terms requires its quantitative analyses in priori. It was found that the fitting ...

  14. Gingival Recession in a Child‑Patient; Easily Missed Etiologies ...

    African Journals Online (AJOL)

    Gingival recession – the apical migration of the marginal gingiva[1]. - results from several factors. In a study of historical interest, Baker and Seymour[2] suggested plaque‑induced inflammation as an important cause of gingival recession. Determinants of gingival recession identified among Nigerians were age, calculus, ...

  15. Development and application of genetic sexing systems for the Mediterranean fruit fly based on a temperature sensitive lethal mutation

    International Nuclear Information System (INIS)

    Franz, G.; Willhoeft, U.; Kerremans, P.; Hendrichs, J.; Rendon, P.

    1997-01-01

    The present status in genetic sexing for the Mediterranean fruit fly is discussed. This includes the selection of the appropriate sexing gene (which determines the feasibility and practical applicability of the sexing system) as well as the selection of the appropriate Y-autosome translocation (which determines the stability of the sexing system). A temperature sensitive lethal mutation is used to eliminate females during the egg stage. This mutation in combination with new Y-autosome translocations allowed the construction of a genetic sexing strain, named VIENNA-42, that is stable enough for large scale mass rearing. Also described are the analysis of this strain under field cage and field conditions and, in preparation for large scale tests in Guatemala, the outcrossing of VIENNA-42 with genetic material from the target area. (author)

  16. Command and Control for Distributed Lethality

    Science.gov (United States)

    2017-06-01

    communications over vast distances, and the need for near-real-time coordination means that stakeholders for the distributed lethality concept can encompass a...and methods of effective communication systems. 14. SUBJECT TERMS command and control (C2) distributed lethality system of systems (SOS) model...refinement through simulations of the C2 structure and further research into technologies and methods of effective communication systems. vi THIS PAGE

  17. Experiences in therapy for lethal midline granuloma

    Energy Technology Data Exchange (ETDEWEB)

    Tosaka, K.; Ishikawa, T. (Kumamoto Univ. (Japan). School of Medicine)

    1982-03-01

    Four cases of the lethal midline granuloma or malignant granuloma of the nose were treated by irradiation and chemotherapy, which are generally prescribed for malignant lymphomas. Clinical, histological and laboratory examination indicated that they were the lethal midline granuloma and clearly differentiated from Wegener's granulomatosis or malignant lymphoma. All of the cases exhibited primary remission. The four cases were observed up to 38, 22, 14, and 10 months since the beginning of the therapy, showing no local or general recurrence.

  18. Is Outdoor Recreation Recession-proof? An Empirical Investigation on Iowan’s Lake Recreation Behavior During 2009 Recession.

    OpenAIRE

    Hoque, Mohammad Mainul; Kling, Catherine L.; Herriges, Joseph A.

    2013-01-01

    The US economy was hit hard by a recession during 2008–2009, which is considered the longest and most severe economic crisis since the end of Great Depression. The recession affected individual economic well-being through unemployment, stock market crashes, and falling real estate prices, all of which generated low consumer confidence. While much is known about the effect of recessions on macro-level variables, much less is known about how the effects of recession alter household-level consum...

  19. Incompatibility between X chromosome factor and pericentric heterochromatic region causes lethality in hybrids between Drosophila melanogaster and its sibling species.

    Science.gov (United States)

    Cattani, M Victoria; Presgraves, Daven C

    2012-06-01

    The Dobzhansky-Muller model posits that postzygotic reproductive isolation results from the evolution of incompatible epistatic interactions between species: alleles that function in the genetic background of one species can cause sterility or lethality in the genetic background of another species. Progress in identifying and characterizing factors involved in postzygotic isolation in Drosophila has remained slow, mainly because Drosophila melanogaster, with all of its genetic tools, forms dead or sterile hybrids when crossed to its sister species, D. simulans, D. sechellia, and D. mauritiana. To circumvent this problem, we used chromosome deletions and duplications from D. melanogaster to map two hybrid incompatibility loci in F(1) hybrids with its sister species. We mapped a recessive factor to the pericentromeric heterochromatin of the X chromosome in D. simulans and D. mauritiana, which we call heterochromatin hybrid lethal (hhl), which causes lethality in F(1) hybrid females with D. melanogaster. As F(1) hybrid males hemizygous for a D. mauritiana (or D. simulans) X chromosome are viable, the lethality of deficiency hybrid females implies that a dominant incompatible partner locus exists on the D. melanogaster X. Using small segments of the D. melanogaster X chromosome duplicated onto the Y chromosome, we mapped a dominant factor that causes hybrid lethality to a small 24-gene region of the D. melanogaster X. We provide evidence suggesting that it interacts with hhl(mau). The location of hhl is consistent with the emerging theme that hybrid incompatibilities in Drosophila involve heterochromatic regions and factors that interact with the heterochromatin.

  20. Recessive Mutations in RTN4IP1 Cause Isolated and Syndromic Optic Neuropathies

    Science.gov (United States)

    Angebault, Claire; Guichet, Pierre-Olivier; Talmat-Amar, Yasmina; Charif, Majida; Gerber, Sylvie; Fares-Taie, Lucas; Gueguen, Naig; Halloy, François; Moore, David; Amati-Bonneau, Patrizia; Manes, Gael; Hebrard, Maxime; Bocquet, Béatrice; Quiles, Mélanie; Piro-Mégy, Camille; Teigell, Marisa; Delettre, Cécile; Rossel, Mireille; Meunier, Isabelle; Preising, Markus; Lorenz, Birgit; Carelli, Valerio; Chinnery, Patrick F.; Yu-Wai-Man, Patrick; Kaplan, Josseline; Roubertie, Agathe; Barakat, Abdelhamid; Bonneau, Dominique; Reynier, Pascal; Rozet, Jean-Michel; Bomont, Pascale; Hamel, Christian P.; Lenaers, Guy

    2015-01-01

    Autosomal-recessive optic neuropathies are rare blinding conditions related to retinal ganglion cell (RGC) and optic-nerve degeneration, for which only mutations in TMEM126A and ACO2 are known. In four families with early-onset recessive optic neuropathy, we identified mutations in RTN4IP1, which encodes a mitochondrial ubiquinol oxydo-reductase. RTN4IP1 is a partner of RTN4 (also known as NOGO), and its ortholog Rad8 in C. elegans is involved in UV light response. Analysis of fibroblasts from affected individuals with a RTN4IP1 mutation showed loss of the altered protein, a deficit of mitochondrial respiratory complex I and IV activities, and increased susceptibility to UV light. Silencing of RTN4IP1 altered the number and morphogenesis of mouse RGC dendrites in vitro and the eye size, neuro-retinal development, and swimming behavior in zebrafish in vivo. Altogether, these data point to a pathophysiological mechanism responsible for RGC early degeneration and optic neuropathy and linking RTN4IP1 functions to mitochondrial physiology, response to UV light, and dendrite growth during eye maturation. PMID:26593267

  1. Integrin alpha 8 recessive mutations are responsible for bilateral renal agenesis in humans.

    Science.gov (United States)

    Humbert, Camille; Silbermann, Flora; Morar, Bharti; Parisot, Mélanie; Zarhrate, Mohammed; Masson, Cécile; Tores, Frédéric; Blanchet, Patricia; Perez, Marie-José; Petrov, Yuliya; Khau Van Kien, Philippe; Roume, Joelle; Leroy, Brigitte; Gribouval, Olivier; Kalaydjieva, Luba; Heidet, Laurence; Salomon, Rémi; Antignac, Corinne; Benmerah, Alexandre; Saunier, Sophie; Jeanpierre, Cécile

    2014-02-06

    Renal hypodysplasia (RHD) is a heterogeneous condition encompassing a spectrum of kidney development defects including renal agenesis, hypoplasia, and (cystic) dysplasia. Heterozygous mutations of several genes have been identified as genetic causes of RHD with various severity. However, these genes and mutations are not associated with bilateral renal agenesis, except for RET mutations, which could be involved in a few cases. The pathophysiological mechanisms leading to total absence of kidney development thus remain largely elusive. By using a whole-exome sequencing approach in families with several fetuses with bilateral renal agenesis, we identified recessive mutations in the integrin α8-encoding gene ITGA8 in two families. Itga8 homozygous knockout in mice is known to result in absence of kidney development. We provide evidence of a damaging effect of the human ITGA8 mutations. These results demonstrate that mutations of ITGA8 are a genetic cause of bilateral renal agenesis and that, at least in some cases, bilateral renal agenesis is an autosomal-recessive disease. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  2. 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.

  3. Labor Unions and the Great Recession

    Directory of Open Access Journals (Sweden)

    Ruth Milkman

    2017-04-01

    Full Text Available This article examines the impact of the Great Recession on the U.S. labor movement. After reviewing the classic industrial relations literature on the relationship between unionization rates and business cycles, we analyze historical union density trends. After documenting the relentless downward trend in the private sector from the early 1980s, with no apparent relationship to the business cycle, we analyze the negative impact of the political dynamic that unfolded in the wake of the Great Recession on public-sector unionism in sharp contrast to what took place during the Great Depression. We also explore the new forms of labor organizing that have emerged in the private sector, which have capitalized on the growing public concern about rising inequality sparked by Occupy Wall Street.

  4. 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.

  5. Recessive inheritance of population-specific intronic LINE-1 insertion causes a rotor syndrome phenotype.

    Science.gov (United States)

    Kagawa, Tatehiro; Oka, Akira; Kobayashi, Yoshinao; Hiasa, Yoichi; Kitamura, Tsuneo; Sakugawa, Hiroshi; Adachi, Yukihiko; Anzai, Kazuya; Tsuruya, Kota; Arase, Yoshitaka; Hirose, Shunji; Shiraishi, Koichi; Shiina, Takashi; Sato, Tadayuki; Wang, Ting; Tanaka, Masayuki; Hayashi, Hideki; Kawabe, Noboru; Robinson, Peter N; Zemojtel, Tomasz; Mine, Tetsuya

    2015-03-01

    Sequences of long-interspersed elements (LINE-1, L1) make up ∼17% of the human genome. De novo insertions of retrotransposition-active L1s can result in genetic diseases. It has been recently shown that the homozygous inactivation of two adjacent genes SLCO1B1 and SLCO1B3 encoding organic anion transporting polypeptides OATP1B1 and OATP1B3 causes a benign recessive disease presenting with conjugated hyperbilirubinemia, Rotor syndrome. Here, we examined SLCO1B1 and SLCO1B3 genes in six Japanese diagnosed with Rotor syndrome on the basis of laboratory data and laparoscopy. All six Japanese patients were homozygous for the c.1738C>T nonsense mutation in SLCO1B1 and homozygous for the insertion of a ∼6.1-kbp L1 retrotransposon in intron 5 of SLCO1B3, which altogether make up a Japanese-specific haplotype. RNA analysis revealed that the L1 insertion induced deleterious splicing resulting in SLCO1B3 transcripts lacking exon 5 or exons 5-7 and containing premature stop codons. The expression of OATP1B1 and OATP1B3 proteins was not detected in liver tissues. This is the first documented case of a population-specific polymorphic intronic L1 transposon insertion contributing to molecular etiology of recessive genetic disease. Since L1 activity in human genomes is currently seen as a major source of individual genetic variation, further investigations are warranted to determine whether this phenomenon results in other autosomal-recessive diseases. © 2014 WILEY PERIODICALS, INC.

  6. 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.

  7. Exome sequencing for gene discovery in lethal fetal disorders--harnessing the value of extreme phenotypes.

    Science.gov (United States)

    Filges, Isabel; Friedman, Jan M

    2015-10-01

    Massively parallel sequencing has revolutionized our understanding of Mendelian disorders, and many novel genes have been discovered to cause disease phenotypes when mutant. At the same time, next-generation sequencing approaches have enabled non-invasive prenatal testing of free fetal DNA in maternal blood. However, little attention has been paid to using whole exome and genome sequencing strategies for gene identification in fetal disorders that are lethal in utero, because they can appear to be sporadic and Mendelian inheritance may be missed. We present challenges and advantages of applying next-generation sequencing approaches to gene discovery in fetal malformation phenotypes and review recent successful discovery approaches. We discuss the implication and significance of recessive inheritance and cross-species phenotyping in fetal lethal conditions. Whole exome sequencing can be used in individual families with undiagnosed lethal congenital anomaly syndromes to discover causal mutations, provided that prior to data analysis, the fetal phenotype can be correlated to a particular developmental pathway in embryogenesis. Cross-species phenotyping allows providing further evidence for causality of discovered variants in genes involved in those extremely rare phenotypes and will increase our knowledge about normal and abnormal human developmental processes. Ultimately, families will benefit from the option of early prenatal diagnosis. © 2014 John Wiley & Sons, Ltd.

  8. 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.

  9. Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis : a European consensus

    NARCIS (Netherlands)

    Döring, G; Conway, S P; Heijerman, H G; Hodson, M E; Høiby, N; Smyth, A; Touw, D J

    2000-01-01

    Cystic fibrosis (CF) is the most common lethal hereditary disorder with autosomal recessive heredity in caucasians. The majority of CF patients suffer from chronic respiratory infection with the opportunistic bacterial pathogen Pseudomonas aeruginosa. No consensus among clinicians has been reached

  10. Lethality Index 2008-2014: Less shootings, same lethality, more opacity

    Directory of Open Access Journals (Sweden)

    Carlos Silva Forné

    2017-11-01

    Full Text Available This article evaluates the use of lethal force by Mexican federal security forces during shootings with presumed members of organized crime from 2008-2014. The authors use official data and press reports on deaths and wounded in shootings to construct indicators such as the number of dead civilians over the number of dead officials from the federal security forces and the number of dead civilians over the number of wounded civilians. In a context where certain factors that contribute to an excessive use of force become more common, the results of the study show a growing use of lethal force. This raises questions over the possible excessive use of lethal force as a normal or systematic practice. The study also shows a growing context of opacity in the information available to evaluate the use of lethal force and the general lack of a legal framework to regulate the use of lethal force in Mexico.

  11. Evidence for increased levels of positive and negative selection on the X chromosome versus autosomes in humans.

    Science.gov (United States)

    Veeramah, Krishna R; Gutenkunst, Ryan N; Woerner, August E; Watkins, Joseph C; Hammer, Michael F

    2014-09-01

    Partially recessive variants under positive selection are expected to go to fixation more quickly on the X chromosome as a result of hemizygosity, an effect known as faster-X. Conversely, purifying selection is expected to reduce substitution rates more effectively on the X chromosome. Previous work in humans contrasted divergence on the autosomes and X chromosome, with results tending to support the faster-X effect. However, no study has yet incorporated both divergence and polymorphism to quantify the effects of both purifying and positive selection, which are opposing forces with respect to divergence. In this study, we develop a framework that integrates previously developed theory addressing differential rates of X and autosomal evolution with methods that jointly estimate the level of purifying and positive selection via modeling of the distribution of fitness effects (DFE). We then utilize this framework to estimate the proportion of nonsynonymous substitutions fixed by positive selection (α) using exome sequence data from a West African population. We find that varying the female to male breeding ratio (β) has minimal impact on the DFE for the X chromosome, especially when compared with the effect of varying the dominance coefficient of deleterious alleles (h). Estimates of α range from 46% to 51% and from 4% to 24% for the X chromosome and autosomes, respectively. While dependent on h, the magnitude of the difference between α values estimated for these two systems is highly statistically significant over a range of biologically realistic parameter values, suggesting faster-X has been operating in humans. © The Author 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  12. The interaction between daughterless and sex-lethal in triploids: a lethal sex-transforming maternal effect linking sex determination and dosage compensation in Drosophila melanogaster.

    Science.gov (United States)

    Cline, T W

    1983-02-01

    Regulation of Drosophila sex determination and X-chromosome dosage compensation in response to the X-chromosome/autosome (X/A) balance of the zygote is shown to require proper functioning of both the da+ gene in the mother and the Sxl+ gene in the zygote. Previous studies led to the hypothesis that zygotic Sxl+ alleles are differentially active in females (XXAA) vs males (XYAA) in response to the X/A balance, and that maternal da+ gene product acts as a positive regulator in this connection. Sxl+ activity was proposed to impose the female developmental sequence on cells which would follow the male sequence in its absence. Important predictions of this proposal are verified. This study focuses primarily on the phenotype of triploid intersexes (XXAAA, X/A = 0.67). They are shown here to survive effects of da and Sxl mutations that would be lethal to diploids. The ambiguous X/A signal of intersexes normally causes them to develop as phenotypic mosaics of male and female tissue. Loss of maternal da+ or zygotic Sxl+ gene function shifts their somatic sexual phenotype to the male alternative. A gain-of-function mutation at Sxl has the opposite effect, imposing female development regardless of the maternal genotype with respect to da. It also reduces their rate of X-linked gene expression. The effects of a duplication of Sxl+ resemble those of the constitutive Sxl allele, but are less extreme. The role of these genes in the process of X-chromosome dosage compensation is inferred indirectly from the strict dependence of the mutations' lethal effects on the X/A balance in haploids, diploids, and triploids, and more directly from the effects of the mutations on the phenotypes of the X-linked neomorphic mutations, Bar and Hairy-wing. The relationship of da+ and Sxl+ gene functions to those of other sex-specific lethal loci in D. melanogaster, and to sex determination mechanisms in other species, is discussed.

  13. Studies on mutagen-sensitive strains of Drosophila melanogaster. IX. Modification of genetic damage induced by X-irradiation of spermatozoa in N2, air or O2 by 4 autosomal repair-deficient mutants

    International Nuclear Information System (INIS)

    Ferro, W.

    1986-01-01

    The influence of defects in DNA repair on the recovery of X-ray-induced genetic damage in spermatozoa of Drosophila melanogaster was studied. Basc males were irradiated in N 2 , air or O 2 and mated to females of 4 repair-deficient mutant types. The responses in the different crosses with repair-deficient females were compared to those with repair-proficient mei + females (maternal effects). The main findings are the following: (1) with excision repair-deficient females the frequencies of spontaneous recessive lethals tend to be higher than with mei + females; (2) with excision repair-deficient females the frequencies of recessive lethals induced in N 2 and air and often in O 2 are higher than with mei + females; (3) with post-replication repair-deficient mutants a maternal effect is found for X-ray-induced translocations. The data are discussed and explained. (Auth.)

  14. 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.

  15. Coal industry defies recession with record exports

    International Nuclear Information System (INIS)

    Casey, Denis.

    1994-01-01

    Despite the worldwide recession which has adversely affected many commodities, the New South Wales coal industry achieved record production and exports during 1992-93. Although saleable coal production increased by only a modest 0.7%, experts rose by an impressive 7.1% to 57.4 million tonnes. Coking coal jumped by 14.6% to 23.6 million tonnes while thermal coal increased by 2.7% to 33.8 million tonnes. The value of coal experts amounted at $3.1 million. 1 tab

  16. 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...

  17. Guidebook for non-lethal experimentation

    NARCIS (Netherlands)

    Paulissen, J.J.M.; Rahimi, R.

    2011-01-01

    In the 2009-2011 timeframe, NATO conducts a capability based assessment of Non-Lethal Weapon (NLW) systems. The work, performed by the RTO study team SAS-078, involves the development of NLW requirement descriptions, which are put against a set of NLW systems. Gaps are likely to occur, indicating

  18. Genetics Home Reference: Amish lethal microcephaly

    Science.gov (United States)

    ... 1 in 500 newborns in the Old Order Amish population of Pennsylvania. It has not been found outside this population. Related Information What information about a genetic condition can statistics provide? Why are some genetic ... gene cause Amish lethal microcephaly . The SLC25A19 gene provides instructions for ...

  19. 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...

  20. 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.

  1. Patterning and gastrulation defects caused by the tw18 lethal are due to loss of Ppp2r1a

    Directory of Open Access Journals (Sweden)

    Lisette Lange

    2017-06-01

    Full Text Available The mouse t haplotype, a variant 20 cM genomic region on Chromosome 17, harbors 16 embryonic control genes identified by recessive lethal mutations isolated from wild mouse populations. Due to technical constraints so far only one of these, the tw5 lethal, has been cloned and molecularly characterized. Here we report the molecular isolation of the tw18 lethal. Embryos carrying the tw18 lethal die from major gastrulation defects commencing with primitive streak formation at E6.5. We have used transcriptome and marker gene analyses to describe the molecular etiology of the tw18 phenotype. We show that both WNT and Nodal signal transduction are impaired in the mutant epiblast, causing embryonic patterning defects and failure of primitive streak and mesoderm formation. By using a candidate gene approach, gene knockout by homologous recombination and genetic rescue, we have identified the gene causing the tw18 phenotype as Ppp2r1a, encoding the PP2A scaffolding subunit PR65alpha. Our work highlights the importance of phosphatase 2A in embryonic patterning, primitive streak formation, gastrulation, and mesoderm formation downstream of WNT and Nodal signaling.

  2. Effect of gamma radiation and sex-linked recessive lethal mutations on sperm transfer in Ephestia kuehniella (Lepidoptera: Pyralidae)

    Czech Academy of Sciences Publication Activity Database

    Koudelová, Jana; Cook, P. A.

    2001-01-01

    Roč. 84, č. 2 (2001), s. 172-182 ISSN 0015-4040 R&D Projects: GA AV ČR IAA6007609 Institutional research plan: CEZ:AV0Z5007907 Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 0.591, year: 2001

  3. 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

  4. 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

  5. Prenatal detection of rare chromosomal autosomal abnormalities in Europe

    NARCIS (Netherlands)

    Baena, N; De Vigan, C; Cariati, E; Clementi, M; Stoll, C; Caballin, MR; Guitart, M

    2003-01-01

    The aim of the present study was to evaluate the prenatal detection of rare chromosomal autosomal abnormalities by ultrasound (US) examination. Data were obtained from 19 congenital malformation registries from 11 European countries, between 01/07/96 and 31/12/98. A total of 664,340 births were

  6. 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 ...

  7. 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 ...

  8. Lethal and sub-lethal effects of copper to the african catfish ( clarias ...

    African Journals Online (AJOL)

    Lethal and sub-lethal effects of copper on Clarias gariepinus were studied using a 96-hour static bioassay. Copper (as copper chloride, CuCl2 . H2O) was used to prepare the stock solution from which five standard concentrations 0.0, 1.8, 3.2, 5.6, and 10.0 mg/L were prepared (coded A – E). 15 juvenile C. gariepinus fish ...

  9. Prevalence of gingival recession after orthodontic tooth movements.

    Science.gov (United States)

    Morris, Jason W; Campbell, Phillip M; Tadlock, Larry P; Boley, Jimmy; Buschang, Peter H

    2017-05-01

    This study was designed to evaluate the long-term prevalence of gingival recession after orthodontic tooth movements, focusing on the effects of mandibular incisor proclination and expansion of maxillary posterior teeth. Records of 205 patients (162 female, 43 male) were obtained from 2 private practice orthodontists. Using pretreatment (age, 14.0 ± 5.9 years) and posttreatment (age, 16.5 ± 6.0 years) lateral cephalograms and dental models, mandibular incisor proclination and maxillary arch widths were measured. Gingival recession was measured based on posttreatment and postretention (age, 32.3 ± 8.5 years) intraoral photographs and models. Associations between tooth movements and gingival recession were evaluated statistically. Only 5.8% of teeth exhibited recession at the end of orthodontic treatment (only 0.6% had recession >1 mm). After retention, 41.7% of the teeth showed recession, but the severity was limited (only 7.0% >1 mm). There was no relationship between mandibular incisor proclination during treatment and posttreatment gingival recession. Incisors that finished treatment angulated (IMPA) at 95° or greater did not show significantly more recession than did those that finished less than 95°. There were weak positive correlations (r = 0.17-0.41) between maxillary arch width increases during treatment and posttreatment recession. Orthodontic treatment is not a major risk factor for the development of gingival recession. Although greater amounts of maxillary expansion during treatment increase the risks of posttreatment recession, the effects are minimal. Copyright © 2017 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.

  10. 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.

  11. 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.

  12. [Co-inheritance of autosomal dominant polycystic kidney disease and sickle cell trait in African Americans].

    Science.gov (United States)

    Peces, R; Peces, C; Cuesta-López, E; Vega-Cabrera, C; Azorín, S; Pérez-Dueñas, V; Selgas, R

    2011-01-01

    Macroscopic haematuria secondary to renal cyst rupture is a frequent complication in autosomal dominant polycystic kidney disease (ADPKD). Sickle-cell disease is an autosomal recessive haemoglobinopathy that involves a qualitative anomaly of haemoglobin due to substitution of valine for the glutamic acid in the sixth position of 3-globin gene on the short arm of chromosome 11. For the full disease to be manifested, this mutation must be present on both inherited alleles. The severity of the disease is proportional to the quantity of haemoglobin S (Hb S) in the red cells; sickle-cell trait (Hb S 75%). In sickle-cell disease, the abnormal Hb S loses its rheological characteristics and is responsible of the various systemic manifestations including those of the kidney, such as macroscopic haematuria secondary to papilar necrosis. Despite the generally benign nature of the sickle-cell trait, several potentially serious complications have been described. Metabolic or environmental changes such as hypoxia, acidosis, dehydration, hyperosmolality or hyperthermia may transform silent sickle-cell trait into a syndrome resembling sickle-cell disease with vaso-occlusive crisis due to an accumulation of low deformable red blood cells in the microcirculation originating haematuria from papilar necrosis. On the other hand, it has been demonstrated an earlier onset of end-stage renal disease (ESRD), in blacks with ADPKD and sickle-cell trait when compared with blacks with ADPKD without the trait. We studied 2 african-american families (4 patients) which presented with both ADPKD and sickle-cell trait (Hb S <50%). The diagnosis of sickle-cell trait was confirmed by haemoglobin electrophoresis. The renal volume was measured by magnetic resonance imaging (MRI). The proband subject in family 1 presented frequent haematuria episodes, associated to increase of renal volume, developed very early ESRD and was dialyzed at the age of 39 years. The other 3 patients in family 2 presented

  13. The Impact of the Recession on College Students

    Science.gov (United States)

    Berg-Cross, Linda; Green, Rodney

    2010-01-01

    This article had three goals: (a) to provide a brief economic review of the relationship between recessionary times, institutional reactions, and the life trajectory of recession-era college students; (b) to discuss the recession-related psychosocial stressors facing today's college students; and (c) to discuss how counseling centers can help…

  14. 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…

  15. On the Nature of the Heisei Recession (in Japanese)

    OpenAIRE

    Kouichi Hamada

    2003-01-01

    The purpose of this paper is to inquire into possible causes of the Heisei Recession, the stagnation that has plagued the Japanese economy since the 1990s. As a preliminary step to interpret empirical analyses, one would need to understand by what linkages of causes and effects this recession has been brought about.

  16. 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

  17. 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…

  18. 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.

  19. 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

  20. Students with Obsessive Compulsive Disorder Participating in Recess

    Science.gov (United States)

    Lucas, Matthew D.; Sturgis, Amanda L.

    2012-01-01

    The participation of a student with Obsessive Compulsive Disorder (OCD) in recess can often be both challenging and rewarding for the student and teacher. This paper will address common characteristics of students with OCD and present basic solutions to improve the experience of these students in the recess setting. Initially the definition,…

  1. Gingival Recession in a Child‑Patient; Easily Missed Etiologies ...

    African Journals Online (AJOL)

    ... be acting in consonance (Concomitant multiple etiologies [CME]). The factors were a high frenal attachment, traumatic overbite and bruxism induced by premature tooth contacts. Pedodontists and periodontists should rule out CME in cases of gingival recession in the child‑patient. Keywords: Bruxism, Gingival recession, ...

  2. 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,…

  3. 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 ...

  4. POU4F3 mutation screening in Japanese hearing loss patients: Massively parallel DNA sequencing-based analysis identified novel variants associated with autosomal dominant hearing loss.

    Science.gov (United States)

    Kitano, Tomohiro; Miyagawa, Maiko; Nishio, Shin-Ya; Moteki, Hideaki; Oda, Kiyoshi; Ohyama, Kenji; Miyazaki, Hiromitsu; Hidaka, Hiroshi; Nakamura, Ken-Ichi; Murata, Takaaki; Matsuoka, Rina; Ohta, Yoko; Nishiyama, Nobuhiro; Kumakawa, Kozo; Furutate, Sakiko; Iwasaki, Satoshi; Yamada, Takechiyo; Ohta, Yumi; Uehara, Natsumi; Noguchi, Yoshihiro; Usami, Shin-Ichi

    2017-01-01

    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 in POU4F3 were a

  5. 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

  6. 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.

  7. Expanding the Clinical Spectrum of SPG11 Gene Mutations in Recessive Hereditary Spastic Paraplegia with Thin Corpus Callosum

    Science.gov (United States)

    Aleem, Alice Abdel; Abu-Shahba, Nourhan; Swistun, Dominika; Silhavy, Jennifer; Bielas, Stephanie L.; Sattar, Shifteh; Gleeson, Joseph G.; Zaki, Maha

    2011-01-01

    Hereditary spastic paraplegia (HSP) represents a large group of neurological disorders characterized by progressive spasticity of the lower limbs. One subtype of HSP shows an autosomal recessive form of inheritance with this corpus callosum (ARHSP-TCC), and displays genetic heterogeneity with four known loci. We identified a consanguineous Egyptian family with five affected individuals with ARHSP-TCC. We found linkage to the SPG11 locus and identified a novel homozygous p.Q498X stop codon mutation in exon 7 in the SPG11 gene encoding Spatacsin. Cognitive impairment and polyneuropathy, reported as frequent in SPG11, were not evident. This family supports the importance of SPG11 as a frequent cause for ARHSP-TCC, and expands the clinic SPG11 spectrum. PMID:20971220

  8. Lethal neonatal short-limbed dwarfism

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Ok Hwa; Yim, Chung Ik; Bahk, Yong Whee [Catholic Medical College, Seoul (Korea, Republic of)

    1986-02-15

    We have detailed our experiences on 6 cases of neonatal lethal short-limbed dwarfism and reviewed the articles. They include, achondrogenesis, thanatophoric dysplasia, asphyxiating thoracic dysplasia, osteogenesis imperfect a congenita, and hypophosphatasia lethals. Five babies were born alive but died soon after birth and one was a stillbirth. The main cause of failure to thrive was respiratory insufficiency. Each case was having quite characteristic radiologic findings, even if the general appearances were similar to the achondroplasts clinically. Precise diagnosis is very important for genetic counselling of the parents and alarm to them the possibility of bone dysplasias to the next offsprings. For this purpose, the radiologists play major role for the correct diagnosis. We stress that when the baby is born with short-limbed dwarfism, whole body radiogram should be taken including lateral view and postmortem radiogram is also very precious.

  9. 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.

  10. 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.

  11. Non-random autosome segregation : A stepping stone for the evolution of sex chromosome complexes?

    NARCIS (Netherlands)

    Schwander, Tanja; Beukeboom, Leo W.

    A new study in Caenorhabditis elegans shows that homologous autosomes segregate non-randomly with the sex chromosome in the heterogametic sex. Segregation occurs according to size, small autosomes segregating with, and large autosomes segregating away from the X-chromosome. Such sex-biased

  12. Lethal Interpersonal Violence in the Middle Pleistocene

    OpenAIRE

    Sala, Nohemi; Arsuaga, Juan Luis; Pantoja-P?rez, Ana; Pablos, Adri?n; Mart?nez, Ignacio; Quam, Rolf M.; G?mez-Olivencia, Asier; Berm?dez de Castro, Jos? Mar?a; Carbonell, Eudald

    2015-01-01

    Evidence of interpersonal violence has been documented previously in Pleistocene members of the genus Homo, but only very rarely has this been posited as the possible manner of death. Here we report the earliest evidence of lethal interpersonal violence in the hominin fossil record. Cranium 17 recovered from the Sima de los Huesos Middle Pleistocene site shows two clear perimortem depression fractures on the frontal bone, interpreted as being produced by two episodes of localized blunt force ...

  13. Lethal midline granuloma syndrome: a diagnostic dilemma

    Energy Technology Data Exchange (ETDEWEB)

    Ribeiro, Bruno Niemeyer de Freitas; Bahia, Paulo Roberto Valle [Radiology, Hospital Universitario Clementino Fraga Filho - Universidade Federal do Rio de Janeiro (HUCFF-UFRJ), Rio de Janeiro, RJ (Brazil); Oliveira, Ana Luiza Vianna Sobral de Magalhaes [Resident of Medical Practice, Hospital Federal da Lagoa, Rio de Janeiro, RJ (Brazil); Marchon Junior, Joao Luiz [Unit of Computed Tomography, Hospital Federal da Lagoa, Rio de Janeiro, RJ (Brazil)

    2012-11-15

    The rare lethal midline granuloma syndrome is difficult to diagnose because of the wide array of related diseases and lack of knowledge by the majority of physicians. In the present report, the authors describe the case of a patient with this disease, caused by squamous cell carcinoma, drawing attention to differential diagnoses and to clinical and radiological findings that may be useful to define the diagnosis. (author)

  14. Non-Lethal Weapons (NLW) Reference Book

    Science.gov (United States)

    2012-01-01

    exist regarding the use of a Optical Distractors (e.g., Dazzling Lasers )? ANSWER: Strict laws, SECDEF guidance, and ROE exist to control the use of...National Guard Bureau (NGB) 1 Domestic Operations Kits (DOK) Joint Non-Lethal Warning Munitions (JNLWM) 2 Green Lasers 2...Chemical Weapons and on their Destruction. Paris, 13 January 1993. 16. UNCCW Protocol on Blinding Laser Weapons (Protocol IV to the 1980

  15. Lethal interpersonal violence in the Middle Pleistocene.

    Directory of Open Access Journals (Sweden)

    Nohemi Sala

    Full Text Available Evidence of interpersonal violence has been documented previously in Pleistocene members of the genus Homo, but only very rarely has this been posited as the possible manner of death. Here we report the earliest evidence of lethal interpersonal violence in the hominin fossil record. Cranium 17 recovered from the Sima de los Huesos Middle Pleistocene site shows two clear perimortem depression fractures on the frontal bone, interpreted as being produced by two episodes of localized blunt force trauma. The type of injuries, their location, the strong similarity of the fractures in shape and size, and the different orientations and implied trajectories of the two fractures suggest they were produced with the same object in face-to-face interpersonal conflict. Given that either of the two traumatic events was likely lethal, the presence of multiple blows implies an intention to kill. This finding shows that the lethal interpersonal violence is an ancient human behavior and has important implications for the accumulation of bodies at the site, supporting an anthropic origin.

  16. Lethal interpersonal violence in the Middle Pleistocene.

    Science.gov (United States)

    Sala, Nohemi; Arsuaga, Juan Luis; Pantoja-Pérez, Ana; Pablos, Adrián; Martínez, Ignacio; Quam, Rolf M; Gómez-Olivencia, Asier; Bermúdez de Castro, José María; Carbonell, Eudald

    2015-01-01

    Evidence of interpersonal violence has been documented previously in Pleistocene members of the genus Homo, but only very rarely has this been posited as the possible manner of death. Here we report the earliest evidence of lethal interpersonal violence in the hominin fossil record. Cranium 17 recovered from the Sima de los Huesos Middle Pleistocene site shows two clear perimortem depression fractures on the frontal bone, interpreted as being produced by two episodes of localized blunt force trauma. The type of injuries, their location, the strong similarity of the fractures in shape and size, and the different orientations and implied trajectories of the two fractures suggest they were produced with the same object in face-to-face interpersonal conflict. Given that either of the two traumatic events was likely lethal, the presence of multiple blows implies an intention to kill. This finding shows that the lethal interpersonal violence is an ancient human behavior and has important implications for the accumulation of bodies at the site, supporting an anthropic origin.

  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. Induction of lethal mutations in the x-chromosome of unirradiated Drosophila oocytes after fertilization by irradiated spermatozoa

    International Nuclear Information System (INIS)

    Shaposhnikov, M.V.; Zainullin, V.G.

    2003-01-01

    Full text: In primary study on Drosophila it was found that irradiated male X-chromosomes induce recessive lethals in unirradiated female homologues (Abeleva et al., 1961, Radiobiologya. 1:123-126). The same effects were obtained in Drosophila in some recent investigations. The mechanisms of these effects is unknown. However it may be responsible for low-dose radiation effects as it induce mutations in unirradiated DNA. We assume that this effect may be a result of activation of error prone repair in response to preliminary DNA lesions in irradiated chromosome. In this research we analyse the frequencies of the recessive lethal mutations in the X-chromosome of Drosophila females mated with irradiated Basc males. We used acute irradiation with a dose rate of 10 Gy. For testing our hypothesis we use the mus209 and mei-41 mutant females. Mus209 is a PCNA gene homologue and mei-41 is a homologue of ATM gene. These genes are involved in post-replication DNA repair which may be error prone repair in Drosophila. It was obtained the tendency to decreasing the mutation rate at the mei-41[D5] background and decreasing mutation rate in mus209[B1] background in comparison with wild type strains CS (p<0.05). The obtained results demonstrate the possible role of mus209[B1] and mei-41[D5] genes in the inducing of mutations in the unirradiated X-chromosome in the presence of irradiated homologue

  19. 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)

  20. [Polycystic liver disease without autosomal dominant polycystic kidney disease].

    Science.gov (United States)

    Peces, R; González, P; Venegas, J L

    2003-01-01

    Polycystic liver disease is characterized by the presence of multiple bile duct-derived epithelial cysts scattered in the liver parenchyma. The natural history and clinical manifestations of polycystic liver disease are based on the disease as it manifests in patients with autosomal dominant polycystic kidney disease (ADPKD). The occurrence of polycystic liver disease independently from polycystic kidney disease has been known for a long time. More recently, a gene for autosomal dominant polycystic liver disease has been identified on chromosome 19p 13.2-13.1. Isolated polycystic liver disease is underdiagnosed and genetically distinct from polycystic liver disease associated with ADPKD but with similar pathogenesis and clinical manifestations. We report here two men with polycystic liver disease no associated with ADPKD. Ultrasound and computed tomography imaging were effective in documenting the underlying lesions non-invasively.

  1. Sacral radicular cysts in autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    Peces, Ramón; Peces, Carlos; Pérez-Dueñas, Virginia; Vega-Cabrera, Cristina; Campos, Isabel

    2009-10-01

    This is the first report of a case of sacral radicular cysts in a patient with autosomal dominant polycystic kidney disease (ADPKD). A 46-year-old woman with ADPKD was found to have bilateral sacral radicular cysts discovered incidentally by magnetic resonance imaging (MRI). Cysts arising from arachnoid or spinal meningeal sac should be considered one of the manifestations of a more widespread connective tissue disorder associated with ADPKD.

  2. Autosomal dominant congenital Horner's syndrome in a Dutch family.

    Science.gov (United States)

    Hageman, G; Ippel, P F; te Nijenhuis, F C

    1992-01-01

    A Dutch family is reported with congenital Horner's syndrome in five cases spanning five generations, with symptoms of varying degree but mainly ptosis and meiosis. Heterochromia iridium, anhidrosis, and enophthalmos were not present. The site of the lesion may be in the region between Gasser's ganglion and the short vertical segment of the internal carotid artery near the siphon. There are only four previous reports showing autosomal dominant inheritance of congenital Horner's syndrome. Images PMID:1548493

  3. Predictors of autosomal dominant polycystic kidney disease progression.

    Science.gov (United States)

    Schrier, Robert W; Brosnahan, Godela; Cadnapaphornchai, Melissa A; Chonchol, Michel; Friend, Keith; Gitomer, Berenice; Rossetti, Sandro

    2014-11-01

    Autosomal dominant polycystic kidney disease is a genetic disorder associated with substantial variability in its natural course within and between affected families. Understanding predictors for rapid progression of this disease has become increasingly important with the emergence of potential new treatments. This systematic review of the literature since 1988 evaluates factors that may predict and/or effect autosomal dominant polycystic kidney disease progression. Predicting factors associated with early adverse structural and/or functional outcomes are considered. These factors include PKD1 mutation (particularly truncating mutation), men, early onset of hypertension, early and frequent gross hematuria, and among women, three or more pregnancies. Increases in total kidney volume and decreases in GFR and renal blood flow greater than expected for a given age also signify rapid disease progression. Concerning laboratory markers include overt proteinuria, macroalbuminuria, and perhaps, elevated serum copeptin levels in affected adults. These factors and others may help to identify patients with autosomal dominant polycystic kidney disease who are most likely to benefit from early intervention with novel treatments. Copyright © 2014 by the American Society of Nephrology.

  4. DOES CONJUNCTIVAL INCISION INFLUENCE MEDIAL RECTUS MUSCLE RECESSIONS?

    Directory of Open Access Journals (Sweden)

    Galina G. Dimitrova

    2015-09-01

    Full Text Available Purpose: To evaluate the role of conjunctival incision in medial rectus muscle recessions as surgical treatment of choice in esotropia. Methods: The study included 200 patients (370 eyes, operated on for esotropia in the period of 2000-2014. 170 of them (340 eyes underwent bilateral medial rectus muscle recessions and 30- unilateral medial rectus muscle recession for various forms of alternating/alternated esotropia. We compared the effect (Δ/mm recession of fornix and limbal approach. Diagnostic, surgical and statistical methods were used. Results: Limbal incision was performed on 110 patients (55,3% and fornix approach was done in 89 cases (44,7%. The mean effect corrected prism diopters for each mm of recession (Δ/mm differed significantly in the two groups, being bigger in cases with fornix incision (p<0,001 . Conclusion: The type of conjunctival incision in medial rectus muscle recessions have an influence not only on the cosmetic appearance, but also on the functional result. This is especially true for large recessions.

  5. 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.

  6. 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

  7. 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

  8. Study on KAL1 Gene Mutations in Idiopathic Hypogonadotropic Hypogonadism Patients with X-Linked Recessive Inheritance.

    Science.gov (United States)

    Ahmadzadeh, Atefeh; Ghods, Elahe; Mojarrad, Majid; Aboutorabi, Robab; Afkhamizadeh, Mojgan; Bonakdaran, Shokoofeh; Mosavi, Zohreh; Taghavi, Seyed Morteza; Hassanzadeh Nazarabadi, Mohammad

    2015-01-01

    Idiopathic hypogonadotropic hypogonadism (IHH) is a condition caused by low doses of hypothalamic gonadotropin-releasing hormone (GnRH) leading to absence or incomplete sexual maturation. One of the disorders leading to IHH is Kallmann syndrome which is characterized by GnRH deficiency with anosmia or hyposmia. This disorder generally occurs as a hereditary syndrome with X-linked recessive inheritance pattern. However, autosomal dominant or recessive and sporadic cases have also been reported. KAL1 is the most common mutated gene among these patients. The aim of this study was to determine the mutation spectrum of KAL1 gene in twenty patients. KAL1 exons were amplified by PCR method and the products were assessed by high resolution melting (HRM) technique. In addition, for one of the patients, all coding exons of the KAL1 gene were sequenced. Deletion of exons 4, 5 and 6 were evident in 5%, 10%, and 10% of patients, respectively. Furthermore, HRM results showed hemizygous mutation of exon 12 with more than 95% probability in 25% of patients. Finding these mutations could be helpful in the early diagnosis and presymptomic treatment of Kallman syndrome.

  9. Onychophagia and postorthodontic isolated gingival recession: diagnosis and treatment.

    Science.gov (United States)

    Alessandri Bonetti, Giulio; Incerti Parenti, Serena; Zucchelli, Giovanni

    2012-12-01

    This clinical report describes the diagnosis and the management of isolated-type recession defects of complex etiology in 2 healthy postorthodontic patients. The lesions were confined to 1 mandibular incisor and were associated with an abnormal buccolingual inclination of the affected tooth despite a lingual retainer made with a round stainless steel twisted wire. After careful questioning, it was determined that the recession defects were indirect effects of habitual onychophagia. The concomitant fingernail-biting habit and the lingual bonded retainer led to the indirect development of bone dehiscence and, consequently, gingival recession. Copyright © 2012 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.

  10. 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.

  11. Laminar flow in a recess of a hydrostatic bearing

    Science.gov (United States)

    San Andres, Luis A.; Velthuis, Johannes F. M.

    1992-01-01

    The flow in a recess of a hydrostatic journal bearing is studied in detail. The Navier-Stokes equations for the laminar flow of an incompressible liquid are solved numerically in a two-dimensional plane of a typical bearing recess. Pressure- and shear-induced flows, as well as a combination of these two flow conditions, are analyzed. Recess friction, pressure-ram effects at discontinuities in the flow region, and film entrance pressure loss effects are calculated. Entrance pressure loss coefficients over a forward-facing step are presented as functions of the mean flow Reynolds number for pure-pressure and shear-induced laminar flows.

  12. 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...

  13. Urbanization and the global malaria recession.

    Science.gov (United States)

    Tatem, Andrew J; Gething, Peter W; Smith, David L; Hay, Simon I

    2013-04-17

    The past century has seen a significant contraction in the global extent of malaria transmission, resulting in over 50 countries being declared malaria free, and many regions of currently endemic countries eliminating the disease. Moreover, substantial reductions in transmission have been seen since 1900 in those areas that remain endemic today. Recent work showed that this malaria recession was unlikely to have been driven by climatic factors, and that control measures likely played a significant role. It has long been considered, however, that economic development, and particularly urbanization, has also been a causal factor. The urbanization process results in profound socio-economic and landscape changes that reduce malaria transmission, but the magnitude and extent of these effects on global endemicity reductions are poorly understood. Global data at subnational spatial resolution on changes in malaria transmission intensity and urbanization trends over the past century were combined to examine the relationships seen over a range of spatial and temporal scales. A consistent pattern of increased urbanization coincident with decreasing malaria transmission and elimination over the past century was found. Whilst it remains challenging to untangle whether this increased urbanization resulted in decreased transmission, or that malaria reductions promoted development, the results point to a close relationship between the two, irrespective of national wealth. The continuing rapid urbanization in malaria-endemic regions suggests that such malaria declines are likely to continue, particularly catalyzed by increasing levels of direct malaria control.

  14. 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.

  15. Brave New Warfare: Autonomy in Lethal UAVs

    Science.gov (United States)

    2011-03-01

    Executions,” United Nations General Assembly, May 28, 2010, http://www2.ohchr.org/english/ bodies /hrcouncil/docs/14session/A.HRC.14.24.Add6.pdf. 34 Rique...capability 40 The Army’s Future Combat Sytems (FCS) program was canceled in May 2009 as part of... bodies /hrcouncil/docs/14session/A.HRC.14.24.Ad d6.pdf. Arkin, Ronald. Governing Lethal Behavior in Autonomous Robots. Boca Raton: CRC Press, 2009. doi

  16. The Structural Variation Is Associated with the Embryonic Lethality of a Novel Red Egg Mutant Fuyin-lre of Silkworm, Bombyx mori.

    Science.gov (United States)

    Chen, Anli; Liao, Pengfei; Li, Qiongyan; Zhao, Qiaoling; Yang, Weike; Zhu, Shuifen; Wu, Fang; He, Rongfan; Dong, Zhanpeng; Huang, Ping

    2015-01-01

    Bombyx mori presents several types of egg color mutations, all of which have been extensively discussed in sericulture. While the red egg mutation has been previously observed, lethal red-egg mutants have not been reported. In the present work, the red egg mutant Fuyin-lre (Fuyin-lethal red egg) was discovered from the Fuyin germplasm resource of B. mori. This mutant features red-colored eggs and embryonic lethality. Genetic analysis showed that Fuyin-lre follows recessive inheritance, with the red egg gene re governing the egg color, and the embryonic lethality of Fuyin-lre may be caused by mutations of other genes closely linked to re. Digital gene expression (DGE) was employed to compare the transcription profiles of Fuyin and Fuyin-lre eggs after 24 and 48 h of incubation. A total of 48 differentially expressed genes followed the same expression patterns in both groups at both time points (FDR < 0.01 and log 2 Ratio ≥ 1). Further analyses indicated that 8 out of the 48 genes (including re) were closely linked to re. These 8 genes were highly expressed in wild-type Fuyin and the red egg mutant re but showed nearly absent expression in Fuyin-lre. Sequencing of the re gene confirmed that the re gene itself does not induce embryonic lethality, and structure analysis showed that the structural variation of the region where the 8 genes were located may be associated with the embryonic lethality of Fuyin-lre. The present work provides a good foundation for future studies on the mechanism of embryonic lethality and embryonic development in Fuyin-lre.

  17. The Structural Variation Is Associated with the Embryonic Lethality of a Novel Red Egg Mutant Fuyin-lre of Silkworm, Bombyx mori.

    Directory of Open Access Journals (Sweden)

    Anli Chen

    Full Text Available Bombyx mori presents several types of egg color mutations, all of which have been extensively discussed in sericulture. While the red egg mutation has been previously observed, lethal red-egg mutants have not been reported. In the present work, the red egg mutant Fuyin-lre (Fuyin-lethal red egg was discovered from the Fuyin germplasm resource of B. mori. This mutant features red-colored eggs and embryonic lethality. Genetic analysis showed that Fuyin-lre follows recessive inheritance, with the red egg gene re governing the egg color, and the embryonic lethality of Fuyin-lre may be caused by mutations of other genes closely linked to re. Digital gene expression (DGE was employed to compare the transcription profiles of Fuyin and Fuyin-lre eggs after 24 and 48 h of incubation. A total of 48 differentially expressed genes followed the same expression patterns in both groups at both time points (FDR < 0.01 and log 2 Ratio ≥ 1. Further analyses indicated that 8 out of the 48 genes (including re were closely linked to re. These 8 genes were highly expressed in wild-type Fuyin and the red egg mutant re but showed nearly absent expression in Fuyin-lre. Sequencing of the re gene confirmed that the re gene itself does not induce embryonic lethality, and structure analysis showed that the structural variation of the region where the 8 genes were located may be associated with the embryonic lethality of Fuyin-lre. The present work provides a good foundation for future studies on the mechanism of embryonic lethality and embryonic development in Fuyin-lre.

  18. Issues surrounding lethal injection as a means of capital punishment.

    Science.gov (United States)

    Romanelli, Frank; Whisman, Tyler; Fink, Joseph L

    2008-12-01

    Lethal injection as a method of state-sanctioned capital punishment was initially proposed in the United States in 1977 and used for the first time in 1982. Most lethal injection protocols use a sequential drug combination of sodium thiopental, pancuronium bromide, and potassium chloride. Lethal injection was originally introduced as a more humane form of execution compared with existing mechanical methods such as electrocution, toxic gassing, hanging, or firing squad. Lethal injection has not, however, been without controversy. Several states are considering whether lethal injection meets constitutional scrutiny forbidding cruel and unusual punishment. Recently in the case of Ralph Baze and Thomas C. Bowling, Petitioners, v John D. Rees, Commissioner, Kentucky Department of Corrections et al, the United States Supreme Court upheld the constitutionality of the lethal injection protocol as carried out in the Commonwealth of Kentucky. Most of the debate has surrounded the dosing and procedures used in lethal injection and whether the drug combinations and measures for administering the drugs truly produce a timely, pain-free, and fail-safe death. Many have also raised issues regarding the "medicalization" of execution and the ethics of health care professionals' participation in any part of the lethal injection process. As a result of all these issues, the future of lethal injection as a means of execution in the United States is under significant scrutiny. Outcomes of ongoing legislative and judicial reviews might result in cessation of lethal injection in totality or in alterations involving specific drug combinations or administration procedures.

  19. 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...

  20. Miniature paint-spray gun for recessed areas

    Science.gov (United States)

    Vanasse, M. A.

    1968-01-01

    Miniature spray gun regulates paints and other liquids to spray at close range, facilitating spraying of remote or recessed areas. Individual valves for regulating air pressure and paint maximizes atomization for low pressure spraying.

  1. Heat Shield Recession Measurements Using Remote Spectral Sensors, Phase I

    Data.gov (United States)

    National Aeronautics and Space Administration — OKSI proposes a minimally invasive in-flight diagnostic to measure heat shield recession during flight tests. These measurements can be used to validate models and...

  2. Lethal congenital contracture syndrome (LCCS) and other lethal arthrogryposes in Finland--an epidemiological study.

    Science.gov (United States)

    Pakkasjärvi, Niklas; Ritvanen, Annukka; Herva, Riitta; Peltonen, Leena; Kestilä, Marjo; Ignatius, Jaakko

    2006-09-01

    Arthrogryposis multiplex congenita is a heterogeneous group of disorders characterized by multiple contractures with an estimated frequency of 1 in 3,000 births. With improving diagnostic methods, increasing numbers of fetuses with arthrogryposis are found. The pathogenetic mechanisms are relatively well known but the epidemiology and genetics of the prenatally lethal forms of arthrogryposis are less well known. In this study we collected all cases of a multiple contractures diagnosed in Finland during 1987-2002 including live born infants, stillbirths, and terminated pregnancies. Ninety-two cases of 214 suffered intrauterine demise (68 selective pregnancy terminations and 24 stillbirths) and 58 died in infancy. In 141 out of these cases the diagnosis could be included within lethal arthrogryposes, with a prevalence of 1 in 6,985 (1.43/10,000) births. Of these, 59 had spinal cord pathology at autopsy and thus were of neurogenic origin. Thirty-nine cases had lethal congenital contracture syndrome (LCCS) clinically characterized by total immobility of the fetus at all ultrasound examinations (12 weeks or later), multiple joint contractures in both upper and lower limbs, hydrops, and fetal death before the 32nd week of pregnancy. LCCS is noted as a unique Finnish disorder with a prevalence of 1 in 25,250 (0.40/10,000) births and is a major cause of lethal arthrogryposis in Finland.

  3. 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.)

  4. 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

  5. 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 ...

  6. 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 ...

  7. 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...

  8. Bilateral lateral rectus recession versus unilateral recession resection for basic intermittent exotropia: a meta-analysis.

    Science.gov (United States)

    Sun, Yuan; Zhang, Ting; Chen, Jingchang

    2018-03-01

    To compare the outcomes between bilateral lateral rectus recession (BLR) and unilateral recession resection (R&R) procedures in the treatment of basic intermittent exotropia. Databases from Medline, Embase, Web of Science and the Cochrane Register of Controlled Trials were searched prior to June 2, 2017. From these searches, three eligible randomized studies and three retrospective cohort trials, which compared conventional BLR versus R&R procedure were identified. Differences observed between these two interventions (BLR versus R&R) were expressed as odds ratio (OR) and 95% confidence intervals (CI). The data on rates of success, recurrence, and overcorrection were pooled and analyzed using a random-effects model. Our findings, as generated from the pooled estimates, suggested that success rates for the R&R procedure were significantly greater than that of BLR (OR, 0.50; 95% CI, 0.31-0.79; P = 0.003) and patients subjected to the BLR procedure were more likely to be recurrent (OR, 2.44; 95% CI, 1.17-5.10; P = 0.02). No statistically significant differences in the combined results for overcorrection rates were present between the BLR and R&R procedures (OR, 0.85; 95% CI, 0.32-2.28; P = 0.75). The overall findings from this meta-analysis indicated that the conventional R&R procedure is associated with higher success rates and lower recurrence rates in patients with basic intermittent exotropia.

  9. Investigation of finite difference recession computation techniques applied to a nonlinear recession problem

    Energy Technology Data Exchange (ETDEWEB)

    Randall, J D

    1978-03-01

    This report presents comparisons of results of five implicit and explicit finite difference recession computation techniques with results from a more accurate ''benchmark'' solution applied to a simple one-dimensional nonlinear ablation problem. In the comparison problem a semi-infinite solid is subjected to a constant heat flux at its surface and the rate of recession is controlled by the solid material's latent heat of fusion. All thermal properties are assumed constant. The five finite difference methods include three front node dropping schemes, a back node dropping scheme, and a method in which the ablation problem is embedded in an inverse heat conduction problem and no nodes are dropped. Constancy of thermal properties and the semiinfinite and one-dimensional nature of the problem at hand are not necessary assumptions in applying the methods studied to more general problems. The best of the methods studied will be incorporated into APL's Standard Heat Transfer Program.

  10. Gingival recession, oral hygiene and associated factors among Tanzanian women.

    Science.gov (United States)

    Mumghamba, E G S; Honkala, S; Honkala, E; Manji, K P

    2009-03-01

    Females are generally more motivated with regard to oral hygiene practices and thus brush their teeth more frequently than males. To determine the prevalence of gingival recession, oral hygiene status, oral hygiene practices and associated factors in women attending a maternity ward in Tanzania. Cross-sectional descriptive study. Maternity ward of Muhimbili National Hospital, Tanzania. Four hundred and forty six women were interviewed on oral hygiene practices and maternal factors, and a full-mouth examination was done to determine the presence of plaque, calculus, gingival bleeding and gingival recession at six sites per tooth. The prevalence of gingival recession (GR) > or =1 mm was 33.6%, calculus 99.3%, plaque 100%, and gingival bleeding 100%. Oral hygiene practices included toothbrushing (98.9%), brushing frequency > or =2 times/day (61.2%), horizontal brushing method (98%), and using a plastic toothbrush (97.8%). Factors that were significantly associated with gingival recession were age (OR = 2.0, 95% CI = 1.3-3.2), presence of calculus (OR(a) = 3.8, 95% CI=2.5-7.1), and gingival bleeding on probing (OR = 4.2, 95% CI = 2.5-7.1). Tooth cleaning practices and maternal factors, especially the number of pregnancies or deliveries were not significantly associated with gingival recession. In this study population, oral hygiene was poor and gingival recession was associated with age, calculus and gingival inflammation rather than with tooth cleaning practices.

  11. 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.

  12. 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

  13. PENCALC: a program for penetrance estimation in autosomal dominant diseases

    Directory of Open Access Journals (Sweden)

    Andréa R.V. Russo Horimoto

    2010-01-01

    Full Text Available We present a computer program developed for estimating penetrance rates in autosomal dominant diseases by means of family kinship and phenotype information contained within the pedigrees. The program also determines the exact 95% credibility interval for the penetrance estimate. Both executable (PenCalc for Windows and web versions (PenCalcWeb of the software are available. The web version enables further calculations, such as heterozygosity probabilities and assessment of offspring risks for all individuals in the pedigrees. Both programs can be accessed and down-loaded freely at the home-page address http://www.ib.usp.br/~otto/software.htm.

  14. 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.

  15. Autosomal dominant partial epilepsy with auditory features: Defining the phenotype

    Science.gov (United States)

    Winawer, Melodie R.; Hauser, W. Allen; Pedley, Timothy A.

    2009-01-01

    The authors previously reported linkage to chromosome 10q22-24 for autosomal dominant partial epilepsy with auditory features. This study describes seizure semiology in the original linkage family in further detail. Auditory hallucinations were most common, but other sensory symptoms (visual, olfactory, vertiginous, and cephalic) were also reported. Autonomic, psychic, and motor symptoms were less common. The clinical semiology points to a lateral temporal seizure origin. Auditory hallucinations, the most striking clinical feature, are useful for identifying new families with this synome. PMID:10851389

  16. Autosomal Linkage Analysis for Cannabis Use Behaviors in Australian Adults

    OpenAIRE

    Agrawal, Arpana; Morley, Katherine I.; Hansell, Narelle K.; Pergadia, Michele L.; Montgomery, Grant W.; Statham, Dixie J.; Todd, Richard D.; Madden, Pamela A. F.; Heath, Andrew C.; Whitfield, John; Martin, Nicholas G.; Lynskey, Michael T.

    2008-01-01

    Cannabis is the most commonly used illicit drug in developed and in developing nations. Twin studies have highlighted the role of genetic influences on early stages of cannabis use, such as a lifetime history of use, early-onset use and frequent use, however, we are not aware of any genomic studies that have examined these phenotypes. Using data on 2,314 families consisting of 5,600 adult Australian offspring and their parents, all of whom were scanned using 1,399 unique autosomal markers, we...

  17. Complex liver cysts in Autosomal Dominant Polycystic Kidney Disease.

    Science.gov (United States)

    Farooq, Zerwa; Behzadi, Ashkan Heshmatzadeh; Blumenfeld, Jon D; Zhao, Yize; Prince, Martin R

    To determine prevalence of complex liver cysts in Autosomal Dominant Polycystic Kidney Disease (ADPKD). Abdominal MRI in 186 ADPKD subjects were evaluated by two independent observers to determine prevalence of complex liver cysts. 23 (12%) of subjects, had at least 1 complex cyst. Only 8 (4%) were reported to have a complex cyst prospectively, representing an under-reporting rate of 65%. Median total cyst volume was 66-times greater for subjects with complex cysts compared to subjects without (p<0.0001). Complex hepatic cysts were observed in 12% of ADPKD cases, occurring more frequently in livers with extensive cystic involvement. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Development of the great recess framework - observational tool to measure contextual and behavioral components of elementary school recess.

    Science.gov (United States)

    Massey, William V; Stellino, Megan B; Mullen, Sean P; Claassen, Jennette; Wilkison, Megan

    2018-03-22

    Physical activity (PA) remains the primary behavioral outcome associated with school recess, while many other potentially relevant indicators of recess remain unexamined. Few studies have assessed observations of teacher/student interactions, peer conflict, social interactions, or safety within the recess environment. Furthermore, a psychometrically-sound instrument does not exist to examine safety, resources, student engagement, adult engagement, pro-social/anti-social behavior, and student empowerment on the playground. The purpose of the current study was to develop a valid, and reliable, assessment tool intended for use in measurement of the contextual factors associated with recess. An iterative and multi-step process was used to develop a tool that measures safety and structure, adult engagement and supervision, student behaviors, and transitions at recess. Exploratory structural equation modeling (Mplus v. 7.4) was used to examine the underlying measurement model with observational data of the recess environment collected at 649 school-based recess periods that spanned across 22 urban/metropolitan areas in the USA. Data were also collected by two researchers at 162 recess sessions across 9 schools to examine reliability. A 17-item observation instrument, the Great Recess Framework - Observational Tool (GRF-OT), was created. Findings of exploratory structural equation modeling (ESEM) analyses supported factorial validity for a 4-factor solution and linear regressions established convergent validity where 'structure and safety', 'adult engagement and supervision', and 'student behaviors' were all significantly related to observed activity levels. Each sub-scale of the GRF-OT showed adequate levels of inter-rater reliability and test-retest reliability analysis indicated a higher level of stability for the GRF-OT when using a three-day average across two time points as compared to a two-day average. Initial evidence for a valid, and reliable, assessment tool to

  19. 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…

  20. Gingival recession in postmenopausal women with and without osteoporosis.

    Science.gov (United States)

    Duncea, Ioana; Pop, Dan; Georgescu, Carmen

    2013-01-01

    The periodontal disease is a complex chronic progressive inflammatory and destructive process of the tooth attachment apparatus: gingiva, alveolar bone, desmodontium, cementum. Systemic osteoporosis has a potential influence on both the periodontal and gingival inflammation indices, on the gingival recession (GR) and teeth mobility. The aim of this study was to investigate the possible relationship between the menopause osteoporosis and gingival recession, by studying the correlations between osteoporosis and gingival recession, and between the bone mineral density (BMD) at the level of L1-L4, femur, hip, mandible and gum recession. The present study included a total of 97 postmenopausal patients. The diagnosis of osteoporosis was made based on the WHO definition. The results were expressed as absolute BMD values in g/cm(2) and as T score form. We used dual x-ray absortiometry (DXA) measurements in assessing the lumbar column, proximal femur and mandible and we calculated the T scores. The gingival recession, which is an indicator of ligament tissue lysis and apical migration of the periodontal tissue, was measured as the distance between the anatomical tooth neck and the gumline. For the statistical analysis the Medcalc program version 12.3 was used. We found statistically significant differences between the two groups of women, with and without osteoporosis, in terms of the distribution of the cases of GR (p=0.003). The only parameter with statistical significance of the differences between the three categories of gingival recessions (absent, moderate, major), was p=0.034 for the femoral neck BMD. There were significant differences between the mean values of lumbar column L1-L4 BMD according to the presence or absence of recession signs. 1) The prevalence of moderate and major gingival recession was statistically significantly higher in the group of postmenopausal women with osteoporosis. 2) In postmenopausal women, statistically significant differences were