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  1. Hutchinson-Gilford Progeria Syndrome

    National Research Council Canada - National Science Library

    Gopal G; Belavadi GB

    2014-01-01

    Hutchinson-Gilford Progeria syndrome (HGPS) is a rare pediatric genetic syndrome associated with a characteristic aged appearance very early in life, generally leading to death in the second decade of life...

  2. Genetics Home Reference: Hutchinson-Gilford progeria syndrome

    Science.gov (United States)

    ... Health Conditions Hutchinson-Gilford progeria syndrome Hutchinson-Gilford progeria syndrome Enable Javascript to view the expand/collapse ... PDF Open All Close All Description Hutchinson-Gilford progeria syndrome is a genetic condition characterized by the ...

  3. Hutchinson-Gilford progeria syndrome

    OpenAIRE

    Amar Singh Bhukya; Bellum Siva Nagi Reddy

    2015-01-01

    Hutchinson-Gilford Progeria syndrome (HGPS) is a rare pediatric genetic syndrome associated with a characteristic aged appearance very early in life, generally leading to death in the second decade of life. Apart from premature aging, the other notable characteristics of children with HGPS include extreme short stature, prominent superficial veins, poor weight gain, alopecia, as well as various skeletal and cardiovascular pathologies associated with advanced age. The pattern of inheritance of...

  4. Hutchinson-Gilford progeria syndrome

    Directory of Open Access Journals (Sweden)

    Zahoor Hussain Daraz

    2017-06-01

    Full Text Available Hutchinson-Gilford progeria syndrome (HGPS is a rare genetic disease in which symptoms of aging are manifested at an early age. In the present report, we describe a 9 months old female child presented with a history of progressive coarsening of skin, failure to thrive and irregular bumps over thighs, buttocks and lower limbs for the last 7½ months. In the course of time, she developed alopecia, hyperpigmented spots over the abdomen with thickening and a typical facial profile of HGPS including micrognathia, absent ear lobules, prominent eyes, loss of eyelashes, eyebrows and a bluish hue over the nose.

  5. Hutchinson-Gilford Progeria Syndrome

    Directory of Open Access Journals (Sweden)

    Gopal G

    2014-08-01

    Full Text Available Hutchinson-Gilford Progeria syndrome (HGPS is a rare pediatric genetic syndrome associated with a characteristic aged appearance very early in life, generally leading to death in the second decade of life. Apart from premature aging, the other notable characteristics of children with HGPS include extreme short stature, prominent superficial veins, poor weight gain, alopecia, as well as various skeletal and cardiovascular pathologies associated with advanced age. The pattern of inheritance of HGPS is uncertain, though both autosomal dominant and autosomal recessive modes have been described. Recent genetic studies have demonstrated mutations in the LMNA gene in children with HGPS. In this article, we report a 16 years old girl who had the phenotypic features of HGPS and was later confirmed to have LMNA mutation by genetic analysis.

  6. Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Ullrich, Nicole J; Gordon, Leslie B

    2015-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare, uniformly fatal, segmental "premature aging" disease in which children exhibit phenotypes that may give us insights into the aging process at both the cellular and organismal levels. Initial presentation in early childhood is primarily based on growth and dermatologic findings. Primary morbidity and mortality for children with HGPS is from atherosclerotic cardiovascular disease and strokes with death occurring at an average age of 14.6 years. There is increasing data to support a unique phenotype of the craniofacial and cerebrovascular anatomy that accompanies the premature aging process. Strokes in HGPS can occur downstream of carotid artery and/or vertebral artery occlusion, stenosis, and calcification, with prominent collateral vessel formation. Both large and small vessel disease are present, and strokes are often clinically silent. Despite the presence of multisystem premature aging, children with HGPS do not appear to have cognitive deterioration, suggesting that some aspects of brain function may be protected from the deleterious effects of progerin, the disease-causing protein. Based on limited autopsy material, there is no pathologic evidence of dementia or Alzheimer-type changes. In a transgenic mouse model of progeria with expression of the most common HGPS mutation in brain, skin, bone, and heart, there are distortions of neuronal nuclei at the ultrastructural level with irregular shape and severe invaginations, but no evidence of inclusions or aberrant tau in brain sections. Importantly, the nuclear distortions did not result in significant changes in gene expression in hippocampal neurons. This chapter will discuss both preclinical and clinical aspects of the genetics, pathobiology, clinical phenotype, clinical care, and treatment of HGPS, with special attention toward neurologic and cutaneous findings.

  7. Hutchinson-Gilford progeria syndrome

    OpenAIRE

    Agarwal Uma; Sitaraman S; Mehta Sharad; Panse Gauri

    2010-01-01

    Progeria is a rare genetic disorder characterized by premature aging, involving the skin, bones, heart, and blood vessels. We report a 4-year-old boy who presented with clinical manifestations of progeria. He had characteristic facies, prominent eyes, scalp and leg veins, senile look, loss of scalp hair, eyebrows and eyelashes, stunted growth, and sclerodermatous changes. The present case is reported due to its rarity.

  8. Hutchinson-Gilford progeria syndrome

    Directory of Open Access Journals (Sweden)

    Agarwal Uma

    2010-01-01

    Full Text Available Progeria is a rare genetic disorder characterized by premature aging, involving the skin, bones, heart, and blood vessels. We report a 4-year-old boy who presented with clinical manifestations of progeria. He had characteristic facies, prominent eyes, scalp and leg veins, senile look, loss of scalp hair, eyebrows and eyelashes, stunted growth, and sclerodermatous changes. The present case is reported due to its rarity.

  9. Hutchinson-Gilford progeria syndrome: a rare case report

    Directory of Open Access Journals (Sweden)

    Kalegowda Deepadarshan

    2016-04-01

    Full Text Available Progeroid syndromes are characterised by clinical features of physiological aging at an early age. Hutchinson-Gilford progeria syndrome is a type of progeroid syndrome, characterised by abnormal facies, bone abnormalities, sclerodermatous skin changes and retarded physical development. Average life expectancy of progeria patients is 13 years. Herein we are reporting a case of progeria who is 21 years old.

  10. Hutchinson-Gilford Progeria Syndrome: A Rare Genetic Disorder

    Science.gov (United States)

    Panigrahi, Rajat G.; Panigrahi, Antarmayee; Vijayakumar, Poornima; Choudhury, Priyadarshini; Bhuyan, Sanat K.; Bhuyan, Ruchi; Maragathavalli, G.; Pati, Abhishek Ranjan

    2013-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare pediatric genetic syndrome with incidence of one per eight million live births. The disorder is characterised by premature aging, generally leading to death at approximately 13.4 years of age. This is a follow-up study of a 9-year-old male with clinical and radiographic features highly suggestive of HGPS and presented here with description of differential diagnosis and dental consideration. This is the first case report of HGPS which showed pectus carinatum structure of chest. PMID:24288630

  11. Hutchinson - Gilford progeria syndrome: A rare case report.

    Science.gov (United States)

    Kashyap, Subhash; Shanker, Vinay; Sharma, Neeraj

    2014-10-01

    Hutchinson - Gilford Progeria Syndrome is a rare genetic disorder characterized by premature aging involving the skin, bones, heart, and blood vessels. We report a three-year-old boy with clinical manifestations characteristic of this syndrome. He had a characteristic "plucked-bird" appearance, prominent eyes and scalp veins, senile look, loss of scalp hair, eyebrows, and eyelashes, stunted growth, and mottled pigmentation with sclerodermatous changes over the trunk and lower limbs. Radiological changes and decreased high-density lipoprotein (HDL) levels were also characteristic of the syndrome. This interesting case is reported for its rarity.

  12. Hutchinson - Gilford progeria syndrome: A rare case report

    Directory of Open Access Journals (Sweden)

    Subhash Kashyap

    2014-01-01

    Full Text Available Hutchinson - Gilford Progeria Syndrome is a rare genetic disorder characterized by premature aging involving the skin, bones, heart, and blood vessels. We report a three-year-old boy with clinical manifestations characteristic of this syndrome. He had a characteristic "plucked-bird" appearance, prominent eyes and scalp veins, senile look, loss of scalp hair, eyebrows, and eyelashes, stunted growth, and mottled pigmentation with sclerodermatous changes over the trunk and lower limbs. Radiological changes and decreased high-density lipoprotein (HDL levels were also characteristic of the syndrome. This interesting case is reported for its rarity.

  13. Hutchinson-Gilford Progeria Syndrome: A Rare Genetic Disorder

    Directory of Open Access Journals (Sweden)

    Rajat G. Panigrahi

    2013-01-01

    Full Text Available Hutchinson-Gilford progeria syndrome (HGPS is a rare pediatric genetic syndrome with incidence of one per eight million live births. The disorder is characterised by premature aging, generally leading to death at approximately 13.4 years of age. This is a follow-up study of a 9-year-old male with clinical and radiographic features highly suggestive of HGPS and presented here with description of differential diagnosis and dental consideration. This is the first case report of HGPS which showed pectus carinatum structure of chest.

  14. Stem cell depletion in Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Rosengardten, Ylva; McKenna, Tomás; Grochová, Diana; Eriksson, Maria

    2011-12-01

    Hutchinson-Gilford progeria syndrome (HGPS or progeria) is a very rare genetic disorder with clinical features suggestive of premature aging. Here, we show that induced expression of the most common HGPS mutation (LMNA c.1824C>T, p.G608G) results in a decreased epidermal population of adult stem cells and impaired wound healing in mice. Isolation and growth of primary keratinocytes from these mice demonstrated a reduced proliferative potential and ability to form colonies. Downregulation of the epidermal stem cell maintenance protein p63 with accompanying activation of DNA repair and premature senescence was the probable cause of this loss of adult stem cells. Additionally, upregulation of multiple genes in major inflammatory pathways indicated an activated inflammatory response. This response has also been associated with normal aging, emphasizing the importance of studying progeria to increase the understanding of the normal aging process.

  15. Ocular manifestations in the Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Chandravanshi, Shivcharan L; Rawat, Ashok Kumar; Dwivedi, Prem Chand; Choudhary, Pankaj

    2011-01-01

    The Hutchinson-Gilford progeria (HGP) syndrome is an extremely rare genetic condition characterized by an appearance of accelerated aging in children. The word progeria is derived from the Greek word progeros meaning 'prematurely old'. It is caused by de novo dominant mutation in the LMNA gene (gene map locus 1q21.2) and characterized by growth retardation and accelerated degenerative changes of the skin, musculoskeletal and cardiovascular systems. The most common ocular manifestations are prominent eyes, loss of eyebrows and eyelashes, and lagophthalmos. In the present case some additional ocular features such as horizontal narrowing of palpebral fissure, superior sulcus deformity, upper lid retraction, upper lid lag in down gaze, poor pupillary dilatation, were noted. In this case report, a 15-year-old Indian boy with some additional ocular manifestations of the HGP syndrome is described.

  16. Ocular manifestations in the Hutchinson-Gilford progeria syndrome

    Science.gov (United States)

    Chandravanshi, Shivcharan L; Rawat, Ashok Kumar; Dwivedi, Prem Chand; Choudhary, Pankaj

    2011-01-01

    The Hutchinson-Gilford progeria (HGP) syndrome is an extremely rare genetic condition characterized by an appearance of accelerated aging in children. The word progeria is derived from the Greek word progeros meaning ‘prematurely old’. It is caused by de novo dominant mutation in the LMNA gene (gene map locus 1q21.2) and characterized by growth retardation and accelerated degenerative changes of the skin, musculoskeletal and cardiovascular systems. The most common ocular manifestations are prominent eyes, loss of eyebrows and eyelashes, and lagophthalmos. In the present case some additional ocular features such as horizontal narrowing of palpebral fissure, superior sulcus deformity, upper lid retraction, upper lid lag in down gaze, poor pupillary dilatation, were noted. In this case report, a 15-year-old Indian boy with some additional ocular manifestations of the HGP syndrome is described. PMID:22011502

  17. Ocular manifestations in the Hutchinson-Gilford progeria syndrome

    Directory of Open Access Journals (Sweden)

    Shivcharan L Chandravanshi

    2011-01-01

    Full Text Available The Hutchinson-Gilford progeria (HGP syndrome is an extremely rare genetic condition characterized by an appearance of accelerated aging in children. The word progeria is derived from the Greek word progeros meaning ′prematurely old′. It is caused by de novo dominant mutation in the LMNA gene (gene map locus 1q21.2 and characterized by growth retardation and accelerated degenerative changes of the skin, musculoskeletal and cardiovascular systems. The most common ocular manifestations are prominent eyes, loss of eyebrows and eyelashes, and lagophthalmos. In the present case some additional ocular features such as horizontal narrowing of palpebral fissure, superior sulcus deformity, upper lid retraction, upper lid lag in down gaze, poor pupillary dilatation, were noted. In this case report, a 15-year-old Indian boy with some additional ocular manifestations of the HGP syndrome is described.

  18. [Three cases of Hutchinson-Gilford progeria syndrome].

    Science.gov (United States)

    Doubaj, Y; Lamzouri, A; Elalaoui, S-C; Laarabi, F-Z; Sefiani, A

    2011-02-01

    Progeria, or Hutchinson-Gilford syndrome, is a rare genetic disease, characterized by several clinical features that develop in childhood, in particular, an accelerated aging aspect. Its incidence is 1-4 per 8 million newborns. Children with progeria syndrome usually appear normal at birth and in early infancy. Profound failure to thrive occurs during the 1st year. Characteristic facies, partial alopecia progressing to total alopecia, loss of subcutaneous fat, stiffness of joints, bone changes, and abnormal tightness of the skin over the abdomen and upper thighs usually become apparent during the 2nd to 3rd years. Motor and mental development is normal. Patients develop severe atherosclerosis. Death occurs as a result of complications of cardiac or cerebrovascular disease (heart attack or stroke) generally between ages 6 and 20 years. The diagnosis of Hutchinson-Gilford progeria syndrome (HGPS) is based on recognition of common clinical features and the detection of the recurrent p.Gly608Gly mutation in exon 11 of the LMNA gene, which is present in almost all individuals with HGPS. We present here 3 patients aged 5, 11, and 12 years referred to genetic consultation for dysmorphic facies and failure to thrive. After careful clinical examination and paraclinical assessment, the diagnosis of progeria syndrome was raised. We performed molecular analysis for the 3 patients by searching for the recurrent mutation c.1824C>T (p.Gly608Gly) of the LMNA gene, which was found only in 1 patient. We discuss the geneticist's role in the diagnosis of rare dysmorphic syndromes and their genetic counseling. We also analyze the clinical spectrum of HGPS by comparing the 3 patients.

  19. Model of human aging: Recent findings on Werner’s and Hutchinson-Gilford progeria syndromes

    Directory of Open Access Journals (Sweden)

    Shian-ling Ding

    2008-09-01

    Full Text Available Shian-ling Ding1, Chen-Yang Shen2,3,41Department of Nursing, Kang-Ning Junior College of Medical Care and Management, Taipei, Taiwan; 2Institute of Biomedical Sciences, and 3Life Science Library, Academia Sinica, Taipei, Taiwan; 4Graduate Institute of Environmental Science, China Medical University, Taichong, TaiwanAbstract: The molecular mechanisms involved in human aging are complicated. Two progeria syndromes, Werner’s syndrome (WS and Hutchinson-Gilford progeria syndrome (HGPS, characterized by clinical features mimicking physiological aging at an early age, provide insights into the mechanisms of natural aging. Based on recent findings on WS and HGPS, we suggest a model of human aging. Human aging can be triggered by two main mechanisms, telomere shortening and DNA damage. In telomere-dependent aging, telomere shortening and dysfunction may lead to DNA damage responses which induce cellular senescence. In DNA damage-initiated aging, DNA damage accumulates, along with DNA repair deficiencies, resulting in genomic instability and accelerated cellular senescence. In addition, aging due to both mechanisms (DNA damage and telomere shortening is strongly dependent on p53 status. These two mechanisms can also act cooperatively to increase the overall level of genomic instability, triggering the onset of human aging phenotypes.Keywords: human aging, Hutchinson-Gilford Progeria syndrome, Werner syndrome

  20. Initial cutaneous manifestations of Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Rork, Jillian F; Huang, Jennifer T; Gordon, Leslie B; Kleinman, Monica; Kieran, Mark W; Liang, Marilyn G

    2014-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare, uniformly fatal, premature aging disease with distinct dermatologic features. We sought to identify and describe the initial skin and hair findings as potential diagnostic signs of the disease. We performed a chart review of the structured initial intake histories of 39 individuals with HGPS enrolled in clinical trials from 2007 to 2010 at Boston Children's Hospital, limited to cutaneous history from birth to 24 months. Medical photographs were provided through the clinical trials and the Progeria Research Foundation Medical and Research Database at Brown University Center for Gerontology and Healthcare Research. All 39 patients reported skin and hair abnormalities within the first 24 months of life. Pathologies included sclerodermoid change, prominent superficial veins, dyspigmentation, and alopecia. The mean age of presentation for each finding was <12 months. The most frequently reported skin feature was sclerodermoid change, which commonly involved the abdomen and bilateral lower extremities. Prominent superficial vasculature manifested as circumoral cyanosis and pronounced veins on the scalp and body. Hypo- and hyperpigmentation were observed over areas of sclerodermoid change. Scalp alopecia progressed in a distinct pattern, with preservation of the hair over the midscalp and vertex areas for the longest period of time. HGPS has distinct cutaneous manifestations during the first 2 years of life that may be the first signs of disease. Awareness of these findings could expedite diagnosis.

  1. Rapamycin activates autophagy in Hutchinson-Gilford progeria syndrome

    Science.gov (United States)

    Graziotto, John J; Cao, Kan; Collins, Francis S

    2012-01-01

    While rapamycin has been in use for years in transplant patients as an antirejection drug, more recently it has shown promise in treating diseases of aging, such as neurodegenerative disorders and atherosclerosis. We recently reported that rapamycin reverses the cellular phenotype of fibroblasts from children with the premature aging disease Hutchinson-Gilford progeria syndrome (HGPS). We found that the causative aberrant protein, progerin, was cleared through autophagic mechanisms when the cells were treated with rapamycin, suggesting a new potential treatment for HGPS. Recent evidence shows that progerin is also present in aged tissues of healthy individuals, suggesting that progerin may contribute to physiological aging. While it is intriguing to speculate that rapamycin may affect normal aging in humans, as it does in lower organisms, it will be important to identify safer analogs of rapamycin for chronic treatments in humans in order to minimize toxicity. In addition to its role in HGPS and normal aging, we discuss the potential of rapamycin for the treatment of age-dependent neurodegenerative diseases. PMID:22170152

  2. Sulforaphane enhances progerin clearance in Hutchinson-Gilford progeria fibroblasts.

    Science.gov (United States)

    Gabriel, Diana; Roedl, Daniela; Gordon, Leslie B; Djabali, Karima

    2015-02-01

    Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare multisystem childhood premature aging disorder linked to mutations in the LMNA gene. The most common HGPS mutation is found at position G608G within exon 11 of the LMNA gene. This mutation results in the deletion of 50 amino acids at the carboxyl-terminal tail of prelamin A, and the truncated protein is called progerin. Progerin only undergoes a subset of the normal post-translational modifications and remains permanently farnesylated. Several attempts to rescue the normal cellular phenotype with farnesyltransferase inhibitors (FTIs) and other compounds have resulted in partial cellular recovery. Using proteomics, we report here that progerin induces changes in the composition of the HGPS nuclear proteome, including alterations to several components of the protein degradation pathways. Consequently, proteasome activity and autophagy are impaired in HGPS cells. To restore protein clearance in HGPS cells, we treated HGPS cultures with sulforaphane (SFN), an antioxidant derived from cruciferous vegetables. We determined that SFN stimulates proteasome activity and autophagy in normal and HGPS fibroblast cultures. Specifically, SFN enhances progerin clearance by autophagy and reverses the phenotypic changes that are the hallmarks of HGPS. Therefore, SFN is a promising therapeutic avenue for children with HGPS.

  3. Hutchinson-Gilford progeria syndrome through the lens of transcription.

    Science.gov (United States)

    Prokocimer, Miron; Barkan, Rachel; Gruenbaum, Yosef

    2013-08-01

    Lamins are nuclear intermediate filaments. In addition to their structural roles, they are implicated in basic nuclear functions such as chromatin organization, DNA replication, transcription, DNA repair, and cell-cycle progression. Mutations in human LMNA gene cause several diseases termed laminopathies. One of the laminopathic diseases is Hutchinson-Gilford progeria syndrome (HGPS), which is caused by a spontaneous mutation and characterized by premature aging. HGPS phenotypes share certain similarities with several apparently comparable medical conditions, such as aging and atherosclerosis, with the conspicuous absence of neuronal degeneration and cancer rarity during the short lifespan of the patients. Cell lines from HGPS patients are characterized by multiple nuclear defects, which include abnormal morphology, altered histone modification patterns, and increased DNA damage. These cell lines provide insight into the molecular pathways including senescence that require lamins A and B1. Here, we review recent data on HGPS phenotypes through the lens of transcriptional deregulation caused by lack of functional lamin A, progerin accumulation, and lamin B1 silencing.

  4. Hutchinson-Gilford progeria syndrome, cardiovascular disease and oxidative stress.

    Science.gov (United States)

    Trigueros-Motos, Laia; Gonzalez, Jose M; Rivera, Jose; Andres, Vicente

    2011-06-01

    Hutchinson-Gilford Progeria Syndrome (HGPS), a rare human disease characterized by premature aging, is mainly caused by the abnormal accumulation of progerin, a mutant form of the mammalian nuclear envelope component lamin A. HGPS patients exhibit vascular alterations and die at an average age of 13 years, predominantly from myocardial infarction or stroke. Animal models of HGPS have been a valuable tool in the study of the pathological processes implicated in the origin of this disease and its associated cardiovascular alterations. Some of the molecular mechanisms of HGPS might be relevant to the process of normal aging, since progerin is detected in cells from normal elderly humans. Conversely, processes linked to normal aging, such as the increase in oxidative stress, might be relevant to the pathogenic mechanisms of HGPS. In this review, we discuss recent advances in the understanding of the molecular mechanisms underlying the cardiovascular alterations associated with HGPS, the potential role of oxidative stress, and therapeutic approaches for the treatment of this devastating disease.

  5. Telomere length in Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Decker, Michelle L; Chavez, Elizabeth; Vulto, Irma; Lansdorp, Peter M

    2009-06-01

    Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare premature aging disorder caused by mutations in the gene LMNA, which encodes the nuclear matrix protein lamin A. Previous research has shown that the average telomere length in fibroblasts from HGPS patients is shorter than in age-matched controls. How mutations in lamin A lead to shortened telomere lengths is not known nor is the contribution of individual chromosome ends to the low average length understood. To measure the telomere length of individual chromosomes, we used quantitative fluorescence in situ hybridization (Q-FISH). In agreement with previous studies, we found that the average telomere length in HPGS fibroblasts is greatly reduced; however, the telomere length at chromosome ends was variable. In contrast, the telomere length in hematopoietic cells which typically do not express lamin A, was within the normal range for three out of four HGPS patient samples. Our results suggest that mutant lamin A decreases telomere length via a direct effect and that expression of mutant LMNA is necessary for telomere loss in HGPS.

  6. Otologic and Audiologic Manifestations of Hutchinson-Gilford Progeria Syndrome

    Science.gov (United States)

    Guardiani, Elizabeth; Zalewski, Christopher; Brewer, Carmen; Merideth, Melissa; Introne, Wendy; Smith, Ann C.M; Gordon, Leslie; Gahl, William; Kim, H. Jeffrey

    2013-01-01

    Objectives To define the audiologic and otologic phenotype of Hutchinson-Gilford Progeria syndrome (HGPS). Study Design Prospective case series. Methods Fifteen patients with HGPS were enrolled in a prospective natural history study; fourteen were evaluated in the neurotology clinic and eleven received audiologic evaluations. The physical exam and audiologic findings of these patients were reviewed to define an otologic and audiologic phenotype for HGPS in the largest series of subjects in the literature. Results All patients were noted to have stiff auricular cartilages, small or absent lobules and hypoplasia of the lateral soft tissue portion of the external ear canal leading to a shortened canal. Ten of 14 patients (71%) had dry cerumen impaction and four of 14 patients (29%) reported a history of recurrent otitis media. Nineteen of 22 ears (86.4%) demonstrated low frequency conductive hearing loss in the 250 Hz to 500 Hz range. Sixteen of 22 ears (73%) had type A tympanograms; three of 22 ears (14%) displayed bimodal or "W" peaked tympanograms; two of 22 ears (9%) had type B tympanograms; one of 22 ears (4%) had a type C tympanogram. Nine of 10 patients had distortion product otoacoustic emissions consistent with normal peripheral hearing sensitivity. Conclusions HGPS is caused by a mutation in the LMNA gene resulting in the production of an abnormal nuclear protein; this in turn affects nuclear structure and function. Patients with HGPS have characteristic otologic features due to cartilaginous and subcutaneous tissue abnormalities and typically demonstrate low frequency conductive hearing loss despite largely normal tympanometry. It is important to be aware of these conditions in managing these patients. PMID:21898437

  7. Mechanisms of premature vascular aging in children with Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Gerhard-Herman, Marie; Smoot, Leslie B; Wake, Nicole; Kieran, Mark W; Kleinman, Monica E; Miller, David T; Schwartzman, Armin; Giobbie-Hurder, Anita; Neuberg, Donna; Gordon, Leslie B

    2012-01-01

    Hutchinson-Gilford progeria syndrome is a rare, segmental premature aging syndrome of accelerated atherosclerosis and early death from myocardial infarction or stroke. This study sought to establish comprehensive characterization of the fatal vasculopathy in Hutchinson-Gilford progeria syndrome and its relevance to normal aging. We performed cardiovascular assessments at a single clinical site on the largest prospectively studied cohort to date. Carotid-femoral pulse wave velocity was dramatically elevated (mean: 13.00±3.83 m/s). Carotid duplex ultrasound echobrightness, assessed in predefined tissue sites as a measure of arterial wall density, was significantly greater than age- and sex-matched controls in the intima-media (Pnormalizing trends of these noninvasive cardiovascular measures. The data demonstrate that, along with peripheral vascular occlusive disease, accelerated vascular stiffening is an early and pervasive mechanism of vascular disease in Hutchinson-Gilford progeria syndrome. There is considerable overlap with cardiovascular changes of normal aging, which reinforces the view that defining mechanisms of cardiovascular disease in Hutchinson-Gilford progeria syndrome provides a unique opportunity to isolate a subset of factors influencing cardiovascular disease in the general aging population.

  8. Accumulation of Mutant Lamin A Causes Progressive Changes in Nuclear Architecture in Hutchinson-Gilford Progeria Syndrome

    National Research Council Canada - National Science Library

    Robert D. Goldman; Dale K. Shumaker; Michael R. Erdos; Maria Eriksson; Anne E. Goldman; Leslie B. Gordon; Yosef Gruenbaum; Satya Khuon; Melissa Mendez; Renée Varga; Francis S. Collins

    2004-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder, commonly caused by a point mutation in the lamin A gene that results in a protein lacking 50 aa near the C terminus, denoted LAΔ50...

  9. Hutchinson-Gilford Progeria Syndrome with G608G LMNA Mutation

    Science.gov (United States)

    Kim, Hui Kwon; Lee, Jong Yoon; Bae, Eun Ju; Oh, Phil Soo; Park, Won Il; Lee, Dong Sung; Kim, Jong-Il

    2011-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare condition originally described by Hutchinson in 1886. Death result from cardiac complications in the majority of cases and usually occurs at average age of thirteen years. A 4-yr old boy had typical clinical findings such as short stature, craniofacial disproportion, alopecia, prominent scalp veins and sclerodermatous skin. This abnormal appearance began at age of 1 yr. On serological and hormonal evaluation, all values are within normal range. He was neurologically intact with motor and mental development. An echocardiogram showed calcification of aortic and mitral valves. Hypertrophy of internal layer at internal carotid artery suggesting atherosclerosis was found by carotid doppler sonography. He is on low dose aspirin to prevent thromboembolic episodes and on regular follow up. Gene study showed typical G608G (GGC- > GGT) point mutation at exon 11 in LMNA gene. This is a rare case of Hutchinson-Gilford progeria syndrome confirmed by genetic analysis in Korea. PMID:22148005

  10. Molecular ageing in progeroid syndromes: Hutchinson-Gilford progeria syndrome as a model

    Directory of Open Access Journals (Sweden)

    da Nóbrega Raphael

    2009-04-01

    Full Text Available Abstract Hutchinson-Gilford progeria syndrome (HGPS is a rare premature aging disorder that belongs to a group of conditions called laminopathies which affect nuclear lamins. Mutations in two genes, LMNA and ZMPSTE24, have been found in patients with HGPS. The p.G608G LMNA mutation is the most commonly reported mutation. The aim of this work was to compile a comprehensive literature review of the clinical features and genetic mutations and mechanisms of this syndrome as a contribution to health care workers. This review shows the necessity of a more detailed clinical identification of Hutchinson-Gilford progeria syndrome and the need for more studies on the pharmacologic and pharmacogenomic approach to this syndrome.

  11. Hutchinson-Gilford progeria syndrome with G608G LMNA mutation.

    Science.gov (United States)

    Kim, Hui Kwon; Lee, Jong Yoon; Bae, Eun Ju; Oh, Phil Soo; Park, Won Il; Lee, Dong Sung; Kim, Jong-Il; Lee, Hong Jin

    2011-12-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare condition originally described by Hutchinson in 1886. Death result from cardiac complications in the majority of cases and usually occurs at average age of thirteen years. A 4-yr old boy had typical clinical findings such as short stature, craniofacial disproportion, alopecia, prominent scalp veins and sclerodermatous skin. This abnormal appearance began at age of 1 yr. On serological and hormonal evaluation, all values are within normal range. He was neurologically intact with motor and mental development. An echocardiogram showed calcification of aortic and mitral valves. Hypertrophy of internal layer at internal carotid artery suggesting atherosclerosis was found by carotid doppler sonography. He is on low dose aspirin to prevent thromboembolic episodes and on regular follow up. Gene study showed typical G608G (GGC- > GGT) point mutation at exon 11 in LMNA gene. This is a rare case of Hutchinson-Gilford progeria syndrome confirmed by genetic analysis in Korea.

  12. Aging of Hutchinson-Gilford progeria syndrome fibroblasts is characterised by hyperproliferation and increased apoptosis.

    Science.gov (United States)

    Bridger, Joanna M; Kill, Ian R

    2004-05-01

    Hutchinson-Gilford progeria syndrome is a rare genetic disorder that mimics certain aspects of aging prematurely. Recent work has revealed that mutations in the lamin A gene are a cause of the disease. We show here that cellular aging of Hutchinson-Gilford progeria syndrome fibroblasts is characterised by a period of hyperproliferation and terminates with a large increase in the rate of apoptosis. The occurrence of cells with abnormal nuclear morphology reported by others is shown to be a result of cell division since the fraction of these abnormalities increases with cellular age. Similarly, the proportion of cells with an abnormal or absent A-type lamina increases with age. These data provide clues as to the cellular basis for premature aging in HGPS and support the view that cellular senescence and tissue homeostasis are important factors in the normal aging process.

  13. Werner and Hutchinson-Gilford progeria syndromes: mechanistic basis of human progeroid diseases.

    Science.gov (United States)

    Kudlow, Brian A; Kennedy, Brian K; Monnat, Raymond J

    2007-05-01

    Progeroid syndromes have been the focus of intense research in part because they might provide a window into the pathology of normal ageing. Werner syndrome and Hutchinson-Gilford progeria syndrome are two of the best characterized human progeroid diseases. Mutated genes that are associated with these syndromes have been identified, mouse models of disease have been developed, and molecular studies have implicated decreased cell proliferation and altered DNA-damage responses as common causal mechanisms in the pathogenesis of both diseases.

  14. Temsirolimus Partially Rescues the Hutchinson-Gilford Progeria Cellular Phenotype

    Science.gov (United States)

    Gabriel, Diana; Gordon, Leslie B.

    2016-01-01

    Hutchinson-Gilford syndrome (HGPS, OMIM 176670, a rare premature aging disorder that leads to death at an average age of 14.7 years due to myocardial infarction or stroke, is caused by mutations in the LMNA gene. Lamins help maintain the shape and stability of the nuclear envelope in addition to regulating DNA replication, DNA transcription, proliferation and differentiation. The LMNA mutation results in the deletion of 50 amino acids from the carboxy-terminal region of prelamin A, producing the truncated, farnesylated protein progerin. The accumulation of progerin in HGPS nuclei causes numerous morphological and functional changes that lead to premature cellular senescence. Attempts to reverse this HGPS phenotype have identified rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), as a drug that is able to rescue the HGPS cellular phenotype by promoting autophagy and reducing progerin accumulation. Rapamycin is an obvious candidate for the treatment of HGPS disease but is difficult to utilize clinically. To further assess rapamycin’s efficacy with regard to proteostasis, mitochondrial function and the degree of DNA damage, we tested temsirolimus, a rapamycin analog with a more favorable pharmacokinetic profile than rapamycin. We report that temsirolimus decreases progerin levels, increases proliferation, reduces misshapen nuclei, and partially ameliorates DNA damage, but does not improve proteasome activity or mitochondrial dysfunction. Our findings suggest that future therapeutic strategies should identify new drug combinations and treatment regimens that target all the dysfunctional hallmarks that characterize HGPS cells. PMID:28033363

  15. Radiological Diagnosis of a Rare Premature Aging Genetic Disorder: Progeria (Hutchinson-Gilford Syndrome

    Directory of Open Access Journals (Sweden)

    Haji Mohammed Nazir

    2017-01-01

    Full Text Available Hutchinson-Gilford Progeria Syndrome (HGPS is a rare disease with a combination of short stature, bone abnormalities, premature ageing, and skin changes. Though the physical appearance of these patients is characteristic, there is little emphasis on the characteristic radiological features. In this paper, we report a 16-year-old boy with clinical and radiological features of this rare genetic disorder. He had a characteristic facial appearance with a large head, large eyes, thin nose with beaked tip, small chin, protruding ears, prominent scalp veins, and absence of hair.

  16. Dental and craniofacial characteristics in a patient with Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Reichert, Christoph; Gölz, Lina; Götz, Werner; Wolf, Michael; Deschner, James; Jäger, Andreas

    2014-07-01

    The Hutchinson-Gilford progeria syndrome (HGPS) is an exceptionally rare medical disorder caused by mutations in the lamin A/C gene. Affected patients display typical features of premature aging. Beside general medical disorders, these patients have several specific features related to the craniofacial phenotype and the oral cavity. In this article, the dental and craniofacial characteristics of a 9-year-old girl with HGPS are presented. It is the first report addressing orthodontic tooth movement and microbiological features in a HGPS patient. We describe and discuss pathologic findings and provide a detailed histology of the teeth which had to be extracted during initial treatment.

  17. All-trans retinoic acid and rapamycin normalize Hutchinson Gilford progeria fibroblast phenotype.

    Science.gov (United States)

    Pellegrini, Camilla; Columbaro, Marta; Capanni, Cristina; D'Apice, Maria Rosaria; Cavallo, Carola; Murdocca, Michela; Lattanzi, Giovanna; Squarzoni, Stefano

    2015-10-06

    Hutchinson Gilford progeria syndrome is a fatal disorder characterized by accelerated aging, bone resorption and atherosclerosis, caused by a LMNA mutation which produces progerin, a mutant lamin A precursor. Progeria cells display progerin and prelamin A nuclear accumulation, altered histone methylation pattern, heterochromatin loss, increased DNA damage and cell cycle alterations. Since the LMNA promoter contains a retinoic acid responsive element, we investigated if all-trans retinoic acid administration could lower progerin levels in cultured fibroblasts. We also evaluated the effect of associating rapamycin, which induces autophagic degradation of progerin and prelamin A. We demonstrate that all-trans retinoic acid acts synergistically with low-dosage rapamycin reducing progerin and prelamin A, via transcriptional downregulation associated with protein degradation, and increasing the lamin A to progerin ratio. These effects rescue cell dynamics and cellular proliferation through recovery of DNA damage response factor PARP1 and chromatin-associated nuclear envelope proteins LAP2α and BAF. The combined all-trans retinoic acid-rapamycin treatment is dramatically efficient, highly reproducible, represents a promising new approach in Hutchinson-Gilford Progeria therapy and deserves investigation in ageing-associated disorders.

  18. Progeria of stem cells: stem cell exhaustion in Hutchinson-Gilford progeria syndrome.

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    Halaschek-Wiener, Julius; Brooks-Wilson, Angela

    2007-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare, fatal genetic disorder that is characterized by segmental accelerated aging. The major causal mutation associated with HGPS triggers abnormal messenger RNA splicing of the lamin A gene leading to changes in the nuclear architecture. To date, two models have been proposed to explain how mutations in the lamin A gene could lead to HGPS, structural fragility and altered gene expression. We favor a compatible model that links HGPS to stem cell-driven tissue regeneration. In this model, nuclear fragility of lamin A-deficient cells increases apoptotic cell death to levels that exhaust tissues' ability for stem cell-driven regeneration. Tissue-specific differences in cell death or regenerative potential, or both, result in the tissue-specific segmental aging pattern seen in HGPS. We propose that the pattern of aging-related conditions present or absent in HGPS can provide insight into the genetic and environmental factors that contribute to normal aging.

  19. Hutchinson-Gilford progeria syndrome caused by an LMNA mutation: a case report.

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    Chu, Yan; Xu, Zi-Gang; Xu, Zhe; Ma, Lin

    2015-01-01

    Hutchinson-Gilford progeria syndrome is a rare genetic disorder characterized by premature aging of the skin, bones, heart, and blood vessels. We report a 6-year-old boy who was born at full term but presented with scleroderma-like appearance at 1 month of age and gradually developed clinical manifestations of progeria. He had characteristic facial features of prominent eyes, scalp, and leg veins; loss of scalp hair, eyebrows, and eyelashes; stunted growth; scleroderma-like changes of the skin; and a premature aged appearance. Metabolic investigations showed transient methylmalonic aciduria, and genetic testing of the peripheral blood identified the c.1824C>T heterozygous LMNA mutation. The present case is reported because of its rarity.

  20. Hypoparathyroidism in an Egyptian child with Hutchinson-Gilford progeria syndrome: a case report

    Science.gov (United States)

    2012-01-01

    Introduction Hutchinson-Gilford progeria syndrome is a rare genetic disorder. It is reported to be present in one in eight million and is characterized by severe growth failure, early loss of hair, lipodystrophy, scleroderma, decreased joint mobility, osteolysis, early atherosclerosis and facial features that resemble those of an aged person. Apart from diabetes mellitus, there are no reported abnormalities of thyroid, parathyroid, pituitary or adrenal function. Here, we report the case of a 10-year-old Egyptian child with Hutchinson-Gilford progeria syndrome and hypoparathyroidism. Case presentation A 10-year-old Egyptian boy was referred to our institution for an evaluation of recurrent attacks of muscle cramps, paresthesia of his fingertips and perioral numbness of two months duration. On examination, we found dilated veins present over his scalp with alopecia and frontal bossing, a beaked nose, thin lips, protruding ears, a high pitched voice with sparse hair over his eyebrows and eyelashes and micrognathia but normal dentition. His eyes appeared prominent and our patient appeared to have poor sexual development. A provisional diagnosis of progeria was made, which was confirmed by molecular genetics study. Chvostek's and Trousseau's signs were positive. He had low total calcium (5.4 mg/dL), low ionized calcium (2.3 mg/dL), raised serum phosphate (7.2 mg/dL), raised alkaline phosphatase (118 U/L) and low intact parathyroid hormone (1.2 pg/mL) levels. He was started on oral calcium salt and vitamin D; his symptoms improved with the treatment and his serum calcium, urinary calcium and alkaline phosphates level were monitored every three months to ensure adequacy of therapy and to avoid hypercalcemia. Conclusion Routine checking of serum calcium, phosphorus and parathyroid hormone will help in the early detection of hypoparathyrodism among children with progeria. PMID:22251708

  1. Hypoparathyroidism in an Egyptian child with Hutchinson-Gilford progeria syndrome: a case report

    Directory of Open Access Journals (Sweden)

    Kalil Kotb

    2012-01-01

    Full Text Available Abstract Introduction Hutchinson-Gilford progeria syndrome is a rare genetic disorder. It is reported to be present in one in eight million and is characterized by severe growth failure, early loss of hair, lipodystrophy, scleroderma, decreased joint mobility, osteolysis, early atherosclerosis and facial features that resemble those of an aged person. Apart from diabetes mellitus, there are no reported abnormalities of thyroid, parathyroid, pituitary or adrenal function. Here, we report the case of a 10-year-old Egyptian child with Hutchinson-Gilford progeria syndrome and hypoparathyroidism. Case presentation A 10-year-old Egyptian boy was referred to our institution for an evaluation of recurrent attacks of muscle cramps, paresthesia of his fingertips and perioral numbness of two months duration. On examination, we found dilated veins present over his scalp with alopecia and frontal bossing, a beaked nose, thin lips, protruding ears, a high pitched voice with sparse hair over his eyebrows and eyelashes and micrognathia but normal dentition. His eyes appeared prominent and our patient appeared to have poor sexual development. A provisional diagnosis of progeria was made, which was confirmed by molecular genetics study. Chvostek's and Trousseau's signs were positive. He had low total calcium (5.4 mg/dL, low ionized calcium (2.3 mg/dL, raised serum phosphate (7.2 mg/dL, raised alkaline phosphatase (118 U/L and low intact parathyroid hormone (1.2 pg/mL levels. He was started on oral calcium salt and vitamin D; his symptoms improved with the treatment and his serum calcium, urinary calcium and alkaline phosphates level were monitored every three months to ensure adequacy of therapy and to avoid hypercalcemia. Conclusion Routine checking of serum calcium, phosphorus and parathyroid hormone will help in the early detection of hypoparathyrodism among children with progeria.

  2. Craniofacial abnormalities in Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Ullrich, N J; Silvera, V M; Campbell, S E; Gordon, L B

    2012-09-01

    HGPS is a rare syndrome of segmental premature aging. Our goal was to expand the scope of structural bone and soft-tissue craniofacial abnormalities in HGPS through CT or MR imaging. Using The Progeria Research Foundation Medical and Research Database, 98 imaging studies on 25 patients, birth to 14.1 years of age, were comprehensively reviewed. Eight newly identified abnormalities involving the calvaria, skull base, and soft tissues of the face and orbits were present with prevalences between 43% and 100%. These included J-shaped sellas, a mottled appearance and increased vascular markings of the calvaria, abnormally configured mandibular condyles, hypoplastic articular eminences, small zygomatic arches, prominent parotid glands, and optic nerve kinking. This expanded craniofacial characterization helps link disease features and improves our ability to evaluate how underlying genetic and cellular abnormalities culminate in a disease phenotype.

  3. Investigation into the human premature ageing disease, Hutchinson Gilford Progeria syndrome, using hTERT immortalised fibroblasts

    OpenAIRE

    Worthington, Gemma Louise

    2016-01-01

    This thesis was submitted for the award of Doctor of Philosophy and was awarded by Brunel University London Hutchinson Gilford Progeria syndrome (HGPS) is a rare premature ageing disease affecting children. 80% of “classic” HGPS patients share the same mutation in the LMNA gene that gives rise to characteristics similar to normal human ageing and they usually die in their teens from heart attacks or strokes. Cells taken from progeria patients have a short replicative lifespan in culture an...

  4. A ceRNA analysis on LMNA gene focusing on the Hutchinson-Gilford progeria syndrome

    Science.gov (United States)

    2013-01-01

    Background Hutchinson-Gilford progeria syndrome is a rare dominant human disease of genetic origin. The average life expectancy is about 20 years, patients’ life quality is still very poor and no efficient therapy has yet been developed. It is caused by mutation of the LMNA gene, which results in accumulation in the nuclear membrane of a particular splicing form of Lamin-A called progerin. The mechanism by which progerin perturbs cellular homeostasis and leads to the symptoms is still under debate. Micro-RNAs are able to negatively regulate transcription by coupling with the 3’ UnTranslated Region of messenger RNAs. Several Micro-RNAs recognize the same 3’ UnTranslated Region and each Micro-RNA can recognize multiple 3’ UnTranslated Regions of different messenger RNAs. When different messenger RNAs are co-regulated via a similar panel of micro-RNAs, these messengers are called Competing Endogenous RNAs, or ceRNAs. The 3’ UnTranslated Region of the longest LMNA transcript was analysed looking for its ceRNAs. The aim of this study was to search for candidate genes and gene ontology functions possibly influenced by LMNA mutations that may exert a role in progeria development. Results 11 miRNAs were isolated as potential LMNA regulators. By computational analysis, the miRNAs pointed to 17 putative LMNA ceRNAs. Gene ontology analysis of isolated ceRNAs showed an enrichment in RNA interference and control of cell cycle functions. Conclusion This study isolated novel genes and functions potentially involved in LMNA network of regulation that could be involved in laminopathies such as the Hutchinson-Gilford progeria syndrome. PMID:23317481

  5. Aberrant DNA methylation profiles in the premature aging disorders Hutchinson-Gilford Progeria and Werner syndrome

    Science.gov (United States)

    Heyn, Holger; Moran, Sebastian; Esteller, Manel

    2013-01-01

    DNA methylation gradiently changes with age and is likely to be involved in aging-related processes with subsequent phenotype changes and increased susceptibility to certain diseases. The Hutchinson-Gilford Progeria (HGP) and Werner Syndrome (WS) are two premature aging diseases showing features of common natural aging early in life. Mutations in the LMNA and WRN genes were associated to disease onset; however, for a subset of patients the underlying causative mechanisms remain elusive. We aimed to evaluate the role of epigenetic alteration on premature aging diseases by performing comprehensive DNA methylation profiling of HGP and WS patients. We observed profound changes in the DNA methylation landscapes of WRN and LMNA mutant patients, which were narrowed down to a set of aging related genes and processes. Although of low overall variance, non-mutant patients revealed differential DNA methylation at distinct loci. Hence, we propose DNA methylation to have an impact on premature aging diseases. PMID:23257959

  6. Extradural hematoma surgery in a child with Hutchinson-Gilford progeria syndrome: Perioperative concerns.

    Science.gov (United States)

    Hansda, Upendra; Agarwal, Jyotsna; Patra, Chitralekha; Ganjoo, Pragati

    2013-05-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a very rare genetic disorder characterized by premature ageing, severe growth failure, and very early onset atherosclerosis. Psychologically and emotionally child-like, these patients suffer from physiological changes of old age. Early and progressive atherosclerosis of intra-cranial vessels in HGPS patients, along with a thin skin and fragile vessels, make these patients susceptible to intra-cranial hematomas following relatively trivial injuries and to severe intra-cranial disease. Anesthetizing HGPS patients for surgery can be challenging due to the presence of a possible difficult airway, multi-system derangements, and associated skin, bone and joint disease. We report here one such child with HGPS who underwent craniotomy and evacuation of an extradural hematoma that developed after minor head trauma. Securing his airway during surgery was difficult.

  7. Vascular disease modeling using induced pluripotent stem cells: Focus in Hutchinson-Gilford Progeria Syndrome.

    Science.gov (United States)

    Pitrez, P R; Rosa, S C; Praça, C; Ferreira, L

    2016-05-06

    Induced pluripotent stem cells (iPSCs) represent today an invaluable tool to create disease cell models for modeling and drug screening. Several lines of iPSCs have been generated in the last 7 years that changed the paradigm for studying diseases and the discovery of new drugs to treat them. In this article we focus our attention to vascular diseases in particular Hutchinson-Gilford Progeria Syndrome (HGPS), a devastating premature aging disease caused by a mutation in the lamin A gene. In general, patients die because of myocardial infarction or stroke. Because the patients are fragile the isolation of a particular type of cells is very difficult. Therefore in the last 5 years, researchers have used cells derived from iPSCs to model aspects of the HGPS and to screen libraries of chemicals to retard or treat the disease.

  8. Aberrant DNA methylation profiles in the premature aging disorders Hutchinson-Gilford Progeria and Werner syndrome.

    Science.gov (United States)

    Heyn, Holger; Moran, Sebastian; Esteller, Manel

    2013-01-01

    DNA methylation gradiently changes with age and is likely to be involved in aging-related processes with subsequent phenotype changes and increased susceptibility to certain diseases. The Hutchinson-Gilford Progeria (HGP) and Werner Syndrome (WS) are two premature aging diseases showing features of common natural aging early in life. Mutations in the LMNA and WRN genes were associated to disease onset; however, for a subset of patients the underlying causative mechanisms remain elusive. We aimed to evaluate the role of epigenetic alteration on premature aging diseases by performing comprehensive DNA methylation profiling of HGP and WS patients. We observed profound changes in the DNA methylation landscapes of WRN and LMNA mutant patients, which were narrowed down to a set of aging related genes and processes. Although of low overall variance, non-mutant patients revealed differential DNA methylation at distinct loci. Hence, we propose DNA methylation to have an impact on premature aging diseases.

  9. Extradural hematoma surgery in a child with Hutchinson-Gilford progeria syndrome: Perioperative concerns

    Directory of Open Access Journals (Sweden)

    Upendra Hansda

    2013-01-01

    Full Text Available Hutchinson-Gilford progeria syndrome (HGPS is a very rare genetic disorder characterized by premature ageing, severe growth failure, and very early onset atherosclerosis. Psychologically and emotionally child-like, these patients suffer from physiological changes of old age. Early and progressive atherosclerosis of intra-cranial vessels in HGPS patients, along with a thin skin and fragile vessels, make these patients susceptible to intra-cranial hematomas following relatively trivial injuries and to severe intra-cranial disease. Anesthetizing HGPS patients for surgery can be challenging due to the presence of a possible difficult airway, multi-system derangements, and associated skin, bone and joint disease. We report here one such child with HGPS who underwent craniotomy and evacuation of an extradural hematoma that developed after minor head trauma. Securing his airway during surgery was difficult.

  10. Hutchinson-Gilford progeria syndrome with severe calcific aortic valve stenosis

    Directory of Open Access Journals (Sweden)

    Natesh B Hanumanthappa

    2011-01-01

    Full Text Available Hutchinson-Gilford progeria syndrome (HGPS is a rare premature aging syndrome that results from mutation in the Laminin A gene. This case report of a 12-year-old girl with HGPS is presented for the rarity of the syndrome and the classical clinical features that were observed in the patient. All patients with this condition should undergo early and periodic evaluation for cardiovascular diseases. However, the prognosis is poor and management is mainly conservative. There is no proven therapy available. Mortality in this uniformly fatal condition is primarily due to myocardial infarction, strokes or congestive cardiac failure between ages 7 and 21 years due to the rapidly progressive arteriosclerosis involving the large vessels.

  11. A 36 years old woman with Hutchinson-Gilford Progeria Syndrome: a case report

    Directory of Open Access Journals (Sweden)

    Akrami S M

    2007-10-01

    Full Text Available Background: Hutchinson-Gilford Progeria Syndrome (HGPS is a very rare genetic disorder with a frequency of 1 in 8 million live births. It is characterised by premature aging phenotype. The median age at death is 13.4 years. It is an autosomal dominat disease due to a de novo point mutation in the Lamin A gene exon 11 in the majority of cases. More than 100 cases have been reported world wide."nCase report: We describe here an exceptionally long-lived patient with HGPS, who is alive at age 36. She was referred by a cardiologist to our endocrinology clinic to be worked up for presence of a metabolic or genetic disorder before a heart surgery."nResults: Having more attention of clinicians about very rare diseases and referring the patients to geneticist are the main goals of this case report as well as describing the disease.

  12. DNA repair defects and genome instability in Hutchinson-Gilford Progeria Syndrome.

    Science.gov (United States)

    Gonzalo, Susana; Kreienkamp, Ray

    2015-06-01

    The integrity of the nuclear lamina has emerged as an important factor in the maintenance of genome stability. In particular, mutations in the LMNA gene, encoding A-type lamins (lamin A/C), alter nuclear morphology and function, and cause genomic instability. LMNA gene mutations are associated with a variety of degenerative diseases and devastating premature aging syndromes such as Hutchinson-Gilford Progeria Syndrome (HGPS) and Restrictive Dermopathy (RD). HGPS is a severe laminopathy, with patients dying in their teens from myocardial infarction or stroke. HGPS patient-derived cells exhibit nuclear shape abnormalities, changes in epigenetic regulation and gene expression, telomere shortening, genome instability, and premature senescence. This review highlights recent advances in identifying molecular mechanisms that contribute to the pathophysiology of HGPS, with a special emphasis on DNA repair defects and genome instability.

  13. Hip pathology in Hutchinson-Gilford progeria syndrome: a report of two children.

    Science.gov (United States)

    Akhbari, Pouya; Jha, Shilpa; James, Kyle D; Hinves, Barry L; Buchanan, Jamie A F

    2012-11-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder. The estimated incidence is one in 4 million births. Orthopaedic manifestations include abnormality of the hips occurring early in the disease process. Severe coxa valga can be apparent by the age of 2 years. We report two cases of HGPS, one in a 7-year-old girl with avascular necrosis of the left hip and the second in a 13-year-old girl with recurrent traumatic hip dislocations. We demonstrate the pathoanatomical changes in the hip with HGPS using a combination of imaging modalities including radiographic, computed tomographic and MRI scans. These include coxa magna, coxa valga and acetabular dysplasia. We also comment on how these would affect the surgical management of this high-risk group of patients.

  14. Prematurely aged children: molecular alterations leading to Hutchinson-Gilford progeria and Werner syndromes.

    Science.gov (United States)

    Domínguez-Gerpe, Lourdes; Araújo-Vilar, David

    2008-12-01

    Ageing is thought to be a polygenic and stochastic process in which multiple mechanisms operate at the same time. At the level of the individual organism ageing is associated with a progressive deterioration of health and quality of life, sharing common features such as: alopecia and grey hair, loss of audition, macular degeneration, neurodegeneration, cardiovascular diseases, osteoporosis, cataract formation, type-2 diabetes, lipodystrophies; a generally increased susceptibility to infection, autoimmune disorders and diseases such as cancer; and an impaired ability to cope with stress. Recent studies of mechanisms involved in the ageing process are contributing to the identification of genes involved in longevity. Monogenic heritable disorders causing premature ageing, and animal models have contributed to the understanding of some of the characteristic organism-level features associated with human ageing. Werner syndrome and Hutchinson-Gilford progeria syndrome are the best characterized human disorders. Werner syndrome patients have a median life expectancy of 47 years with clinical conditions from the second decade of life. Hutchinson-Gilford progeria syndrome patients die at a median age of 11-13 years with clinical conditions appearing soon after birth. In both syndromes, alterations in specific genes have been identified, with mutations in the WRN and LMNA genes respectively being the most closely associated with each syndrome. Results from molecular studies strongly suggest an increase in DNA damage and cell senescence as the underlying mechanism of pathological premature ageing in these two human syndromes. The same general mechanism has also been observed in human cells undergoing the normal ageing process. In the present article the molecular mechanisms currently proposed for explaining these two syndromes, which may also partly explain the normal ageing process, are reviewed.

  15. Impact of Farnesylation Inhibitors on Survival in Hutchinson-Gilford Progeria Syndrome

    Science.gov (United States)

    Gordon, Leslie B.; Massaro, Joe; D'Agostino, Ralph B.; Campbell, Susan E.; Brazier, Joan; Brown, W. Ted; Kleinman, Monica E; Kieran, Mark W.

    2014-01-01

    Background Hutchinson-Gilford progeria syndrome is an ultra-rare segmental premature aging disease resulting in early death from heart attack or stroke. There is no approved treatment, but starting in 2007, several recent single arm clinical trials have administered inhibitors of protein farnesylation aimed at reducing toxicity of the disease-producing protein progerin. No study has assessed whether treatments influence patient survival. The key elements necessary for this analysis are a robust natural history of survival and comparison with a sufficiently large patient population that has been treated for a sufficient time period with disease-targeting medications. Methods and Results We generated survival Kaplan-Meier survival analyses for the largest untreated Hutchinson-Gilford progeria syndrome cohort to date. Mean survival was 14.6 years. Comparing survival for treated versus age-and-gender-matched untreated cohorts, hazard ratio was 0.13 (95% CI 0.04-0.37; P<0.001) with median follow-up of 5.3 years from time of treatment initiation. There were 21/43 deaths in untreated versus 5/43 deaths among treated subjects. Treatment increased mean survival by 1.6 years. Conclusions This study provides a robust untreated disease survival profile, which can be utilized for comparisons now and in the future to assess changes in survival with treatments for HGPS. The current comparisons estimating increased survival with protein farnesylation inhibitors provide the first evidence of treatments influencing survival for this fatal disease. Clinical Trial Registration Information www.clinicaltrials.gov. Indentifiers: NCT00425607, NCT00879034 and NCT00916747. PMID:24795390

  16. DNA-damage accumulation and replicative arrest in Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Musich, Phillip R; Zou, Yue

    2011-12-01

    A common feature of progeria syndromes is a premature aging phenotype and an enhanced accumulation of DNA damage arising from a compromised repair system. HGPS (Hutchinson-Gilford progeria syndrome) is a severe form of progeria in which patients accumulate progerin, a mutant lamin A protein derived from a splicing variant of the lamin A/C gene (LMNA). Progerin causes chromatin perturbations which result in the formation of DSBs (double-strand breaks) and abnormal DDR (DNA-damage response). In the present article, we review recent findings which resolve some mechanistic details of how progerin may disrupt DDR pathways in HGPS cells. We propose that progerin accumulation results in disruption of functions of some replication and repair factors, causing the mislocalization of XPA (xeroderma pigmentosum group A) protein to the replication forks, replication fork stalling and, subsequently, DNA DSBs. The binding of XPA to the stalled forks excludes normal binding by repair proteins, leading to DSB accumulation, which activates ATM (ataxia telangiectasia mutated) and ATR (ATM- and Rad3-related) checkpoints, and arresting cell-cycle progression.

  17. Effect of progerin on the accumulation of oxidized proteins in fibroblasts from Hutchinson Gilford progeria patients.

    Science.gov (United States)

    Viteri, Gabriela; Chung, Youn Wook; Stadtman, Earl R

    2010-01-01

    The mutation responsible for Hutchinson Gilford Progeria Syndrome (HGPS) causes abnormal nuclear morphology. Previous studies show that free radicals and reactive oxygen species play major roles in the etiology and/or progression of neurodegenerative diseases and aging. This study compares oxidative stress responses between progeric and normal fibroblasts. Our data revealed higher ROS levels in HGPS cells compared to age-matched controls. In response to oxidative challenge, progeric cells showed increased mRNA levels for mitochondrial superoxide dismutase (SOD) and SOD protein content. However, this did not prevent a drop in the ATP content of progeria fibroblasts. Previous studies have shown that declines in human fibroblast ATP levels interfere with programmed cell death and promote necrotic inflammation. Notably, in our investigations the ATP content of progeria fibroblasts was only approximately 50% of that found in healthy controls. Furthermore, HGPS fibroblast analysis revealed a decrease in total caspase-like proteasome activity and in the levels of two active proteolytic complex subunits (beta(5) and beta(7)). A number of studies indicate that the molecular mechanisms causing accelerated aging in progeric patients also occur in healthy cells of older individuals. Thus, the results of this study may also help explain some of the cellular changes that accompany normal aging.

  18. Vitamin D receptor signaling improves Hutchinson-Gilford progeria syndrome cellular phenotypes.

    Science.gov (United States)

    Kreienkamp, Ray; Croke, Monica; Neumann, Martin A; Bedia-Diaz, Gonzalo; Graziano, Simona; Dusso, Adriana; Dorsett, Dale; Carlberg, Carsten; Gonzalo, Susana

    2016-05-24

    Hutchinson-Gilford Progeria Syndrome (HGPS) is a devastating incurable premature aging disease caused by accumulation of progerin, a toxic lamin A mutant protein. HGPS patient-derived cells exhibit nuclear morphological abnormalities, altered signaling pathways, genomic instability, and premature senescence. Here we uncover new molecular mechanisms contributing to cellular decline in progeria. We demonstrate that HGPS cells reduce expression of vitamin D receptor (VDR) and DNA repair factors BRCA1 and 53BP1 with progerin accumulation, and that reconstituting VDR signaling via 1α,25-dihydroxyvitamin D3 (1,25D) treatment improves HGPS phenotypes, including nuclear morphological abnormalities, DNA repair defects, and premature senescence. Importantly, we discovered that the 1,25D/VDR axis regulates LMNA gene expression, as well as expression of DNA repair factors. 1,25D dramatically reduces progerin production in HGPS cells, while stabilizing BRCA1 and 53BP1, two key factors for genome integrity. Vitamin D/VDR axis emerges as a new target for treatment of HGPS and potentially other lamin-related diseases exhibiting VDR deficiency and genomic instability. Because progerin expression increases with age, maintaining vitamin D/VDR signaling could keep the levels of progerin in check during physiological aging.

  19. Bilateral stenosis of carotid siphon in Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Narazaki, Ryo; Makimura, Mika; Sanefuji, Masafumi; Fukamachi, Shigeru; Akiyoshi, Hidetaka; So, Hidenori; Yamamura, Kenichiro; Doisaki, Sayoko; Kojima, Seiji; Ihara, Kenji; Hara, Toshiro; Ohga, Shouichi

    2013-08-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disease, caused by a de novo mutation of lamin-A gene, LMNA G608G. Accumulation of abnormal lamin-A (progerin) compromises nuclear membrane integrity and results in the accelerated senescence. Affected patients show a typical feature of birdlike face, alopecia, sclerotic skin, loss of subcutaneous fat, and short stature with advancing years. Neonatal scleroderma is the first presentation, although early diagnosis is challenging. The leading cause of death is cardio-/cerebro-vascular accidents associated with atherosclerosis. However, not all findings may recapitulate the aging process. We herein report a 9-year-old Japanese male with HGPS who developed cerebral infarction. The genetic study of peripheral blood-derived DNA determined a heterozygous c.1824C>T mutation, p.G608G. Telomere length of lymphocytes was normal. Bilateral stenosis of carotid siphons was prominent, while systemic arteriosclerosis was unremarkable assessed by the ankle-brachial index, carotid ultrasound imaging and funduscopic study. HGPS patients have marked loss and functional defects in vascular smooth muscle cells, leading to the vulnerability to circulatory stress. Symmetrical stenosis of siphons might occur as a distinctive cerebral vasculopathy of HGPS, rather than simple vascular senescence. Peripheral blood study on LMNA G608G and telomere length could screen progerias in infancy for early therapeutic intervention.

  20. Interruption of progerin–lamin A/C binding ameliorates Hutchinson-Gilford progeria syndrome phenotype

    Science.gov (United States)

    Lee, Su-Jin; Jung, Youn-Sang; Yoon, Min-Ho; Kang, So-mi; Oh, Ah-Young; Lee, Jee-Hyun; Jun, So-Young; Woo, Tae-Gyun; Chun, Ho-Young; Kim, Sang Kyum; Chung, Kyu Jin; Lee, Ho-Young; Lee, Kyeong; Jin, Guanghai; Na, Min-Kyun; Ha, Nam Chul; Bárcena, Clea; Freije, José M.P.; López-Otín, Carlos; Song, Gyu Yong

    2016-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare autosomal dominant genetic disease that is caused by a silent mutation of the LMNA gene encoding lamins A and C (lamin A/C). The G608G mutation generates a more accessible splicing donor site than does WT and produces an alternatively spliced product of LMNA called progerin, which is also expressed in normal aged cells. In this study, we determined that progerin binds directly to lamin A/C and induces profound nuclear aberrations. Given this observation, we performed a random screening of a chemical library and identified 3 compounds (JH1, JH4, and JH13) that efficiently block progerin–lamin A/C binding. These 3 chemicals, particularly JH4, alleviated nuclear deformation and reversed senescence markers characteristic of HGPS cells, including growth arrest and senescence-associated β-gal (SA–β-gal) activity. We then used microarray-based analysis to demonstrate that JH4 is able to rescue defects of cell-cycle progression in both HGPS and aged cells. Furthermore, administration of JH4 to LmnaG609G/G609G-mutant mice, which phenocopy human HGPS, resulted in a marked improvement of several progeria phenotypes and an extended lifespan. Together, these findings indicate that specific inhibitors with the ability to block pathological progerin–lamin A/C binding may represent a promising strategy for improving lifespan and health in both HGPS and normal aging. PMID:27617860

  1. Interruption of progerin-lamin A/C binding ameliorates Hutchinson-Gilford progeria syndrome phenotype.

    Science.gov (United States)

    Lee, Su-Jin; Jung, Youn-Sang; Yoon, Min-Ho; Kang, So-Mi; Oh, Ah-Young; Lee, Jee-Hyun; Jun, So-Young; Woo, Tae-Gyun; Chun, Ho-Young; Kim, Sang Kyum; Chung, Kyu Jin; Lee, Ho-Young; Lee, Kyeong; Jin, Guanghai; Na, Min-Kyun; Ha, Nam Chul; Bárcena, Clea; Freije, José M P; López-Otín, Carlos; Song, Gyu Yong; Park, Bum-Joon

    2016-10-03

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare autosomal dominant genetic disease that is caused by a silent mutation of the LMNA gene encoding lamins A and C (lamin A/C). The G608G mutation generates a more accessible splicing donor site than does WT and produces an alternatively spliced product of LMNA called progerin, which is also expressed in normal aged cells. In this study, we determined that progerin binds directly to lamin A/C and induces profound nuclear aberrations. Given this observation, we performed a random screening of a chemical library and identified 3 compounds (JH1, JH4, and JH13) that efficiently block progerin-lamin A/C binding. These 3 chemicals, particularly JH4, alleviated nuclear deformation and reversed senescence markers characteristic of HGPS cells, including growth arrest and senescence-associated β-gal (SA-β-gal) activity. We then used microarray-based analysis to demonstrate that JH4 is able to rescue defects of cell-cycle progression in both HGPS and aged cells. Furthermore, administration of JH4 to LmnaG609G/G609G-mutant mice, which phenocopy human HGPS, resulted in a marked improvement of several progeria phenotypes and an extended lifespan. Together, these findings indicate that specific inhibitors with the ability to block pathological progerin-lamin A/C binding may represent a promising strategy for improving lifespan and health in both HGPS and normal aging.

  2. Pluripotent stem cells to model Hutchinson-Gilford progeria syndrome (HGPS): Current trends and future perspectives for drug discovery.

    Science.gov (United States)

    Lo Cicero, Alessandra; Nissan, Xavier

    2015-11-01

    Progeria, or Hutchinson-Gilford progeria syndrome (HGPS), is a rare, fatal genetic disease characterized by an appearance of accelerated aging in children. This syndrome is typically caused by mutations in codon 608 (p.G608G) of the LMNA, leading to the production of a mutated form of lamin A precursor called progerin. In HGPS, progerin accumulates in cells causing progressive molecular defects, including nuclear shape abnormalities, chromatin disorganization, damage to DNA and delays in cell proliferation. Here we report how, over the past five years, pluripotent stem cells have provided new insights into the study of HGPS and opened new original therapeutic perspectives to treat the disease.

  3. Simultaneous Shoulder and Hip Dislocation in a 12-Year-Old Girl with Hutchinson-Gilford Progeria Syndrome

    Directory of Open Access Journals (Sweden)

    Shirin Mardookhpour

    2012-06-01

    Full Text Available Hutchinson-Gilford progeria syndrome (HGPS is a rare premature ageing disorder that is characterized by accelerated degenerative changes of the cutaneous, musculoskeletal and cardiovascular systems. Mean age at diagnosis is 2.9 years and generally leading to death at approximately 13 years of age due to myocardial infarction or stroke. Orthopedic manifestations of HGPS are multiple and shoulder dislocation is a rare skeletal trauma in progeria syndrome. Our patient had simultaneous shoulder and hip dislocation associated with a low energy trauma. This subject has not been reported. Treatment accomplished as close reduction under general anesthesia and immobilization.

  4. Clinical and radiographic features of Hutchinson-Gilford progeria syndrome: A case report.

    Science.gov (United States)

    Alves, Daniel Berretta; Silva, Juliana Melo; Menezes, Tatiany Oliveira; Cavaleiro, Rosely Santos; Tuji, Fabrício Mesquita; Lopes, Marcio Ajudarte; Zaia, Alexandre Augusto; Coletta, Ricardo Della

    2014-03-16

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare dysmorphic syndrome characterized by several features of premature aging with clinical involvement of the skin, bones, and cardiovascular system. HGPS has an estimated incidence of one in four million to one in eight million births. The main clinical features of HGPS include short stature, craniofacial dimorphism, alopecia, bone fragility, and cardiovascular disorders. The most frequent cause of death is myocardial infarction at a mean age of 13 years old. Dental manifestations include delayed development and eruption of teeth, discoloration, crowding and rotation of teeth, and displaced teeth. Cone beam computed tomography images revealed the absence of the sphenoid, frontal, and maxillary sinus, flattening of the condyles and glenoid fossa, and bilateral hypoplasia of the mandibular condyles. The disease is caused by mutations in lamin A/C (LMNA). Here, we present a case report of an 11-year-old boy with classical features of HGPS, which was caused by a de novo germ-line mutation (C1824T, G608G) in exon 11 of the LMNA gene. Some uncommon HGPS-associated features in our patient, such as alterations in the facial sinuses and hypoplasia of the condyles, contributed to the expansion of the phenotypic spectrum of this syndrome from a dentomaxillofacial perspective.

  5. Abberent expression analysis of LMNA gene in hutchinson-gilford progeria syndrome

    Science.gov (United States)

    Navid, Afifa; Khan, Mohammad Haroon; Rashid, Hamid

    2012-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is caused by de novo dominant point mutations of the genes encoding nuclear lamina proteins, leading towards premature aging. A protein sequence is subjected to mutations in nature which can affect the function and folding pattern of the protein by different ways. Mutations involved in HGPS were identified and were substituted in the seed sequence retrieved from the UniProt database to get the mutated versions. Tertiary structure of the Lamin A protein was previously unpredicted so was performed for all the mutated as well as for the seed protein to analyze the effects of mutations on the protein structure, folding and interactions. All the predicted models were refined and validated through multiple servers for multiple parameters. The validated 3D structure of seed protein was then successfully submitted to the Protein Model Database and was assigned with the PMDB ID PM0077829. All the predicted structures were superimposed with a root mean square deviation value of 7.0 Å and a high Dali Z-score of 1.9. It was observed that mutations affected physiochemical properties as well as instability index and thus is affecting the domains in specific and the whole structure in general. It was further analyzed that HGPS is the result of affected Lamin a protein interactions with other integral and binding proteins in the inner nuclear membrane affecting the link in between the nuclear membrane and the network of the lamina. PMID:22493523

  6. MECHANISMS OF PREMATURE VASCULAR AGING IN CHILDREN WITH HUTCHINSON-GILFORD PROGERIA SYNDROME

    Science.gov (United States)

    Gerhard-Herman, Marie; Smoot, Leslie B.; Wake, Nicole; Kieran, Mark W.; Kleinman, Monica E.; Miller, David T.; Schwartzman, Armin; Giobbie-Hurder, Anita; Neuberg, Donna; Gordon, Leslie B.

    2011-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare, segmental premature aging syndrome of accelerated atherosclerosis and early death from myocardial infarction or stroke. This study sought to establish comprehensive characterization of the fatal vasculopathy in HGPS and its relevance to normal aging. We performed cardiovascular assessments at a single clinical site on the largest prospectively studied cohort to date. Carotid-femoral pulse wave velocity was dramatically elevated (mean 13.00±3.83 m/s). Carotid duplex ultrasound echobrightness, assessed in predefined tissue sites as a measure of arterial wall density, was significantly greater than age- and gender-matched controls in the intima-media (P<0.02), near adventitia (P<0.003) and deep adventitia (P<0.01), as was internal carotid artery mean flow velocity (p<0.0001). Ankle-brachial indices were abnormal in 78% of patients. Effective disease treatments may be heralded by normalizing trends of these noninvasive cardiovascular measures. The data demonstrates that, along with peripheral vascular occlusive disease, accelerated vascular stiffening is an early and pervasive mechanism of vascular disease in HGPS. There is considerable overlap with cardiovascular changes of normal aging, which reinforces the view that defining mechanisms of cardiovascular disease in HGPS provides a unique opportunity to isolate a subset of factors influencing cardiovascular disease in the general aging population. PMID:22083160

  7. Hutchinson-Gilford progeria syndrome as a model for vascular aging.

    Science.gov (United States)

    Brassard, Jonathan A; Fekete, Natalie; Garnier, Alain; Hoesli, Corinne A

    2016-02-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder caused by a de novo genetic mutation that leads to the accumulation of a splicing isoform of lamin A termed progerin. Progerin expression alters the organization of the nuclear lamina and chromatin. The life expectancy of HGPS patients is severely reduced due to critical cardiovascular defects. Progerin also accumulates in an age-dependent manner in the vascular cells of adults that do not carry genetic mutations associated with HGPS. The molecular mechanisms that lead to vascular dysfunction in HGPS may therefore also play a role in vascular aging. The vascular phenotypic and molecular changes observed in HGPS are strikingly similar to those seen with age, including increased senescence, altered mechanotransduction and stem cell exhaustion. This article discusses the similarities and differences between age-dependent and HGPS-related vascular aging to highlight the relevance of HGPS as a model for vascular aging. Induced pluripotent stem cells derived from HGPS patients are suggested as an attractive model to study vascular aging in order to develop novel approaches to treat cardiovascular disease.

  8. Rapamycin reverses cellular phenotypes and enhances mutant protein clearance in Hutchinson-Gilford progeria syndrome cells.

    Science.gov (United States)

    Cao, Kan; Graziotto, John J; Blair, Cecilia D; Mazzulli, Joseph R; Erdos, Michael R; Krainc, Dimitri; Collins, Francis S

    2011-06-29

    Hutchinson-Gilford progeria syndrome (HGPS) is a lethal genetic disorder characterized by premature aging. HGPS is most commonly caused by a de novo single-nucleotide substitution in the lamin A/C gene (LMNA) that partially activates a cryptic splice donor site in exon 11, producing an abnormal lamin A protein termed progerin. Accumulation of progerin in dividing cells adversely affects the integrity of the nuclear scaffold and leads to nuclear blebbing in cultured cells. Progerin is also produced in normal cells, increasing in abundance as senescence approaches. Here, we report the effect of rapamycin, a macrolide antibiotic that has been implicated in slowing cellular and organismal aging, on the cellular phenotypes of HGPS fibroblasts. Treatment with rapamycin abolished nuclear blebbing, delayed the onset of cellular senescence, and enhanced the degradation of progerin in HGPS cells. Rapamycin also decreased the formation of insoluble progerin aggregates and induced clearance through autophagic mechanisms in normal fibroblasts. Our findings suggest an additional mechanism for the beneficial effects of rapamycin on longevity and encourage the hypothesis that rapamycin treatment could provide clinical benefit for children with HGPS.

  9. Progerin reduces LAP2α-telomere association in Hutchinson-Gilford progeria.

    Science.gov (United States)

    Chojnowski, Alexandre; Ong, Peh Fern; Wong, Esther S M; Lim, John S Y; Mutalif, Rafidah A; Navasankari, Raju; Dutta, Bamaprasad; Yang, Henry; Liow, Yi Y; Sze, Siu K; Boudier, Thomas; Wright, Graham D; Colman, Alan; Burke, Brian; Stewart, Colin L; Dreesen, Oliver

    2015-08-27

    Hutchinson-Gilford progeria (HGPS) is a premature ageing syndrome caused by a mutation in LMNA, resulting in a truncated form of lamin A called progerin. Progerin triggers loss of the heterochromatic marker H3K27me3, and premature senescence, which is prevented by telomerase. However, the mechanism how progerin causes disease remains unclear. Here, we describe an inducible cellular system to model HGPS and find that LAP2α (lamina-associated polypeptide-α) interacts with lamin A, while its interaction with progerin is significantly reduced. Super-resolution microscopy revealed that over 50% of telomeres localize to the lamina and that LAP2α association with telomeres is impaired in HGPS. This impaired interaction is central to HGPS since increasing LAP2α levels rescues progerin-induced proliferation defects and loss of H3K27me3, whereas lowering LAP2 levels exacerbates progerin-induced defects. These findings provide novel insights into the pathophysiology underlying HGPS, and how the nuclear lamina regulates proliferation and chromatin organization.

  10. Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Gordon, Leslie B; Kleinman, Monica E; Miller, David T; Neuberg, Donna S; Giobbie-Hurder, Anita; Gerhard-Herman, Marie; Smoot, Leslie B; Gordon, Catherine M; Cleveland, Robert; Snyder, Brian D; Fligor, Brian; Bishop, W Robert; Statkevich, Paul; Regen, Amy; Sonis, Andrew; Riley, Susan; Ploski, Christine; Correia, Annette; Quinn, Nicolle; Ullrich, Nicole J; Nazarian, Ara; Liang, Marilyn G; Huh, Susanna Y; Schwartzman, Armin; Kieran, Mark W

    2012-10-09

    Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA that produces the farnesylated aberrant lamin A protein, progerin. This multisystem disorder causes failure to thrive and accelerated atherosclerosis leading to early death. Farnesyltransferase inhibitors have ameliorated disease phenotypes in preclinical studies. Twenty-five patients with HGPS received the farnesyltransferase inhibitor lonafarnib for a minimum of 2 y. Primary outcome success was predefined as a 50% increase over pretherapy in estimated annual rate of weight gain, or change from pretherapy weight loss to statistically significant on-study weight gain. Nine patients experienced a ≥50% increase, six experienced a ≥50% decrease, and 10 remained stable with respect to rate of weight gain. Secondary outcomes included decreases in arterial pulse wave velocity and carotid artery echodensity and increases in skeletal rigidity and sensorineural hearing within patient subgroups. All patients improved in one or more of these outcomes. Results from this clinical treatment trial for children with HGPS provide preliminary evidence that lonafarnib may improve vascular stiffness, bone structure, and audiological status.

  11. Drug screening on Hutchinson Gilford progeria pluripotent stem cells reveals aminopyrimidines as new modulators of farnesylation.

    Science.gov (United States)

    Blondel, S; Egesipe, A-L; Picardi, P; Jaskowiak, A-L; Notarnicola, M; Ragot, J; Tournois, J; Le Corf, A; Brinon, B; Poydenot, P; Georges, P; Navarro, C; Pitrez, P R; Ferreira, L; Bollot, G; Bauvais, C; Laustriat, D; Mejat, A; De Sandre-Giovannoli, A; Levy, N; Bifulco, M; Peschanski, M; Nissan, X

    2016-02-18

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by a dramatic appearance of premature aging. HGPS is due to a single-base substitution in exon 11 of the LMNA gene (c.1824C>T) leading to the production of a toxic form of the prelamin A protein called progerin. Because farnesylation process had been shown to control progerin toxicity, in this study we have developed a screening method permitting to identify new pharmacological inhibitors of farnesylation. For this, we have used the unique potential of pluripotent stem cells to have access to an unlimited and relevant biological resource and test 21,608 small molecules. This study identified several compounds, called monoaminopyrimidines, which target two key enzymes of the farnesylation process, farnesyl pyrophosphate synthase and farnesyl transferase, and rescue in vitro phenotypes associated with HGPS. Our results opens up new therapeutic possibilities for the treatment of HGPS by identifying a new family of protein farnesylation inhibitors, and which may also be applicable to cancers and diseases associated with mutations that involve farnesylated proteins.

  12. Metformin Alleviates Aging Cellular Phenotypes in Hutchinson-Gilford Progeria Syndrome Dermal Fibroblasts.

    Science.gov (United States)

    Park, Seul-Ki; Shin, Ok Sarah

    2017-02-13

    Metformin is a popular antidiabetic biguanide, which has been considered as a candidate drug for cancer treatment and aging prevention. Hutchinson-Gilford progeria syndrome (HGPS) is a devastating disease characterized by premature aging and severe age-associated complications leading to death. The effects of metformin on HGPS dermal fibroblasts remain largely undefined. In this study, we investigated whether metformin could exert a beneficial effect on nuclear abnormalities and delay senescence in fibroblasts derived from HGPS patients. Metformin treatment partially restored normal nuclear phenotypes, delayed senescence, activated the phosphorylation of AMP-activated protein kinase, and decreased reactive oxygen species formation in HGPS dermal fibroblasts. Interestingly, metformin reduced the number of phosphorylated histone variant H2AX-positive DNA damage foci and suppressed progerin protein expression, compared to the control. Furthermore, metformin-supplemented aged mice showed higher splenocyte proliferation and mRNA expression of the antioxidant enzyme, superoxide dismutase 2 than the control mice. Collectively, our results show that metformin treatment alleviates the nuclear defects and premature aging phenotypes in HGPS fibroblasts. Thus, metformin can be considered a promising therapeutic approach for life extension in HGPS. This article is protected by copyright. All rights reserved.

  13. A-type lamins and Hutchinson-Gilford progeria syndrome: pathogenesis and therapy.

    Science.gov (United States)

    Gonzalez, Jose M; Pla, Davinia; Perez-Sala, Dolores; Andres, Vicente

    2011-06-01

    Lamin A and lamin C (A-type lamins, both encoded by the LMNA gene) are major components of the mammalian nuclear lamina, a complex proteinaceous structure that acts as a scaffold for protein complexes that regulate nuclear structure and function. Abnormal accumulation of farnesylated-progerin, a mutant form of prelamin A, plays a key role in the pathogenesis of the Hutchinson-Gilford progeria syndrome (HGPS), a devastating disorder that causes the death of affected children at an average age of 13.5 years, predominantly from premature atherosclerosis and myocardial infarction or stroke. Remarkably, progerin is also present in normal cells and appears to progressively accumulate during aging of non-HGPS cells. Therefore, understanding how this mutant form of lamin A provokes HGPS may shed significant insight into physiological aging. In this review, we discuss recent advances into the pathogenic mechanisms underlying HGPS, the main murine models of the disease, and the therapeutic strategies developed in cellular and animal models with the aim of reducing the accumulation of farnesylated-progerin, as well as their use in clinical trials of HGPS.

  14. Aggrecan expression is substantially and abnormally upregulated in Hutchinson-Gilford Progeria Syndrome dermal fibroblasts.

    Science.gov (United States)

    Lemire, Joan M; Patis, Carrie; Gordon, Leslie B; Sandy, John D; Toole, Bryan P; Weiss, Anthony S

    2006-08-01

    Hutchinson-Gilford Progeria syndrome (HGPS) is a rare genetic disorder that displays features of segmental aging. It is manifested predominantly in connective tissue, with most prominent histological changes occurring in the skin, cartilage, bone and cardiovascular tissues. Detailed quantitative real time reverse-transcription polymerase chain reaction studies confirmed the previous observation that platelet-derived growth factor A-chain transcripts are consistently elevated 11+/-2- to 13+/-2-fold in two HGPS dermal fibroblast lines compared with age-matched controls. Furthermore, we identified two additional genes with substantially altered transcript levels. Nucleotide pyrophosphatase transcription was virtually shut down with decreased expression of 13+/-3- to 59+/-3-fold in HGPS, whereas aggrecan mRNA was elevated to 24+/-5 times to 41+/-4 times that of chronologically age-matched controls. Aggrecan, normally a component of cartilage and not always detectable in normal fibroblasts cultures, was secreted by HGPS fibroblast lines and was produced as a proteoglycan. This demonstrates that elevated aggrecan expression and its secretion are aberrant features of HGPS. We conclude that HGPS cells can display massively altered transcript levels leading to the secretion of inappropriate protein species.

  15. Increased expression of the Hutchinson-Gilford progeria syndrome truncated lamin A transcript during cell aging.

    Science.gov (United States)

    Rodriguez, Sofia; Coppedè, Fabio; Sagelius, Hanna; Eriksson, Maria

    2009-07-01

    Most cases of the segmental progeroid syndrome, Hutchinson-Gilford progeria syndrome (HGPS), are caused by a de novo dominant mutation within a single codon of the LMNA gene. This mutation leads to the increased usage of an internal splice site that generates an alternative lamin A transcript with an internal deletion of 150 nucleotides, called lamin A Delta 150. The LMNA gene encodes two major proteins of the inner nuclear lamina, lamins A and C, but not much is known about their expression levels. Determination of the overall expression levels of the LMNA gene transcripts is an important step to further the understanding of the HGPS. In this study, we have performed absolute quantification of the lamins A, C and A Delta 150 transcripts in primary dermal fibroblasts from HGPS patients and unaffected age-matched and parent controls. We show that the lamin A Delta 150 transcript is present in unaffected controls but its expression is >160-fold lower than that in samples from HGPS patients. Analysis of transcript expression during in vitro aging shows that although the levels of lamin A and lamin C transcripts remain unchanged, the lamin A Delta 150 transcript increases in late passage cells from HGPS patients and parental controls. This study provides a new method for LMNA transcript analysis and insights into the expression of the LMNA gene in HGPS and normal cells.

  16. Interfacial binding and aggregation of lamin A tail domains associated with Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Kalinowski, Agnieszka; Yaron, Peter N; Qin, Zhao; Shenoy, Siddharth; Buehler, Markus J; Lösche, Mathias; Dahl, Kris Noel

    2014-12-01

    Hutchinson-Gilford progeria syndrome is a premature aging disorder associated with the expression of ∆50 lamin A (∆50LA), a mutant form of the nuclear structural protein lamin A (LA). ∆50LA is missing 50 amino acids from the tail domain and retains a C-terminal farnesyl group that is cleaved from the wild-type LA. Many of the cellular pathologies of HGPS are thought to be a consequence of protein-membrane association mediated by the retained farnesyl group. To better characterize the protein-membrane interface, we quantified binding of purified recombinant ∆50LA tail domain (∆50LA-TD) to tethered bilayer membranes composed of phosphatidylserine and phosphocholine using surface plasmon resonance. Farnesylated ∆50LA-TD binds to the membrane interface only in the presence of Ca(2+) or Mg(2+) at physiological ionic strength. At extremely low ionic strength, both the farnesylated and non-farnesylated forms of ∆50LA-TD bind to the membrane surface in amounts that exceed those expected for a densely packed protein monolayer. Interestingly, the wild-type LA-TD with no farnesylation also associates with membranes at low ionic strength but forms only a single layer. We suggest that electrostatic interactions are mediated by charge clusters with a net positive charge that we calculate on the surface of the LA-TDs. These studies suggest that the accumulation of ∆50LA at the inner nuclear membrane observed in cells is due to a combination of aggregation and membrane association rather than simple membrane binding; electrostatics plays an important role in mediating this association.

  17. Epigenetic involvement in Hutchinson-Gilford progeria syndrome: a mini-review.

    Science.gov (United States)

    Arancio, Walter; Pizzolanti, Giuseppe; Genovese, Swonild I; Pitrone, Maria; Giordano, Carla

    2014-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare human genetic disease that leads to a severe premature ageing phenotype, caused by mutations in the LMNA gene. The LMNA gene codes for lamin-A and lamin-C proteins, which are structural components of the nuclear lamina. HGPS is usually caused by a de novo C1824T mutation that leads to the accumulation of a dominant negative form of lamin-A called progerin. Progerin also accumulates physiologically in normal ageing cells as a rare splicing form of lamin-A transcripts. From this perspective, HGPS cells seem to be good candidates for the study of the physiological mechanisms of ageing. Progerin accumulation leads to faster cellular senescence, stem cell depletion and the progeroid phenotype. Tissues of mesodermic origin are especially affected by HGPS. HGPS patients usually have a bad quality of life and, with current treatments, their life expectancy does not exceed their second decade at best. Though progerin can be expressed in almost any tissue, when death occurs, it is usually due to cardiovascular complications. In HGPS, severe epigenetic alterations have been reported. Histone-covalent modifications are radically different from control specimens, with the tendency to lose the bipartition into euchromatin and heterochromatin. This is reflected in an altered spatial compartmentalization and conformation of chromatin within the nucleus. Moreover, it seems that microRNAs and microRNA biosynthesis might play a role in HGPS. Exemplary in this connection is the suggested protective effect of miR-9 on the central nervous system of affected individuals. This mini-review will report on the state of the art of HGPS epigenetics, and there will be a discussion of how epigenetic alterations in HGPS cells can alter the cellular metabolism and lead to the systemic syndrome.

  18. Induced pluripotent stem cells reveal functional differences between drugs currently investigated in patients with hutchinson-gilford progeria syndrome.

    Science.gov (United States)

    Blondel, Sophie; Jaskowiak, Anne-Laure; Egesipe, Anne-Laure; Le Corf, Amelie; Navarro, Claire; Cordette, Véronique; Martinat, Cécile; Laabi, Yacine; Djabali, Karima; de Sandre-Giovannoli, Annachiara; Levy, Nicolas; Peschanski, Marc; Nissan, Xavier

    2014-04-01

    Hutchinson-Gilford progeria syndrome is a rare congenital disease characterized by premature aging in children. Identification of the mutation and related molecular mechanisms has rapidly led to independent clinical trials testing different marketed drugs with a preclinically documented impact on those mechanisms. However, the extensive functional effects of those drugs remain essentially unexplored. We have undertaken a systematic comparative study of the three main treatments currently administered or proposed to progeria-affected children, namely, a farnesyltransferase inhibitor, the combination of an aminobisphosphonate and a statin (zoledronate and pravastatin), and the macrolide antibiotic rapamycin. This work was based on the assumption that mesodermal stem cells, which are derived from Hutchinson-Gilford progeria syndrome-induced pluripotent stem cells expressing major defects associated with the disease, may be instrumental to revealing such effects. Whereas all three treatments significantly improved misshapen cell nuclei typically associated with progeria, differences were observed in terms of functional improvement in prelamin A farnesylation, progerin expression, defective cell proliferation, premature osteogenic differentiation, and ATP production. Finally, we have evaluated the effect of the different drug combinations on this cellular model. This study revealed no additional benefit compared with single-drug treatments, whereas a cytostatic effect equivalent to that of a farnesyltransferase inhibitor alone was systematically observed. Altogether, these results reveal the complexity of the modes of action of different drugs, even when they have been selected on the basis of a similar mechanistic hypothesis, and underscore the use of induced pluripotent stem cell derivatives as a critical and powerful tool for standardized, comparative pharmacological studies.

  19. Importance of molecular cell biology investigations in human medicine in the story of the Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Raška, Ivan

    2010-09-01

    Ranged among laminopathies, Hutchinson-Gilford progeria syndrome is a syndrome that involves premature aging, leading usually to death at the age between 10 to 14 years predominatly due to a myocardial infarction or a stroke. In the lecture I shall overview the importance of molecular cell biology investigations that led to the discovery of the basic mechanism standing behind this rare syndrome. The genetic basis in most cases is a mutation at the nucleotide position 1824 of the lamin A gene. At this position, cytosine is substituted for thymine so that a cryptic splice site within the precursor mRNA for lamin A is generated. This results in a production of abnormal lamin A, termed progerin, its presence in cells having a deleterious dominant effect. Depending on the cell type and tissue, progerin induces a pleiotropy of defects that vary in different tissues. The present endeavour how to challenge this terrible disease will be also mentioned.

  20. Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Goldman, Robert D; Shumaker, Dale K; Erdos, Michael R; Eriksson, Maria; Goldman, Anne E; Gordon, Leslie B; Gruenbaum, Yosef; Khuon, Satya; Mendez, Melissa; Varga, Renée; Collins, Francis S

    2004-06-15

    Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder, commonly caused by a point mutation in the lamin A gene that results in a protein lacking 50 aa near the C terminus, denoted LADelta50. Here we show by light and electron microscopy that HGPS is associated with significant changes in nuclear shape, including lobulation of the nuclear envelope, thickening of the nuclear lamina, loss of peripheral heterochromatin, and clustering of nuclear pores. These structural defects worsen as HGPS cells age in culture, and their severity correlates with an apparent increase in LADelta50. Introduction of LADelta50 into normal cells by transfection or protein injection induces the same changes. We hypothesize that these alterations in nuclear structure are due to a concentration-dependent dominant-negative effect of LADelta50, leading to the disruption of lamin-related functions ranging from the maintenance of nuclear shape to regulation of gene expression and DNA replication.

  1. Hutchinson-Gilford progeria syndrome%Hutchinson-Gilford早老综合征

    Institute of Scientific and Technical Information of China (English)

    张韡; 苏忠兰; 吴侃; 宋昊; 温斯健; 杨莹; 刘白; 林志淼; 孙建方

    2016-01-01

    To report a case of Hutchinson-Gilford progeria syndrome (HGPS).Peripheral blood samples were collected from a 5-year-old boy with HGPS and his parents.DNA was extracted from these samples,and PCR was performed to amplify exon 11 of the LMNA gene and its flanking sequences followed by DNA sequencing.The patient presented with scleroderma-like skin changes all over the body,growth retardation,distinctive facial features and hypotrichosis.His hip and knee joints could not be straightened completely,giving a horse-riding stance.A heterozygous mutation C.1824C > T was identified in exon 11 of the LMNA gene in the patient but not in either of his parents.A retrospective analysis was carried out on 18 Chinese patients with genetically diagnosed HPGS.Of them,9 classical cases were all sporadic with a heterozygous mutation of C.1824C>T.None of the patients with classical HPGS showed abnormality at birth,but all of them developed symptoms within 1 year after birth.Boys were more frequent to be affected by classical HPGS than girls,with the male/female ratio being 2:1.There was a familial tendency for the occurrence of atypical HPGS,and boys and girls appeared to be affected by HPGS at a similar probability.Three families with atypical HPGS all showed a homozygous LMNA mutation c.1579C>T.%报告1例Hutchinson-Gilford早老综合征(HGPS).对1例患儿及其父母外周血LMNA基因11号外显子和侧翼序列进行测序.患者男,5岁,全身皮肤呈硬皮病样改变,生长迟滞,特殊面容,毛发稀少.髋、膝关节均不能完全伸直,呈“骑马样站姿”.患儿LMNA基因11号外显子c.1824C>T杂合点突变,父母均未检测到该位点突变.文中还通过回顾性分析,探讨中国人群中通过基因学诊断的18例病例的疾病特点.我国基因学诊断的18例HGPS中,9例经典型HGPS均为散发病例,基因表型均上出现c.1824C>T杂合突变.患儿均在1岁以内发病,出生时基本未表现出“异常”.

  2. Replication Factor C1, the Large Subunit of Replication Factor C, Is Proteolytically Truncated in Hutchinson-Gilford Progeria Syndrome

    Science.gov (United States)

    Tang, Hui; Hilton, Benjamin; Musich, Phillip R.; Fang, Ding Zhi; Zou, Yue

    2011-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder due to a LMNA gene mutation which produces a mutant lamin A protein (progerin). Progerin also has been correlated to physiological aging and related diseases. However, how progerin causes the progeria remains unknown. Here we report that the large subunit (RFC1) of replication factor C is cleaved in HGPS cells, leading to the production of a truncated RFC1 of ~75 kDa which appears to be defective in loading PCNA and pol δ onto DNA for replication. Interestingly, the cleavage can be inhibited by a serine protease inhibitor, suggesting that RFC1 is cleaved by a serine protease. Due to the crucial role of RFC in DNA replication our findings provide a mechanistic interpretation for the observed replicative arrest and premature aging phenotypes of HPGS, and may lead to novel strategies in HGPS treatment. Furthermore, this unique truncated form of RFC1 may serve as a potential marker for HGPS. PMID:22168243

  3. Chemical screening identifies ROCK as a target for recovering mitochondrial function in Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Kang, Hyun Tae; Park, Joon Tae; Choi, Kobong; Choi, Hyo Jei Claudia; Jung, Chul Won; Kim, Gyu Ree; Lee, Young-Sam; Park, Sang Chul

    2017-03-19

    Hutchinson-Gilford progeria syndrome (HGPS) constitutes a genetic disease wherein an aging phenotype manifests in childhood. Recent studies indicate that reactive oxygen species (ROS) play important roles in HGPS phenotype progression. Thus, pharmacological reduction in ROS levels has been proposed as a potentially effective treatment for patient with this disorder. In this study, we performed high-throughput screening to find compounds that could reduce ROS levels in HGPS fibroblasts and identified rho-associated protein kinase (ROCK) inhibitor (Y-27632) as an effective agent. To elucidate the underlying mechanism of ROCK in regulating ROS levels, we performed a yeast two-hybrid screen and discovered that ROCK1 interacts with Rac1b. ROCK activation phosphorylated Rac1b at Ser71 and increased ROS levels by facilitating the interaction between Rac1b and cytochrome c. Conversely, ROCK inactivation with Y-27632 abolished their interaction, concomitant with ROS reduction. Additionally, ROCK activation resulted in mitochondrial dysfunction, whereas ROCK inactivation with Y-27632 induced the recovery of mitochondrial function. Furthermore, a reduction in the frequency of abnormal nuclear morphology and DNA double-strand breaks was observed along with decreased ROS levels. Thus, our study reveals a novel mechanism through which alleviation of the HGPS phenotype is mediated by the recovery of mitochondrial function upon ROCK inactivation.

  4. Progerin impairs chromosome maintenance by depleting CENP-F from metaphase kinetochores in Hutchinson-Gilford progeria fibroblasts.

    Science.gov (United States)

    Eisch, Veronika; Lu, Xiang; Gabriel, Diana; Djabali, Karima

    2016-04-26

    Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare premature aging disorder that leads to death at an average age of 14.7 years due to myocardial infarction or stroke. The most common mutation in HGPS is at position G608G (GGC>GGT) within exon 11 of the LMNA gene. This mutation results in the deletion of 50 amino acids at the carboxyl-terminal tail of prelamin A, producing a truncated farnesylated protein called progerin. Lamins play important roles in the organization and structure of the nucleus. The nuclear build-up of progerin causes severe morphological and functional changes in interphase HGPS cells. In this study, we investigated whether progerin elicits spatiotemporal deviations in mitotic processes in HGPS fibroblasts. We analyzed the nuclear distribution of endogenous progerin during mitosis in relation to components of the nuclear lamina, nuclear envelope (NE) and nuclear pores. We found that progerin caused defects in chromosome segregation as early as metaphase, delayed NE reformation and trapped lamina components and inner NE proteins in the endoplasmic reticulum at the end of mitosis. Progerin displaced the centromere protein F (CENP-F) from metaphase chromosome kinetochores, which caused increased chromatin lagging, binucleated cells and genomic instability. This accumulation of progerin-dependent defects with each round of mitosis predisposes cells to premature senescence.

  5. Defective lamin A-Rb signaling in Hutchinson-Gilford Progeria Syndrome and reversal by farnesyltransferase inhibition.

    Directory of Open Access Journals (Sweden)

    Jackleen Marji

    Full Text Available Hutchinson-Gilford Progeria Syndrome (HGPS is a rare premature aging disorder caused by a de novo heterozygous point mutation G608G (GGC>GGT within exon 11 of LMNA gene encoding A-type nuclear lamins. This mutation elicits an internal deletion of 50 amino acids in the carboxyl-terminus of prelamin A. The truncated protein, progerin, retains a farnesylated cysteine at its carboxyl terminus, a modification involved in HGPS pathogenesis. Inhibition of protein farnesylation has been shown to improve abnormal nuclear morphology and phenotype in cellular and animal models of HGPS. We analyzed global gene expression changes in fibroblasts from human subjects with HGPS and found that a lamin A-Rb signaling network is a major defective regulatory axis. Treatment of fibroblasts with a protein farnesyltransferase inhibitor reversed the gene expression defects. Our study identifies Rb as a key factor in HGPS pathogenesis and suggests that its modulation could ameliorate premature aging and possibly complications of physiological aging.

  6. Hutchinson-Gilford progeria syndrome alters nuclear shape and reduces cell motility in three dimensional model substrates.

    Science.gov (United States)

    Booth-Gauthier, Elizabeth A; Du, Vicard; Ghibaudo, Marion; Rape, Andrew D; Dahl, Kris Noel; Ladoux, Benoit

    2013-03-01

    Cell migration through tight interstitial spaces in three dimensional (3D) environments impacts development, wound healing and cancer metastasis and is altered by the aging process. The stiffness of the extracellular matrix (ECM) increases with aging and affects the cells and cytoskeletal processes involved in cell migration. However, the nucleus, which is the largest and densest organelle, has not been widely studied during cell migration through the ECM. Additionally, the nucleus is stiffened during the aging process through the accumulation of a mutant nucleoskeleton protein lamin A, progerin. By using microfabricated substrates to mimic the confined environment of surrounding tissues, we characterized nuclear movements and deformation during cell migration into micropillars where interspacing can be tuned to vary nuclear confinement. Cell motility decreased with decreased micropillar (μP) spacing and correlated with increased dysmorphic shapes of nuclei. We examined the effects of increased nuclear stiffness which correlates with cellular aging by studying Hutchinson-Gilford progeria syndrome cells which are known to accumulate progerin. With the expression of progerin, cells showed a threshold response to decreased μP spacing. Cells became trapped in the close spacing, possibly from visible micro-defects in the nucleoskeleton induced by cell crawling through the μP and from reduced force generation, measured independently. We suggest that ECM changes during aging could be compounded by the increasing stiffness of the nucleus and thus changes in cell migration through 3D tissues.

  7. Rapamycin activates autophagy in Hutchinson-Gilford progeria syndrome: implications for normal aging and age-dependent neurodegenerative disorders.

    Science.gov (United States)

    Graziotto, John J; Cao, Kan; Collins, Francis S; Krainc, Dimitri

    2012-01-01

    While rapamycin has been in use for years in transplant patients as an antirejection drug, more recently it has shown promise in treating diseases of aging, such as neurodegenerative disorders and atherosclerosis. We recently reported that rapamycin reverses the cellular phenotype of fibroblasts from children with the premature aging disease Hutchinson-Gilford progeria syndrome (HGPS). We found that the causative aberrant protein, progerin, was cleared through autophagic mechanisms when the cells were treated with rapamycin, suggesting a new potential treatment for HGPS. Recent evidence shows that progerin is also present in aged tissues of healthy individuals, suggesting that progerin may contribute to physiological aging. While it is intriguing to speculate that rapamycin may affect normal aging in humans, as it does in lower organisms, it will be important to identify safer analogues of rapamycin for chronic treatments in humans in order to minimize toxicity. In addition to its role in HGPS and normal aging, we discuss the potential of rapamycin for the treatment of age-dependent neurodegenerative diseases.

  8. The Defective Nuclear Lamina in Hutchinson-Gilford Progeria Syndrome Disrupts the Nucleocytoplasmic Ran Gradient and Inhibits Nuclear Localization of Ubc9▿

    Science.gov (United States)

    Kelley, Joshua B.; Datta, Sutirtha; Snow, Chelsi J.; Chatterjee, Mandovi; Ni, Li; Spencer, Adam; Yang, Chun-Song; Cubeñas-Potts, Caelin; Matunis, Michael J.; Paschal, Bryce M.

    2011-01-01

    The mutant form of lamin A responsible for the premature aging disease Hutchinson-Gilford progeria syndrome (termed progerin) acts as a dominant negative protein that changes the structure of the nuclear lamina. How the perturbation of the nuclear lamina in progeria is transduced into cellular changes is undefined. Using patient fibroblasts and a variety of cell-based assays, we determined that progerin expression in Hutchinson-Gilford progeria syndrome inhibits the nucleocytoplasmic transport of several factors with key roles in nuclear function. We found that progerin reduces the nuclear/cytoplasmic concentration of the Ran GTPase and inhibits the nuclear localization of Ubc9, the sole E2 for SUMOylation, and of TPR, the nucleoporin that forms the basket on the nuclear side of the nuclear pore complex. Forcing the nuclear localization of Ubc9 in progerin-expressing cells rescues the Ran gradient and TPR import, indicating that these pathways are linked. Reducing nuclear SUMOylation decreases the nuclear mobility of the Ran nucleotide exchange factor RCC1 in vivo, and the addition of SUMO E1 and E2 promotes the dissociation of RCC1 and Ran from chromatin in vitro. Our data suggest that the cellular effects of progerin are transduced, at least in part, through reduced function of the Ran GTPase and SUMOylation pathways. PMID:21670151

  9. The defective nuclear lamina in Hutchinson-gilford progeria syndrome disrupts the nucleocytoplasmic Ran gradient and inhibits nuclear localization of Ubc9.

    Science.gov (United States)

    Kelley, Joshua B; Datta, Sutirtha; Snow, Chelsi J; Chatterjee, Mandovi; Ni, Li; Spencer, Adam; Yang, Chun-Song; Cubeñas-Potts, Caelin; Matunis, Michael J; Paschal, Bryce M

    2011-08-01

    The mutant form of lamin A responsible for the premature aging disease Hutchinson-Gilford progeria syndrome (termed progerin) acts as a dominant negative protein that changes the structure of the nuclear lamina. How the perturbation of the nuclear lamina in progeria is transduced into cellular changes is undefined. Using patient fibroblasts and a variety of cell-based assays, we determined that progerin expression in Hutchinson-Gilford progeria syndrome inhibits the nucleocytoplasmic transport of several factors with key roles in nuclear function. We found that progerin reduces the nuclear/cytoplasmic concentration of the Ran GTPase and inhibits the nuclear localization of Ubc9, the sole E2 for SUMOylation, and of TPR, the nucleoporin that forms the basket on the nuclear side of the nuclear pore complex. Forcing the nuclear localization of Ubc9 in progerin-expressing cells rescues the Ran gradient and TPR import, indicating that these pathways are linked. Reducing nuclear SUMOylation decreases the nuclear mobility of the Ran nucleotide exchange factor RCC1 in vivo, and the addition of SUMO E1 and E2 promotes the dissociation of RCC1 and Ran from chromatin in vitro. Our data suggest that the cellular effects of progerin are transduced, at least in part, through reduced function of the Ran GTPase and SUMOylation pathways.

  10. A Prospective Study of Radiographic Manifestations in Hutchinson-Gilford Progeria Syndrome

    Science.gov (United States)

    Cleveland, Robert H.; Gordon, Leslie B.; Kleinman, Monica E.; Miller, David T.; Gordon, Catherine M.; Snyder, Brian D.; Nazarian, Ara; Giobbie-Hurder, Anita; Neuberg, Donna; Kieran, Mark W.

    2014-01-01

    Background/Objective Progeria is a rare segmental premature aging disease with significant skeletal abnormalities. Defining the full scope of radiologic abnormalities requires examination of a large proportion of the world’s Progeria population (estimated at 1 in 4 million). There has been no comprehensive prospective study describing the skeletal abnormalities associated with Progeria. We define characteristic radiographic features of this syndrome. Materials and Methods Thirty-nine children with classic Progeria, ages 2–17 years, from 29 countries were studied at a single site. Comprehensive radiographic imaging studies were performed. Results Sample included 23 females/16 males, the largest number of prospectively evaluated patients with Progeria to date. Eight new and two little known Progeria-associated radiologic findings were identified (frequencies of 3–36%). Additionally, 23 commonly reported findings were evaluated. Of these, 2 were not encountered, 21 were present and ranked according to their frequency. Nine abnormalities were associated with increasing patient age (P=0.02–0.0001). Conclusion This study considerably expands the radiographic morphologic spectrum of Progeria. A better understanding of the radiologic abnormalities associated with Progeria and improved understanding of the biology of progerin (the molecule responsible for this disease), will improve our ability to treat the spectrum of bony abnormalities. PMID:22752073

  11. A prospective study of radiographic manifestations in Hutchinson-Gilford progeria syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Cleveland, Robert H. [Harvard Medical School, Pediatric Radiology, Children' s Hospital Boston, Boston, MA (United States); Gordon, Leslie B. [Harvard Medical School, Department of Anesthesia, Children' s Hospital Boston, Boston, MA (United States); Warren Alpert Medical School of Brown University, Department of Pediatrics, Hasbro Children' s Hospital, Providence, RI (United States); Kleinman, Monica E. [Harvard Medical School, Department of Anesthesia, Children' s Hospital Boston, Boston, MA (United States); Miller, David T. [Harvard Medical School, Division of Genetics, Children' s Hospital Boston, Boston, MA (United States); Gordon, Catherine M. [Harvard Medical School, Division of Endocrinology and Adolescent Medicine, Children' s Hospital Boston, Boston, MA (United States); Snyder, Brian D. [Harvard Medical School, Department of Orthopedic Surgery, Children' s Hospital Boston, Boston, MA (United States); Nazarian, Ara [Harvard Medical School, Boston, MA (United States); Giobbie-Hurder, Anita [Dana-Farber Cancer Institute, Department of Biostatistics and Computational Biology, Boston, MA (United States); Neuberg, Donna [Dana-Farber Cancer Institute, Department of Biostatistics and Computational Biology, Boston, MA (United States); Harvard School of Public Health, Department of Biostatistics, Boston, MA (United States); Kieran, Mark W. [Dana-Farber Cancer Institute and Children' s Hospital Boston, Division of Pediatric Oncology, Boston, MA (United States)

    2012-09-15

    Progeria is a rare segmental premature aging disease with significant skeletal abnormalities. Defining the full scope of radiologic abnormalities requires examination of a large proportion of the world's progeria population (estimated at 1 in 4 million). There has been no comprehensive prospective study describing the skeletal abnormalities associated with progeria. To define characteristic radiographic features of this syndrome. Thirty-nine children with classic progeria, ages 2-17 years, from 29 countries were studied at a single site. Comprehensive radiographic imaging studies were performed. Sample included 23 girls and 16 boys - the largest number of patients with progeria evaluated prospectively to date. Eight new and two little known progeria-associated radiologic findings were identified (frequencies of 3-36%). Additionally, 23 commonly reported findings were evaluated. Of these, 2 were not encountered and 21 were present and ranked according to their frequency. Nine abnormalities were associated with increasing patient age (P = 0.02-0.0001). This study considerably expands the radiographic morphological spectrum of progeria. A better understanding of the radiologic abnormalities associated with progeria and improved understanding of the biology of progerin (the molecule responsible for this disease), will improve our ability to treat the spectrum of bony abnormalities. (orig.)

  12. Farnesyltransferase inhibitor treatment restores chromosome territory positions and active chromosome dynamics in Hutchinson-Gilford progeria syndrome cells

    Science.gov (United States)

    2011-01-01

    Background Hutchinson-Gilford progeria syndrome (HGPS) is a premature ageing syndrome that affects children leading to premature death, usually from heart infarction or strokes, making this syndrome similar to normative ageing. HGPS is commonly caused by a mutation in the A-type lamin gene, LMNA (G608G). This leads to the expression of an aberrant truncated lamin A protein, progerin. Progerin cannot be processed as wild-type pre-lamin A and remains farnesylated, leading to its aberrant behavior during interphase and mitosis. Farnesyltransferase inhibitors prevent the accumulation of farnesylated progerin, producing a less toxic protein. Results We have found that in proliferating fibroblasts derived from HGPS patients the nuclear location of interphase chromosomes differs from control proliferating cells and mimics that of control quiescent fibroblasts, with smaller chromosomes toward the nuclear interior and larger chromosomes toward the nuclear periphery. For this study we have treated HGPS fibroblasts with farnesyltransferase inhibitors and analyzed the nuclear location of individual chromosome territories. We have found that after exposure to farnesyltransferase inhibitors mis-localized chromosome territories were restored to a nuclear position akin to chromosomes in proliferating control cells. Furthermore, not only has this treatment afforded chromosomes to be repositioned but has also restored the machinery that controls their rapid movement upon serum removal. This machinery contains nuclear myosin 1β, whose distribution is also restored after farnesyltransferase inhibitor treatment of HGPS cells. Conclusions This study not only progresses the understanding of genome behavior in HGPS cells but demonstrates that interphase chromosome movement requires processed lamin A. PMID:21838864

  13. New Lmna knock-in mice provide a molecular mechanism for the 'segmental aging' in Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Jung, Hea-Jin; Tu, Yiping; Yang, Shao H; Tatar, Angelica; Nobumori, Chika; Wu, Daniel; Young, Stephen G; Fong, Loren G

    2014-03-15

    Lamins A and C (products of the LMNA gene) are found in roughly equal amounts in peripheral tissues, but the brain produces mainly lamin C and little lamin A. In HeLa cells and fibroblasts, the expression of prelamin A (the precursor to lamin A) can be reduced by miR-9, but the relevance of those cell culture studies to lamin A regulation in the brain was unclear. To address this issue, we created two new Lmna knock-in alleles, one (Lmna(PLAO-5NT)) with a 5-bp mutation in a predicted miR-9 binding site in prelamin A's 3' UTR, and a second (Lmna(PLAO-UTR)) in which prelamin A's 3' UTR was replaced with lamin C's 3' UTR. Neither allele had significant effects on lamin A levels in peripheral tissues; however, both substantially increased prelamin A transcript levels and lamin A protein levels in the cerebral cortex and the cerebellum. The increase in lamin A expression in the brain was more pronounced with the Lmna(PLAO-UTR) allele than with the Lmna(PLAO-5NT) allele. With both alleles, the increased expression of prelamin A transcripts and lamin A protein was greater in the cerebral cortex than in the cerebellum. Our studies demonstrate the in vivo importance of prelamin A's 3' UTR and its miR-9 binding site in regulating lamin A expression in the brain. The reduced expression of prelamin A in the brain likely explains why children with Hutchinson-Gilford progeria syndrome (a progeroid syndrome caused by a mutant form of prelamin A) are spared from neurodegenerative disease.

  14. Blocking farnesylation of the prelamin A variant in Hutchinson-Gilford progeria syndrome alters the distribution of A-type lamins

    Science.gov (United States)

    Wang, Yuexia; Ӧstlund, Cecilia; Choi, Jason C.; Swayne, Theresa C.; Gundersen, Gregg G.; Worman, Howard J.

    2012-01-01

    Mutations in the lamin A/C gene that cause Hutchinson-Gilford progeria syndrome lead to expression of a truncated, permanently farnesylated prelamin A variant called progerin. Blocking farnesylation leads to an improvement in the abnormal nuclear morphology observed in cells expressing progerin, which is associated with a re-localization of the variant protein from the nuclear envelope to the nuclear interior. We now show that a progerin construct that cannot be farnesylated is localized primarily in intranuclear foci and that its diffusional mobility is significantly greater than that of farnesylated progerin localized predominantly at the nuclear envelope. Expression of non-farnesylated progerin in transfected cells leads to a redistribution of lamin A and lamin C away from the nuclear envelope into intranuclear foci but does not significantly affect the localization of endogenous lamin B1 at nuclear envelope. There is a similar redistribution of lamin A and lamin C into intranuclear foci in transfected cells expressing progerin in which protein farnesylation is blocked by treatment with a protein farnesyltransferase inhibitor. Blocking farnesylation of progerin can lead to a redistribution of normal A-type lamins away from the inner nuclear envelope. This may have implications for using drugs that block protein prenylation to treat children with Hutchinson-Gilford progeria syndrome. These findings also provide additional evidence that A-type and B-type lamins can form separate microdomains within the nucleus. PMID:22895092

  15. Can Hutchinson-Gilford progeria syndrome be cured in the future?

    Science.gov (United States)

    Rehman, Neeha Abdul; Rehman, Aneeqa Abdul; Ashraf, Isra Najib; Ahmed, Shahrukh

    2015-05-01

    Progeria is a rare genetic disease that manifests with progressive symptoms eventually leading to death. The only current treatment protocol of such patients is symptom based. However, recent trials are testing potential and promising drugs to treat the underlying genetic mutation and increase life expectancy of such patients.

  16. Treatment considerations in hutchinson-gilford progeria syndrome: a case report.

    Science.gov (United States)

    Hazan-Molina, H; Aizenbud, D; Dror, Aizenbud D

    2015-01-01

    Hutchinson-Guilford progeria syndrome is an extremely rare condition classified as one of the premature ageing syndromes. This case presents a 16-year-old Israeli female patient, suffering from a variant of Hutchinson-Guilford progeria with a history of treatment with oral biphosphnates. The patient presented with typical cranial and facial features of the syndrome including delayed teeth eruption and root development probably due to insufficient jaw growth and severs retrognatic position of the maxilla and mandible. Orthodontic treatment considerations are described along with those required in light of the previous treatment by oral biphosphonates.All primary teeth were extracted in three appointments while creating as minimal trauma as possible to the surrounding tissue and alveolar bone. For now, the patient refuses to begin the orthodontic treatment course. There are no limitations to conduct any dental procedures in progeria patients, however, extreme caution must be exercised during oral surgery due to the inelasticity of tissues and dermal atrophy. Orthodontic procedure commencement should be early enough to manage the delayed development and eruption of teeth. Patients taking oral biphosphonates should be advised of this potential complication. If orthodontic treatment is considered appropriate, plans should be assessed and modified to include compromises.

  17. Oral and maxillofacial surgical considerations for a case of Hutchinson-Gilford progeria.

    Science.gov (United States)

    Batstone, M D; Macleod, A W G

    2002-11-01

    Hutchinson-Guilford progeria is a rare genetic condition showing the stigmata of accelerated ageing combined with severe growth retardation. Patients with this condition show a classical facies and clinical features with an average age of death of 13, usually due to atherosclerotic changes. Craniofacial and dental manifestations include mandibular and maxillary hypoplasia, both vertically and horizontally. Delayed and abnormal tooth eruption and morphology are commonly present. The long-term medical prognosis and eruption potential of individual teeth is important when considering treatment. In addition to this, surgical planning and surgical technique must be modified by the abnormal facial morphology, dermal inelasticity, potential anaesthetic difficulties, and ongoing deterioration in the medical condition. These factors mandate early and definitive intervention for oral surgical conditions. We report the case of a 13-year-old male treated for pericoronitis and oral pain relating to delayed eruption of first permanent molars.

  18. Transgene silencing of the Hutchinson-Gilford progeria syndrome mutation results in a reversible bone phenotype, whereas resveratrol treatment does not show overall beneficial effects

    DEFF Research Database (Denmark)

    Strandgren, Charlotte; Nasser, Hasina Abdul; McKenna, Tomás

    2015-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder that is most commonly caused by a de novo point mutation in exon 11 of the LMNA gene, c.1824C>T, which results in an increased production of a truncated form of lamin A known as progerin. In this study, we used a mouse...... model to study the possibility of recovering from HGPS bone disease upon silencing of the HGPS mutation, and the potential benefits from treatment with resveratrol. We show that complete silencing of the transgenic expression of progerin normalized bone morphology and mineralization already after 7...... weeks. The improvements included lower frequencies of rib fractures and callus formation, an increased number of osteocytes in remodeled bone, and normalized dentinogenesis. The beneficial effects from resveratrol treatment were less significant and to a large extent similar to mice treated with sucrose...

  19. Expression of the Hutchinson-Gilford Progeria Mutation during Osteoblast Development Results in Loss of Osteocytes, Irregular Mineralization, and Poor Biomechanical Properties*

    Science.gov (United States)

    Schmidt, Eva; Nilsson, Ola; Koskela, Antti; Tuukkanen, Juha; Ohlsson, Claes; Rozell, Björn; Eriksson, Maria

    2012-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a very rare genetic disorder that is characterized by multiple features of premature aging and largely affects tissues of mesenchymal origin. In this study, we describe the development of a tissue-specific mouse model that overexpresses the most common HGPS mutation (LMNA, c.1824C>T, p.G608G) in osteoblasts. Already at the age of 5 weeks, HGPS mutant mice show growth retardation, imbalanced gait and spontaneous fractures. Histopathological examination revealed an irregular bone structure, characterized by widespread loss of osteocytes, defects in mineralization, and a hypocellular red bone marrow. Computerized tomography analysis demonstrated impaired skeletal geometry and altered bone structure. The skeletal defects, which resemble the clinical features reported for bone disease in HGPS patients, was associated with an abnormal osteoblast differentiation. The osteoblast-specific expression of the HGPS mutation increased DNA damage and affected Wnt signaling. In the teeth, irregular dentin formation, as was previously demonstrated in human progeria cases, caused severe dental abnormalities affecting the incisors. The observed phenotype also shows similarities to reported bone abnormalities in aging mice and may therefore help to uncover general principles of the aging process. PMID:22893709

  20. Expression of the Hutchinson-Gilford progeria mutation during osteoblast development results in loss of osteocytes, irregular mineralization, and poor biomechanical properties.

    Science.gov (United States)

    Schmidt, Eva; Nilsson, Ola; Koskela, Antti; Tuukkanen, Juha; Ohlsson, Claes; Rozell, Björn; Eriksson, Maria

    2012-09-28

    Hutchinson-Gilford progeria syndrome (HGPS) is a very rare genetic disorder that is characterized by multiple features of premature aging and largely affects tissues of mesenchymal origin. In this study, we describe the development of a tissue-specific mouse model that overexpresses the most common HGPS mutation (LMNA, c.1824C>T, p.G608G) in osteoblasts. Already at the age of 5 weeks, HGPS mutant mice show growth retardation, imbalanced gait and spontaneous fractures. Histopathological examination revealed an irregular bone structure, characterized by widespread loss of osteocytes, defects in mineralization, and a hypocellular red bone marrow. Computerized tomography analysis demonstrated impaired skeletal geometry and altered bone structure. The skeletal defects, which resemble the clinical features reported for bone disease in HGPS patients, was associated with an abnormal osteoblast differentiation. The osteoblast-specific expression of the HGPS mutation increased DNA damage and affected Wnt signaling. In the teeth, irregular dentin formation, as was previously demonstrated in human progeria cases, caused severe dental abnormalities affecting the incisors. The observed phenotype also shows similarities to reported bone abnormalities in aging mice and may therefore help to uncover general principles of the aging process.

  1. Defective DSB repair correlates with abnormal nuclear morphology and is improved with FTI treatment in Hutchinson-Gilford progeria syndrome fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Constantinescu, Dan [Department of Cell Biology-Physiology, University of Pittsburgh, Pittsburgh, PA 15260 (United States); Pittsburgh Development Center, Magee-Women' s Research Institute, University of Pittsburgh, Pittsburgh, PA 15260 (United States); Csoka, Antonei B. [Division of Geriatrics, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15260 (United States); Navara, Christopher S. [Division of Developmental and Regenerative Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA 15260 (United States); Pittsburgh Development Center, Magee-Women' s Research Institute, University of Pittsburgh, Pittsburgh, PA 15260 (United States); Schatten, Gerald P., E-mail: schattengp@upmc.edu [Division of Developmental and Regenerative Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA 15260 (United States); Department of Cell Biology-Physiology, University of Pittsburgh, Pittsburgh, PA 15260 (United States); Pittsburgh Development Center, Magee-Women' s Research Institute, University of Pittsburgh, Pittsburgh, PA 15260 (United States)

    2010-10-15

    Impaired DSB repair has been implicated as a molecular mechanism contributing to the accelerating aging phenotype in Hutchinson-Gilford progeria syndrome (HGPS), but neither the extent nor the cause of the repair deficiency has been fully elucidated. Here we perform a quantitative analysis of the steady-state number of DSBs and the repair kinetics of ionizing radiation (IR)-induced DSBs in HGPS cells. We report an elevated steady-state number of DSBs and impaired repair of IR-induced DSBs, both of which correlated strongly with abnormal nuclear morphology. We recreated the HGPS cellular phenotype in human coronary artery endothelial cells for the first time by lentiviral transduction of GFP-progerin, which also resulted in impaired repair of IR-induced DSBs, and which correlated with abnormal nuclear morphology. Farnesyl transferase inhibitor (FTI) treatment improved the repair of IR-induced DSBs, but only in HGPS cells whose nuclear morphology was also normalized. Interestingly, FTI treatment did not result in a statistically significant reduction in the higher steady-state number of DSBs. We also report a delay in localization of phospho-NBS1 and MRE11, MRN complex repair factors necessary for homologous recombination (HR) repair, to DSBs in HGPS cells. Our results demonstrate a correlation between nuclear structural abnormalities and the DSB repair defect, suggesting a mechanistic link that may involve delayed repair factor localization to DNA damage. Further, our results show that similar to other HGPS phenotypes, FTI treatment has a beneficial effect on DSB repair.

  2. Naïve adult stem cells from patients with Hutchinson-Gilford progeria syndrome express low levels of progerin in vivo

    Science.gov (United States)

    Wenzel, Vera; Roedl, Daniela; Gabriel, Diana; Gordon, Leslie B.; Herlyn, Meenhard; Schneider, Reinhard; Ring, Johannes; Djabali, Karima

    2012-01-01

    Summary Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare disorder characterized by segmental accelerated aging and early death from coronary artery disease or stroke. Nearly 90% of HGPS sufferers carry a G608G mutation within exon 11 of LMNA, producing a truncated form of prelamin A, referred to as “progerin”. Here, we report the isolation of naïve multipotent skin-derived precursor (SKP) cells from dermal fibroblast cultures from HGPS donors. These cells form spheres and express the neural crest marker, nestin, in addition to the multipotent markers, OCT4, Sox2, Nanog and TG30; these cells can self-renew and differentiate into smooth muscle cells (SMCs) and fibroblasts. The SMCs derived from the HGPS-SKPs accumulate nuclear progerin with increasing passages. A subset of the HGPS-naïve SKPs express progerin in vitro and in situ in HGPS skin sections. This is the first in vivo evidence that progerin is produced in adult stem cells, and implies that this protein could induce stem cells exhaustion as a mechanism contributing to aging. Our study provides a basis on which to explore therapeutic applications for HGPS stem cells and opens avenues for investigating the pathogenesis of other genetic diseases. PMID:23213444

  3. Correlated alterations in genome organization, histone methylation, and DNA–lamin A/C interactions in Hutchinson-Gilford progeria syndrome

    Science.gov (United States)

    McCord, Rachel Patton; Nazario-Toole, Ashley; Zhang, Haoyue; Chines, Peter S.; Zhan, Ye; Erdos, Michael R.; Collins, Francis S.; Dekker, Job; Cao, Kan

    2013-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease that is frequently caused by a de novo point mutation at position 1824 in LMNA. This mutation activates a cryptic splice donor site in exon 11, and leads to an in-frame deletion within the prelamin A mRNA and the production of a dominant-negative lamin A protein, known as progerin. Here we show that primary HGPS skin fibroblasts experience genome-wide correlated alterations in patterns of H3K27me3 deposition, DNA-lamin A/C associations, and, at late passages, genome-wide loss of spatial compartmentalization of active and inactive chromatin domains. We further demonstrate that the H3K27me3 changes associate with gene expression alterations in HGPS cells. Our results support a model that the accumulation of progerin in the nuclear lamina leads to altered H3K27me3 marks in heterochromatin, possibly through the down-regulation of EZH2, and disrupts heterochromatin–lamina interactions. These changes may result in transcriptional misregulation and eventually trigger the global loss of spatial chromatin compartmentalization in late passage HGPS fibroblasts. PMID:23152449

  4. Transgene silencing of the Hutchinson-Gilford progeria syndrome mutation results in a reversible bone phenotype, whereas resveratrol treatment does not show overall beneficial effects.

    Science.gov (United States)

    Strandgren, Charlotte; Nasser, Hasina Abdul; McKenna, Tomás; Koskela, Antti; Tuukkanen, Juha; Ohlsson, Claes; Rozell, Björn; Eriksson, Maria

    2015-08-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder that is most commonly caused by a de novo point mutation in exon 11 of the LMNA gene, c.1824C>T, which results in an increased production of a truncated form of lamin A known as progerin. In this study, we used a mouse model to study the possibility of recovering from HGPS bone disease upon silencing of the HGPS mutation, and the potential benefits from treatment with resveratrol. We show that complete silencing of the transgenic expression of progerin normalized bone morphology and mineralization already after 7 weeks. The improvements included lower frequencies of rib fractures and callus formation, an increased number of osteocytes in remodeled bone, and normalized dentinogenesis. The beneficial effects from resveratrol treatment were less significant and to a large extent similar to mice treated with sucrose alone. However, the reversal of the dental phenotype of overgrown and laterally displaced lower incisors in HGPS mice could be attributed to resveratrol. Our results indicate that the HGPS bone defects were reversible upon suppressed transgenic expression and suggest that treatments targeting aberrant progerin splicing give hope to patients who are affected by HGPS.

  5. Blocking protein farnesylation improves nuclear shape abnormalities in keratinocytes of mice expressing the prelamin A variant in Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Wang, Yuexia; Ostlund, Cecilia; Worman, Howard J

    2010-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is an accelerated aging disorder caused by mutations in LMNA leading to expression of a truncated prelamin A variant termed progerin. Whereas a farnesylated polypeptide is normally removed from the carboxyl-terminus of prelamin A during endoproteolytic processing to lamin A, progerin lacks the cleavage site and remains farnesylated. Cultured cells from human subjects with HGPS and genetically modified mice expressing progerin have nuclear morphological abnormalities, which are reversed by inhibitors of protein farnesylation. In addition, treatment with protein farnesyltransferase inhibitors improves whole animal phenotypes in mouse models of HGPS. However, improvement in nuclear morphology in tissues after treatment of animals has not been demonstrated. We therefore treated transgenic mice that express progerin in epidermis with the protein farnesyltransferase inhibitor FTI-276 or a combination of pravastatin and zoledronate to determine if they reversed nuclear morphological abnormalities in tissue. Immunofluorescence microscopy and "blinded" electron microscopic analysis demonstrated that systemic administration of FTI-276 or pravastatin plus zoledronate significantly improved nuclear morphological abnormalities in keratinocytes of transgenic mice. These results show that pharmacological blockade of protein prenylation reverses nuclear morphological abnormalities that occur in HGPS in vivo. They further suggest that skin biopsy may be useful to determine if protein farnesylation inhibitors are exerting effects in subjects with HGPS in clinical trials.

  6. Correlated alterations in genome organization, histone methylation, and DNA-lamin A/C interactions in Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    McCord, Rachel Patton; Nazario-Toole, Ashley; Zhang, Haoyue; Chines, Peter S; Zhan, Ye; Erdos, Michael R; Collins, Francis S; Dekker, Job; Cao, Kan

    2013-02-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease that is frequently caused by a de novo point mutation at position 1824 in LMNA. This mutation activates a cryptic splice donor site in exon 11, and leads to an in-frame deletion within the prelamin A mRNA and the production of a dominant-negative lamin A protein, known as progerin. Here we show that primary HGPS skin fibroblasts experience genome-wide correlated alterations in patterns of H3K27me3 deposition, DNA-lamin A/C associations, and, at late passages, genome-wide loss of spatial compartmentalization of active and inactive chromatin domains. We further demonstrate that the H3K27me3 changes associate with gene expression alterations in HGPS cells. Our results support a model that the accumulation of progerin in the nuclear lamina leads to altered H3K27me3 marks in heterochromatin, possibly through the down-regulation of EZH2, and disrupts heterochromatin-lamina interactions. These changes may result in transcriptional misregulation and eventually trigger the global loss of spatial chromatin compartmentalization in late passage HGPS fibroblasts.

  7. Naïve adult stem cells from patients with Hutchinson-Gilford progeria syndrome express low levels of progerin in vivo

    Directory of Open Access Journals (Sweden)

    Vera Wenzel

    2012-04-01

    Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670 is a rare disorder characterized by segmental accelerated aging and early death from coronary artery disease or stroke. Nearly 90% of HGPS sufferers carry a G608G mutation within exon 11 of LMNA, producing a truncated form of prelamin A, referred to as “progerin”. Here, we report the isolation of naïve multipotent skin-derived precursor (SKP cells from dermal fibroblast cultures from HGPS donors. These cells form spheres and express the neural crest marker, nestin, in addition to the multipotent markers, OCT4, Sox2, Nanog and TG30; these cells can self-renew and differentiate into smooth muscle cells (SMCs and fibroblasts. The SMCs derived from the HGPS-SKPs accumulate nuclear progerin with increasing passages. A subset of the HGPS-naïve SKPs express progerin in vitro and in situ in HGPS skin sections. This is the first in vivo evidence that progerin is produced in adult stem cells, and implies that this protein could induce stem cells exhaustion as a mechanism contributing to aging. Our study provides a basis on which to explore therapeutic applications for HGPS stem cells and opens avenues for investigating the pathogenesis of other genetic diseases.

  8. Unique Preservation of Neural Cells in Hutchinson- Gilford Progeria Syndrome Is Due to the Expression of the Neural-Specific miR-9 MicroRNA

    Directory of Open Access Journals (Sweden)

    Xavier Nissan

    2012-07-01

    Full Text Available One puzzling observation in patients affected with Hutchinson-Gilford progeria syndrome (HGPS, who overall exhibit systemic and dramatic premature aging, is the absence of any conspicuous cognitive impairment. Recent studies based on induced pluripotent stem cells derived from HGPS patient cells have revealed a lack of expression in neural derivatives of lamin A, a major isoform of LMNA that is initially produced as a precursor called prelamin A. In HGPS, defective maturation of a mutated prelamin A induces the accumulation of toxic progerin in patient cells. Here, we show that a microRNA, miR-9, negatively controls lamin A and progerin expression in neural cells. This may bear major functional correlates, as alleviation of nuclear blebbing is observed in nonneural cells after miR-9 overexpression. Our results support the hypothesis, recently proposed from analyses in mice, that protection of neural cells from progerin accumulation in HGPS is due to the physiologically restricted expression of miR-9 to that cell lineage.

  9. The mutant form of lamin A that causes Hutchinson-Gilford progeria is a biomarker of cellular aging in human skin.

    Directory of Open Access Journals (Sweden)

    Dayle McClintock

    Full Text Available Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670 is a rare disorder characterized by accelerated aging and early death, frequently from stroke or coronary artery disease. 90% of HGPS cases carry the LMNA G608G (GGC>GGT mutation within exon 11 of LMNA, activating a splice donor site that results in production of a dominant negative form of lamin A protein, denoted progerin. Screening 150 skin biopsies from unaffected individuals (newborn to 97 years showed that a similar splicing event occurs in vivo at a low level in the skin at all ages. While progerin mRNA remains low, the protein accumulates in the skin with age in a subset of dermal fibroblasts and in a few terminally differentiated keratinocytes. Progerin-positive fibroblasts localize near the basement membrane and in the papillary dermis of young adult skin; however, their numbers increase and their distribution reaches the deep reticular dermis in elderly skin. Our findings demonstrate that progerin expression is a biomarker of normal cellular aging and may potentially be linked to terminal differentiation and senescence in elderly individuals.

  10. Unique preservation of neural cells in Hutchinson- Gilford progeria syndrome is due to the expression of the neural-specific miR-9 microRNA.

    Science.gov (United States)

    Nissan, Xavier; Blondel, Sophie; Navarro, Claire; Maury, Yves; Denis, Cécile; Girard, Mathilde; Martinat, Cécile; De Sandre-Giovannoli, Annachiara; Levy, Nicolas; Peschanski, Marc

    2012-07-26

    One puzzling observation in patients affected with Hutchinson-Gilford progeria syndrome (HGPS), who overall exhibit systemic and dramatic premature aging, is the absence of any conspicuous cognitive impairment. Recent studies based on induced pluripotent stem cells derived from HGPS patient cells have revealed a lack of expression in neural derivatives of lamin A, a major isoform of LMNA that is initially produced as a precursor called prelamin A. In HGPS, defective maturation of a mutated prelamin A induces the accumulation of toxic progerin in patient cells. Here, we show that a microRNA, miR-9, negatively controls lamin A and progerin expression in neural cells. This may bear major functional correlates, as alleviation of nuclear blebbing is observed in nonneural cells after miR-9 overexpression. Our results support the hypothesis, recently proposed from analyses in mice, that protection of neural cells from progerin accumulation in HGPS is due to the physiologically restricted expression of miR-9 to that cell lineage.

  11. Genome-scale expression profiling of Hutchinson-Gilford progeria syndrome reveals widespread transcriptional misregulation leading to mesodermal/mesenchymal defects and accelerated atherosclerosis.

    Science.gov (United States)

    Csoka, Antonei B; English, Sangeeta B; Simkevich, Carl P; Ginzinger, David G; Butte, Atul J; Schatten, Gerald P; Rothman, Frank G; Sedivy, John M

    2004-08-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease with widespread phenotypic features resembling premature aging. HGPS was recently shown to be caused by dominant mutations in the LMNA gene, resulting in the in-frame deletion of 50 amino acids near the carboxyl terminus of the encoded lamin A protein. Children with this disease typically succumb to myocardial infarction or stroke caused by severe atherosclerosis at an average age of 13 years. To elucidate further the molecular pathogenesis of this disease, we compared the gene expression patterns of three HGPS fibroblast cell strains heterozygous for the LMNA mutation with three normal, age-matched cell strains. We defined a set of 361 genes (1.1% of the approximately 33,000 genes analysed) that showed at least a 2-fold, statistically significant change. The most prominent categories encode transcription factors and extracellular matrix proteins, many of which are known to function in the tissues severely affected in HGPS. The most affected gene, MEOX2/GAX, is a homeobox transcription factor implicated as a negative regulator of mesodermal tissue proliferation. Thus, at the gene expression level, HGPS shows the hallmarks of a developmental disorder affecting mesodermal and mesenchymal cell lineages. The identification of a large number of genes implicated in atherosclerosis is especially valuable, because it provides clues to pathological processes that can now be investigated in HGPS patients or animal models.

  12. The mutant form of lamin A that causes Hutchinson-Gilford progeria is a biomarker of cellular aging in human skin.

    Science.gov (United States)

    McClintock, Dayle; Ratner, Desiree; Lokuge, Meepa; Owens, David M; Gordon, Leslie B; Collins, Francis S; Djabali, Karima

    2007-12-05

    Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare disorder characterized by accelerated aging and early death, frequently from stroke or coronary artery disease. 90% of HGPS cases carry the LMNA G608G (GGC>GGT) mutation within exon 11 of LMNA, activating a splice donor site that results in production of a dominant negative form of lamin A protein, denoted progerin. Screening 150 skin biopsies from unaffected individuals (newborn to 97 years) showed that a similar splicing event occurs in vivo at a low level in the skin at all ages. While progerin mRNA remains low, the protein accumulates in the skin with age in a subset of dermal fibroblasts and in a few terminally differentiated keratinocytes. Progerin-positive fibroblasts localize near the basement membrane and in the papillary dermis of young adult skin; however, their numbers increase and their distribution reaches the deep reticular dermis in elderly skin. Our findings demonstrate that progerin expression is a biomarker of normal cellular aging and may potentially be linked to terminal differentiation and senescence in elderly individuals.

  13. Signaling pathway activation drift during aging: Hutchinson-Gilford Progeria Syndrome fibroblasts are comparable to normal middle-age and old-age cells.

    Science.gov (United States)

    Aliper, Alexander M; Csoka, Antonei Benjamin; Buzdin, Anton; Jetka, Tomasz; Roumiantsev, Sergey; Moskalev, Alexy; Zhavoronkov, Alex

    2015-01-01

    For the past several decades, research in understanding the molecular basis of human aging has progressed significantly with the analysis of premature aging syndromes. Progerin, an altered form of lamin A, has been identified as the cause of premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS), and may be a contributing causative factor in normal aging. However, the question of whether HGPS actually recapitulates the normal aging process at the cellular and organismal level, or simply mimics the aging phenotype is widely debated. In the present study we analyzed publicly available microarray datasets for fibroblasts undergoing cellular aging in culture, as well as fibroblasts derived from young, middle-age, and old-age individuals, and patients with HGPS. Using GeroScope pathway analysis and drug discovery platform we analyzed the activation states of 65 major cellular signaling pathways. Our analysis reveals that signaling pathway activation states in cells derived from chronologically young patients with HGPS strongly resemble cells taken from normal middle-aged and old individuals. This clearly indicates that HGPS may truly represent accelerated aging, rather than being just a simulacrum. Our data also points to potential pathways that could be targeted to develop drugs and drug combinations for both HGPS and normal aging.

  14. Defective DSB repair correlates with abnormal nuclear morphology and is improved with FTI treatment in Hutchinson-Gilford progeria syndrome fibroblasts.

    Science.gov (United States)

    Constantinescu, Dan; Csoka, Antonei B; Navara, Christopher S; Schatten, Gerald P

    2010-10-15

    Impaired DSB repair has been implicated as a molecular mechanism contributing to the accelerating aging phenotype in Hutchinson-Gilford progeria syndrome (HGPS), but neither the extent nor the cause of the repair deficiency has been fully elucidated. Here we perform a quantitative analysis of the steady-state number of DSBs and the repair kinetics of ionizing radiation (IR)-induced DSBs in HGPS cells. We report an elevated steady-state number of DSBs and impaired repair of IR-induced DSBs, both of which correlated strongly with abnormal nuclear morphology. We recreated the HGPS cellular phenotype in human coronary artery endothelial cells for the first time by lentiviral transduction of GFP-progerin, which also resulted in impaired repair of IR-induced DSBs, and which correlated with abnormal nuclear morphology. Farnesyl transferase inhibitor (FTI) treatment improved the repair of IR-induced DSBs, but only in HGPS cells whose nuclear morphology was also normalized. Interestingly, FTI treatment did not result in a statistically significant reduction in the higher steady-state number of DSBs. We also report a delay in localization of phospho-NBS1 and MRE11, MRN complex repair factors necessary for homologous recombination (HR) repair, to DSBs in HGPS cells. Our results demonstrate a correlation between nuclear structural abnormalities and the DSB repair defect, suggesting a mechanistic link that may involve delayed repair factor localization to DNA damage. Further, our results show that similar to other HGPS phenotypes, FTI treatment has a beneficial effect on DSB repair.

  15. Discordant gene expression signatures and related phenotypic differences in lamin A- and A/C-related Hutchinson-Gilford progeria syndrome (HGPS.

    Directory of Open Access Journals (Sweden)

    Martina Plasilova

    Full Text Available Hutchinson-Gilford progeria syndrome (HGPS is a genetic disorder displaying features reminiscent of premature senescence caused by germline mutations in the LMNA gene encoding lamin A and C, essential components of the nuclear lamina. By studying a family with homozygous LMNA mutation (K542N, we showed that HGPS can also be caused by mutations affecting both isoforms, lamin A and C. Here, we aimed to elucidate the molecular mechanisms underlying the pathogenesis in both, lamin A- (sporadic and lamin A and C-related (hereditary HGPS. For this, we performed detailed molecular studies on primary fibroblasts of hetero- and homozygous LMNA K542N mutation carriers, accompanied with clinical examinations related to the molecular findings. By assessing global gene expression we found substantial overlap in altered transcription profiles (13.7%; 90/657 in sporadic and hereditary HGPS, with 83.3% (75/90 concordant and 16.7% (15/90 discordant transcriptional changes. Among the concordant ones we observed down-regulation of TWIST2, whose inactivation in mice and humans leads to loss of subcutaneous fat and dermal appendages, and loss of expression in dermal fibroblasts and periadnexial cells from a LMNA(K542N/K542N patient further confirming its pivotal role in skin development. Among the discordant transcriptional profiles we identified two key mediators of vascular calcification and bone metabolism, ENPP1 and OPG, which offer a molecular explanation for the major phenotypic differences in vascular and bone disease in sporadic and hereditary HGPS. Finally, this study correlates reduced TWIST2 and OPG expression with increased osteocalcin levels, thereby linking altered bone remodeling to energy homeostasis in hereditary HGPS.

  16. Discordant Gene Expression Signatures and Related Phenotypic Differences in Lamin A- and A/C-Related Hutchinson-Gilford Progeria Syndrome (HGPS)

    Science.gov (United States)

    Plasilova, Martina; Chattopadhyay, Chandon; Ghosh, Apurba; Wenzel, Friedel; Demougin, Philippe; Noppen, Christoph; Schaub, Nathalie; Szinnai, Gabor; Terracciano, Luigi; Heinimann, Karl

    2011-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a genetic disorder displaying features reminiscent of premature senescence caused by germline mutations in the LMNA gene encoding lamin A and C, essential components of the nuclear lamina. By studying a family with homozygous LMNA mutation (K542N), we showed that HGPS can also be caused by mutations affecting both isoforms, lamin A and C. Here, we aimed to elucidate the molecular mechanisms underlying the pathogenesis in both, lamin A- (sporadic) and lamin A and C-related (hereditary) HGPS. For this, we performed detailed molecular studies on primary fibroblasts of hetero- and homozygous LMNA K542N mutation carriers, accompanied with clinical examinations related to the molecular findings. By assessing global gene expression we found substantial overlap in altered transcription profiles (13.7%; 90/657) in sporadic and hereditary HGPS, with 83.3% (75/90) concordant and 16.7% (15/90) discordant transcriptional changes. Among the concordant ones we observed down-regulation of TWIST2, whose inactivation in mice and humans leads to loss of subcutaneous fat and dermal appendages, and loss of expression in dermal fibroblasts and periadnexial cells from a LMNAK542N/K542N patient further confirming its pivotal role in skin development. Among the discordant transcriptional profiles we identified two key mediators of vascular calcification and bone metabolism, ENPP1 and OPG, which offer a molecular explanation for the major phenotypic differences in vascular and bone disease in sporadic and hereditary HGPS. Finally, this study correlates reduced TWIST2 and OPG expression with increased osteocalcin levels, thereby linking altered bone remodeling to energy homeostasis in hereditary HGPS. PMID:21738662

  17. Loss of H3K9me3 Correlates with ATM Activation and Histone H2AX Phosphorylation Deficiencies in Hutchinson-Gilford Progeria Syndrome

    Science.gov (United States)

    Zhang, Haoyue; Sun, Linlin; Wang, Kun; Wu, Di; Trappio, Mason; Witting, Celeste; Cao, Kan

    2016-01-01

    Compelling evidence suggests that defective DNA damage response (DDR) plays a key role in the premature aging phenotypes in Hutchinson-Gilford progeria syndrome (HGPS). Studies document widespread alterations in histone modifications in HGPS cells, especially, the global loss of histone H3 trimethylated on lysine 9 (H3K9me3). In this study, we explore the potential connection(s) between H3K9me3 loss and the impaired DDR in HGPS. When cells are exposed to a DNA-damaging agent Doxorubicin (Dox), double strand breaks (DSBs) are generated that result in the phosphorylation of histone H2A variant H2AX (gammaH2AX) within an hour. We find that the intensities of gammaH2AX foci appear significantly weaker in the G0/G1 phase HGPS cells compared to control cells. This reduction is associated with a delay in the recruitment of essential DDR factors. We further demonstrate that ataxia-telangiectasia mutated (ATM) is responsible for the amplification of gammaH2AX signals at DSBs during G0/G1 phase, and its activation is inhibited in the HGPS cells that display significant loss of H3K9me3. Moreover, methylene (MB) blue treatment, which is known to save heterochromatin loss in HGPS, restores H3K9me3, stimulates ATM activity, increases gammaH2AX signals and rescues deficient DDR. In summary, this study demonstrates an early DDR defect of attenuated gammaH2AX signals in G0/G1 phase HGPS cells and provides a plausible connection between H3K9me3 loss and DDR deficiency. PMID:27907109

  18. Dermal fibroblasts in Hutchinson-Gilford progeria syndrome with the lamin A G608G mutation have dysmorphic nuclei and are hypersensitive to heat stress

    Directory of Open Access Journals (Sweden)

    Worman Howard J

    2005-06-01

    Full Text Available Abstract Background Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670 is a rare sporadic disorder with an incidence of approximately 1 per 8 million live births. The phenotypic appearance consists of short stature, sculptured nose, alopecia, prominent scalp veins, small face, loss of subcutaneous fat, faint mid-facial cyanosis, and dystrophic nails. HGPS is caused by mutations in LMNA, the gene that encodes nuclear lamins A and C. The most common mutation in subjects with HGPS is a de novo single-base pair substitution, G608G (GGC>GGT, within exon 11 of LMNA. This creates an abnormal splice donor site, leading to expression of a truncated protein. Results We studied a new case of a 5 year-old girl with HGPS and found a heterozygous point mutation, G608G, in LMNA. Complementary DNA sequencing of RNA showed that this mutation resulted in the deletion of 50 amino acids in the carboxyl-terminal tail domain of prelamin A. We characterized a primary dermal fibroblast cell line derived from the subject's skin. These cells expressed the mutant protein and exhibited a normal growth rate at early passage in primary culture but showed alterations in nuclear morphology. Expression levels and overall distributions of nuclear lamins and emerin, an integral protein of the inner nuclear membrane, were not dramatically altered. Ultrastructural analysis of the nuclear envelope using electron microscopy showed that chromatin is in close association to the nuclear lamina, even in areas with abnormal nuclear envelope morphology. The fibroblasts were hypersensitive to heat shock, and demonstrated a delayed response to heat stress. Conclusion Dermal fibroblasts from a subject with HGPS expressing a mutant truncated lamin A have dysmorphic nuclei, hypersensitivity to heat shock, and delayed response to heat stress. This suggests that the mutant protein, even when expressed at low levels, causes defective cell stability, which may be responsible for phenotypic

  19. 早老症的分子机制%Molecular mechanism of Hutchinson-Gilford Progeria Syndrome

    Institute of Scientific and Technical Information of China (English)

    刘新光; 赵炜; 周中军

    2010-01-01

    @@ 儿童早老症(Hutchinson Giford Progeria Syn-drome,HGPS)是由于基因突变导致的疾病,它的发病率很低,大概是八百万分之一,患者出生的早期就开始出现衰老的容貌"[1]. 这种疾病最早由Hutchins于1886年报道"[2],1904年Gilford报道了第二例,他在文章中使用了progeria(早老)这个词[3].1962年,DeBusk总结了60例病例,其中包括4例他本人报道的病人,他将这种疾病命名为Hutchinson-Giford Progefia Syndrome,HGPS.

  20. The Pathogenic Mechanisms and Therapeutic Strategies of Hutchinson-Gilford Progeria Syndrome%早老症(HGPS)的发病机制与治疗策略

    Institute of Scientific and Technical Information of China (English)

    曾涛; 刘新光; 周中军

    2007-01-01

    早老症(Hutchinson-Gilford Progeria Syndrome,HGPS)是一种早发而严重的过早老化性疾病.它是由于编码A/C型核纤层蛋白的LMNA基因发生点突变而引起.这个突变激活了基因11号外显子上一个隐蔽的剪接位点,产生了一种被截短了50个氨基酸的A型核纤层蛋白.然而,一个广泛分布于核膜上结构蛋白的突变,如何引起HGPS患者的早老表现,目前还不太清楚.最近研究发现,HGPS患者的细胞核结构与功能发生了各种异常,主要表现在:progerin蓄积与核变形、细胞核机械性质的改变、组蛋白修饰方式与外遗传控制的改变、基因表达调控异常、p53信号传导通路激活和基因组不稳定等方面.目前存在机械应激假说和基因表达失控假说两种假说解释HGPS的发病机制.对于HGPS患者,尚无有效的临床干预措施,但有学者提出了一些治疗策略,如应用法尼基化的抑制剂、反义寡核苷酸和RNA干扰方法.HGPS被认为是研究正常衰老机制的一个模型.对HGPS深入研究将有助于阐明A型核纤层蛋白和核膜的正常生理功能,及其在生理衰老和疾病中的作用.

  1. 一个儿童早老症家系临床特征分析和致病基因研究%Analysis of clinical characteristics and causative genes of Hutchinson-Gilford progeria syndrome in a family

    Institute of Scientific and Technical Information of China (English)

    覃霞; 罗彦彦; 袁广之; 畅荣妮; 赖青鸟; 杨益金; 华荣; 李福记; 方玲

    2015-01-01

    Objective To assess clinicopathological features of and genetic factors in Hutchinson-Gilford progeria syndrome (HGPS) in a family.Methods General information was collected from 3 patients with HutchinsonGilford progeria syndrome in a family,which included 5 members over 2 generations with all the 3 children affected by HGPS.All the 3 patients underwent clinical investigation,image analysis of hands,lungs and mandibles,as well as karyotype analysis of chromosomes.LMNA gene mutations were analyzed in these family members.Results All the 3 patients developed skin sclerosis with severe growth retardation and appearance of extreme aging at about 6 months of age.Image analysis showed osteoporosis and mandibular hypoplasia in the elder patient.Karyotype analysis showed no abnormality in the patients or their parents.Mutation analysis revealed a homozygous mutation 1579 C > T (R527C) in exon 9 of the LMNA gene in all the patients,but a heterozygous mutation R527C in the LMNA gene in their parents.Conclusions The patients in this family present characteristic manifestations of HGPS,which may be caused by the homozygous LMNA mutation R527C.%目的 通过对一个罕见早老症家系的分析,探讨早老症患者的临床病理学特征和遗传学因素.方法 收集1个早老症家系(2代共5名家庭成员,子女3人均为患者)3例患者的基本资料,对其进行临床检查,并对患者手部、肺脏和下颌骨进行影像学分析;同时对3例患者进行染色体核型分析,对该家系进行LMNA基因突变分析.结果 家系中的3例患者半岁左右即可见皮肤硬化症,并表现出生长严重迟缓,极度衰老面容.年长患者影像学检查显示骨质疏松,下颌骨发育不全.染色体核型分析显示,3例患者及其父母核型正常.基因突变分析显示,3例患者均为LMNA基因第9号外显子的纯合突变1579C>T(R527C),父母均为LMNAR527C杂合突变.结论 该早老症家系患者符合儿童

  2. Progeria

    OpenAIRE

    Mohamed Riyaz S; Jayachandran S

    2009-01-01

    Hutchinson Gilford Progeria Syndrome (HGPS) is a rare, sporadic, autosomal dominant syndrome that involves premature ageing and death at early age due to myocardial infarction or stroke. A 30-year-old male with clinical and radiologic features highly suggestive of HGPS is presented here with description of differential diagnosis, dental considerations and review of literature.

  3. Progeria

    Directory of Open Access Journals (Sweden)

    Mohamed Riyaz S

    2009-01-01

    Full Text Available Hutchinson Gilford Progeria Syndrome (HGPS is a rare, sporadic, autosomal dominant syndrome that involves premature ageing and death at early age due to myocardial infarction or stroke. A 30-year-old male with clinical and radiologic features highly suggestive of HGPS is presented here with description of differential diagnosis, dental considerations and review of literature.

  4. Reactivation of latently infected HIV-1 viral reservoirs and correction of aberrant alternative splicing in the LMNA gene via AMPK activation: Common mechanism of action linking HIV-1 latency and Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Finley, Jahahreeh

    2015-09-01

    Although the use of antiretroviral therapy (ART) has proven highly effective in controlling and suppressing HIV-1 replication, the persistence of latent but replication-competent proviruses in a small subset of CD4(+) memory T cells presents significant challenges to viral eradication from infected individuals. Attempts to eliminate latent reservoirs are epitomized by the 'shock and kill' approach, a strategy involving the combinatorial usage of compounds that influence epigenetic modulation and initiation of proviral transcription. However, efficient regulation of viral pre-mRNA splicing through manipulation of host cell splicing machinery is also indispensible for HIV-1 replication. Interestingly, aberrant alternative splicing of the LMNA gene via the usage of a cryptic splice site has been shown to be the cause of most cases of Hutchinson-Gilford progeria syndrome (HGPS), a rare genetic condition characterized by an accelerated aging phenotype due to the accumulation of a truncated form of lamin A known as progerin. Recent evidence has shown that inhibition of the splicing factors ASF/SF2 (or SRSF1) and SRp55 (or SRSF6) leads to a reduction or an increase in progerin at both the mRNA and protein levels, respectively, thus altering the LMNA pre-mRNA splicing ratio. It is also well-established that during the latter stages of HIV-1 infection, an increase in the production and nuclear export of unspliced viral mRNA is indispensible for efficient HIV-1 replication and that the presence of ASF/SF2 leads to excessive viral pre-mRNA splicing and a reduction of unspliced mRNA, while the presence of SRp55 inhibits viral pre-mRNA splicing and aids in the generation and translation of unspliced HIV-1 mRNAs. The splicing-factor associated protein and putative mitochondrial chaperone p32 has also been shown to inhibit ASF/SF2, increase unspliced HIV-1 viral mRNA, and enhance mitochondrial DNA replication and oxidative phosphorylation. It is our hypothesis that activation of

  5. Analysis of a case with typical Hutchinson-Gilford progeria syndrome with scleroderma-like skin changes and review of literature%伴硬皮病样改变的典型Hutchinson-Gilford早老综合征一例并文献复习

    Institute of Scientific and Technical Information of China (English)

    黄姗; 梁雁; 吴薇; 付溪; 廖立红; 罗小平

    2014-01-01

    目的 探讨典型Hutchinson-Gilford早老综合征(HGPS)的临床特点及诊断.方法 回顾性分析华中科技大学同济医学院附属同济医院儿科诊断的1例典型HGPS患儿,并复习相关文献,分析本病的临床表现、影像学特点、基因突变特点及诊疗方法.结果 患儿男,8月龄,身高65.6 cm,体重6.2 kg,前额突出,枕部秃发,头皮静脉显露,小颌畸形伴下颌纵向沟,胸部以下皮肤呈硬皮病样改变,双膝关节挛缩呈“骑马样站姿”,踝关节活动亦受限.血常规示血小板(416~490)×109/L;双下肢MRI发现皮下脂肪组织减少.家系外周血LMNA基因分析示患儿携带经典杂合突变:c.1824C>T,(p.G608G),其父母均正常.13月龄随访时X线检查示双手指骨及锁骨远端有骨质溶解改变.随访15个月后,患儿早老样外貌更明显.总结相关文献发现国内结合临床特征和基因分析明确诊断的典型HGPS有2例,其中1例有硬皮病样皮肤改变.结论 患儿呈典型HGPS表型;婴儿期皮肤出现硬皮病样改变,应考虑典型HGPS的可能,且LMNA基因分析有助于典型HGPS的早期确诊,避免其他不必要的检查.应对患儿长期进行随访,观察病情持续进展.%Objective To explore clinical,radiographical and genetic characteristics of classical Hutchinson-Gilford progeria syndrome (HGPS).Method Data of a case of HGPS diagnosed at Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology was analyzed and related literature was reviewed.Result At the age of 8 months,the affected-infant presented with characteristic manifestation such as short stature,low weight,frontal bossing,alopecia,prominent scalp veins,micrognathia with a vertical midline groove in the chin,sclerodermatous skin,knee joints contracture with a horse-riding stance,and limited range of movement of ankle joints.Blood test showed blood platelet count (416-490) × 109/L.Lower extremities MRI showed reduced

  6. Study of Three Cases of Hutchinson - Gilford Progeria Syndrome in A Guangxi Han Family:Analysis of Mitochondrial DNA D-loop Region Mutations%广西汉族早老症家系三例病例研究--线粒体 DNAD -环区突变分析

    Institute of Scientific and Technical Information of China (English)

    李福记; 方玲; 胡启平; 袁志刚; 舒伟; 吴华裕; 韩焕钦; 陈凤平; 覃霞; 吕宇; 林有坤; 舒艳; 张伟峰

    2015-01-01

    目的:探讨广西汉族1个早老症家系中3例儿童早老症(HGPS)患者线粒体 DNA D -环区(D - loop区)突变是否呈现年龄相关的突变累积。方法采用聚合酶链反应(PCR)对3例 HGPS 患者及其父母、8例正常老人(正常老人组)的线粒体 DNA D - loop 区进行扩增、测序。结果正常老年人线粒体 DNA D - loop 区较 Cambridge 序列存在较多的突变位点,HGPS 患者与正常老人组线粒体 DNA D - loop 区突变率差异具有统计学意义( P ﹤0.05);3例HGPS 患者线粒体 DNA D - loop 区单体型与其母亲一致;未检测到3例 HGPS 患者线粒体 DNA D - loop 区发生新突变,也未检测到3例 HGPS 患者线粒体 DNA D - loop 区存在差异。结论该家系3例 HGPS 患者在7岁前未发生线粒体DNA D - loop 突变累积,且不同年龄患者均未见年龄相关的突变累积,推论线粒体 DNA 突变不是该家系 HGPS 患者加速衰老的重要原因。%Objective To investigate whether age - related mutation accumulation occurs in the mitochondrial DNA (mtDNA)D - loop region of three cases with Hutchinson - Gilford progeria syndrome( HGPS)in a Guangxi Han family. Methods Polymerase chain reaction(PCR)was used to amplify the mtDNA D - loop region of the three HGPS cases and their parents,as well as 8 normal seniors,and all the PCR products were sequenced and analyzed. Results The normal elders had more mutation sites in the mtDNA D - loop region compared with Cambridge standard sequence,and the three HGPS cases and the normal elders were significantly different in the mutation in the mtDNA D - loop region(P ﹤ 0. 05);the three HGPS cases had same haplotype with their mothers;no new mutations were noted in the mtDNA D - loop region of the three HGPS cases,and no differences were observed in the mtDNA D - loop region among the three HGPS cases. Conclusion No mutation accumulation was observed in the mtDNA D - loop region of the three HGPS cases

  7. Study of Three Cases of Hutchinson - Gilford Progeria Syndrome in A Guangxi Han Family:Analysis of Imaging Featu re%广西汉族早老症家系三例病例研究--影像学特征分析

    Institute of Scientific and Technical Information of China (English)

    吴华裕; 林有坤; 方玲; 覃霞; 舒艳; 张伟峰; 李福记; 舒伟; 马军; 胡启平; 袁志刚

    2015-01-01

    Objective To study the imaging data of three cases of Hutchinson - Gilford Progeria Syndrome(HGPS) in Guangxi Han family,and to explore the patients' imaging features. Methods We collected the clinical data,CT,X - ray and MRI of three HGPS patients in Guangxi and made a summary of the imaging features. Results The proband was a 7 - year- old girl,and the other two patients were her younger sister(3 years old)and brother(1 years old). The proband neck radiograph showed abnormal scale between the calvarium and the mandible,mandibular hypoplasia,clavicle disappearing and pear shaped chest. The X - ray of 3 patients' hands showed that all the 3 cases were with flexion deformity in digintal joints and osteoporosis,and two older patients showed retardation of bone age and obvious osteolysis in distal phalanx. The lung CT scaning results of the 3 patients did not show lung fibrosis,but the chest and lung of the proband were smaller than normal children,and the fat thickness of the chest was thinner than normal girls. The brain MRI imaging of the proband showed the proportion of cerebral cranium became larger,but the pituitary size was normal. Conclusion The characteristic changes of the imaging occur in HGPS patients,including osteoporosis,mandibular hypoplasia,clavicle and distal phalanx disappearing and shortening, flexion deformity of digital joints and pear shaped chest. The findings have great significance on the diagnosis and differential diagnosis of progeria.%目的:分析广西汉族1个罕见早老症家系3例患者的影像学资料,探讨该家系早老症患者的影像学特征。方法收集广西汉族1个早老症家系3例患者的临床资料及 CT、X 线、MRI 影像学检查资料,对其影像学特点进行总结。结果先证者为7岁女孩,另2例患者分别为先证者的妹妹(3岁)和弟弟(1岁)。先证者颈部正侧位片示颅盖骨与下颌骨比例不协调,下颌骨发育不全,锁骨消失,梨形胸。3例患

  8. Targeting Protein Prenylation in Progeria

    Science.gov (United States)

    Young, Stephen G.; Yang, Shao H.; Davies, Brandon S. J.; Jung, Hea-Jin; Fong, Loren G.

    2013-01-01

    A clinical trial of a protein farnesyltransferase inhibitor (lonafarnib) for the treatment of Hutchinson-Gilford progeria syndrome (HGPS) was recently completed. Here, we discuss the mutation that causes HGPS, the rationale for inhibiting protein farnesyltransferase, the potential limitations of this therapeutic approach, and new potential strategies for treating the disease. PMID:23390246

  9. Targeting Protein Prenylation in Progeria

    OpenAIRE

    Young, Stephen G.; Yang, Shao H.; Davies, Brandon S.J.; Jung, Hea-Jin; Fong, Loren G.

    2013-01-01

    A clinical trial of a protein farnesyltransferase inhibitor (lonafarnib) for the treatment of Hutchinson-Gilford progeria syndrome (HGPS) was recently completed. Here, we discuss the mutation that causes HGPS, the rationale for inhibiting protein farnesyltransferase, the potential limitations of this therapeutic approach, and new potential strategies for treating the disease.

  10. Targeting protein prenylation in progeria.

    Science.gov (United States)

    Young, Stephen G; Yang, Shao H; Davies, Brandon S J; Jung, Hea-Jin; Fong, Loren G

    2013-02-06

    A clinical trial of a protein farnesyltransferase inhibitor (lonafarnib) for the treatment of Hutchinson-Gilford progeria syndrome (HGPS) was recently completed. Here, we discuss the mutation that causes HGPS, the rationale for inhibiting protein farnesyltransferase, the potential limitations of this therapeutic approach, and new potential strategies for treating the disease.

  11. Progeria: Medical Aspects, Psychosocial Perspectives, and Intervention Guidelines.

    Science.gov (United States)

    Livneh, Hanoch; And Others

    1995-01-01

    Discusses progeria (or Hutchinson-Gilford syndrome), a rare childhood disorder that invariably results in death during adolescence. Describes the major medical aspects of progeria, and discusses the psychosocial implications of the disorder with particular emphasis on grief-triggered reactions. Presents an overview of psychosocial intervention…

  12. Growth hormone therapy in progeria.

    Science.gov (United States)

    Sadeghi-Nejad, Ab; Demmer, Laurie

    2007-05-01

    Catabolic processes seen in Hutchinson-Gilford progeria resemble those of normal aging and, in the affected children, usually result in death at an early age. In addition to its growth promoting effects, growth hormone (GH) has potent anabolic properties. Administration of GH ameliorates some of the catabolic effects of normal aging. We report the results of GH treatment in a young child with progeria.

  13. Compound heterozygosity for mutations in LMNA causes a progeria syndrome without prelamin A accumulation.

    NARCIS (Netherlands)

    Verstraeten, V.L.; Broers, J.L.; Steensel, M.A.M. van; Zinn-Justin, S.; Ramaekers, F.C.S.; Steijlen, P.M.; Kamps, M.; Kuijpers, H.J.; Merckx, D.; Smeets, H.J.M.; Hennekam, R.C.M.; Marcelis, C.L.M.; Wijngaard, A. van de

    2006-01-01

    LMNA-associated progeroid syndromes have been reported with both recessive and dominant inheritance. We report a 2-year-old boy with an apparently typical Hutchinson-Gilford progeria syndrome (HGPS) due to compound heterozygous missense mutations (p.T528M and p.M540T) in LMNA. Both mutations affect

  14. Compound heterozygosity for mutations in LMNA causes a progeria syndrome without prelamin A accumulation.

    NARCIS (Netherlands)

    Verstraeten, V.L.; Broers, J.L.; Steensel, M.A.M. van; Zinn-Justin, S.; Ramaekers, F.C.S.; Steijlen, P.M.; Kamps, M.; Kuijpers, H.J.; Merckx, D.; Smeets, H.J.M.; Hennekam, R.C.M.; Marcelis, C.L.M.; Wijngaard, A. van de

    2006-01-01

    LMNA-associated progeroid syndromes have been reported with both recessive and dominant inheritance. We report a 2-year-old boy with an apparently typical Hutchinson-Gilford progeria syndrome (HGPS) due to compound heterozygous missense mutations (p.T528M and p.M540T) in LMNA. Both mutations affect

  15. PROGERIA IN SIBLINGS: A RARE CASE REPORT

    Science.gov (United States)

    Sowmiya, R; Prabhavathy, D; Jayakumar, S

    2011-01-01

    Progeria, also known as Hutchinson-Gilford syndrome, is an extremely rare, severe genetic condition wherein symptoms resembling aspects of aging are manifested at an early age. It is an autosomal dominant disorder. It is not seen in siblings of affected children although there are very few case reports of progeria affecting more than one child in a family. Here we are presenting two siblings, a 14-year-old male and a 13-year-old female with features of progeria, suggesting a possible autosomal recessive inheritance. PMID:22121285

  16. Progeria in siblings: A rare case report

    OpenAIRE

    Sowmiya, R; Prabhavathy, D; S Jayakumar

    2011-01-01

    Progeria, also known as Hutchinson-Gilford syndrome, is an extremely rare, severe genetic condition wherein symptoms resembling aspects of aging are manifested at an early age. It is an autosomal dominant disorder. It is not seen in siblings of affected children although there are very few case reports of progeria affecting more than one child in a family. Here we are presenting two siblings, a 14-year-old male and a 13-year-old female with features of progeria, suggesting a possible autosoma...

  17. Progeria in siblings: A rare case report

    Directory of Open Access Journals (Sweden)

    R Sowmiya

    2011-01-01

    Full Text Available Progeria, also known as Hutchinson-Gilford syndrome, is an extremely rare, severe genetic condition wherein symptoms resembling aspects of aging are manifested at an early age. It is an autosomal dominant disorder. It is not seen in siblings of affected children although there are very few case reports of progeria affecting more than one child in a family. Here we are presenting two siblings, a 14-year-old male and a 13-year-old female with features of progeria, suggesting a possible autosomal recessive inheritance.

  18. Progeria syndromes and ageing: what is the connection?

    Science.gov (United States)

    Burtner, Christopher R; Kennedy, Brian K

    2010-08-01

    One of the many debated topics in ageing research is whether progeroid syndromes are really accelerated forms of human ageing. The answer requires a better understanding of the normal ageing process and the molecular pathology underlying these rare diseases. Exciting recent findings regarding a severe human progeria, Hutchinson-Gilford progeria syndrome, have implicated molecular changes that are also linked to normal ageing, such as genome instability, telomere attrition, premature senescence and defective stem cell homeostasis in disease development. These observations, coupled with genetic studies of longevity, lead to a hypothesis whereby progeria syndromes accelerate a subset of the pathological changes that together drive the normal ageing process.

  19. Progeria syndrome with characteristic deformation of proximal radius observed on CT

    Energy Technology Data Exchange (ETDEWEB)

    Sood, S.; Rao, R.C.K.; Ragav, B.; Berry, M. (All India Inst. of Medical Sciences, New Delhi (India). Dept. of Radio-Diagnosis)

    1991-01-01

    The progeria syndrome (Hutchinson-Gilford) is an uncommon disease. A peculiar shape of the proximal radial metaphyseal region caused by an infolding of the cortex was observed on CT in 2 brothers suffering from this disorder, a feature not previously reported. A brief review of the radiologic literature was undertaken. This new observation needs to be further evaluated as it may provide a clinching diagnostic feature of this disease. (orig.).

  20. Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria

    OpenAIRE

    V. Cenni; C. Capanni; Columbaro, M.; Ortolani, M.; M.R. D'Apice; Novelli, G; Fini, M.; S. Marmiroli; Scarano, E.; Maraldi, N.M.; Squarzoni, S.; S. Prencipe; Lattanzi, G

    2011-01-01

    Farnesylated prelamin A is a processing intermediate produced in the lamin A maturation pathway. Accumulation of a truncated farnesylated prelamin A form, called progerin, is a hallmark of the severe premature ageing syndrome, Hutchinson-Gilford progeria. Progerin elicits toxic effects in cells, leading to chromatin damage and cellular senescence and ultimately causes skin and endothelial defects, bone resorption, lipodystrophy and accelerated ageing. Knowledge of the mechanism underlying pre...

  1. Progeria Research Day at Brunel University

    Science.gov (United States)

    Eskiw, Christopher H.; Makarov, Evgeny M.; Tree, David; Kill, Ian R.

    2011-01-01

    Hutchinson-Gilford Progeria Syndrome (HGPS) is a severe premature aging syndrome that affects children. These children display characteristics associated with normal aging and die young usually from cardiovascular problems or stroke. Classical HGPS is caused by mutations in the gene encoding the nuclear structural protein lamin A. This mutation leads to a novel version of lamin A that retains a farnesyl group from its processing. This protein is called Progerin and is toxic to cellular function. Pre-lamin A is an immature version of lamin A and also has a farnesylation modification, which is cleaved in the maturation process to create lamin A. PMID:22064469

  2. Genetics of aging, progeria and lamin disorders.

    Science.gov (United States)

    Ghosh, Shrestha; Zhou, Zhongjun

    2014-06-01

    Premature aging disorders, like Werner syndrome, Bloom's syndrome, and Hutchinson-Gilford Progeria Syndrome (HGPS), have been the subjects of immense interest as they recapitulate many of the phenotypes observed in physiological aging. They, therefore, not only provide model systems to study normal aging processes but also give valuable insights into the intricate mechanisms underlying senescence. Recent works on HGPS have revealed alterations in a spectrum of cellular and molecular pathways involved in the maintenance of genomic integrity, thus suggesting a profound impact of the nuclear lamina in nuclear organization, chromatin dynamics, regulation of gene expression and epigenetics.

  3. Progeria: translational insights from cell biology.

    Science.gov (United States)

    Gordon, Leslie B; Cao, Kan; Collins, Francis S

    2012-10-01

    Cell biologists love to think outside the box, pursuing many surprising twists and unexpected turns in their quest to unravel the mysteries of how cells work. But can cell biologists think outside the bench? We are certain that they can, and clearly some already do. To encourage more cell biologists to venture into the realm of translational research on a regular basis, we would like to share a handful of the many lessons that we have learned in our effort to develop experimental treatments for Hutchinson-Gilford progeria syndrome (HGPS), an endeavor that many view as a "poster child" for how basic cell biology can be translated to the clinic.

  4. Depleting the methyltransferase Suv39h1 improves DNA repair and extends lifespan in a progeria mouse model.

    Science.gov (United States)

    Liu, Baohua; Wang, Zimei; Zhang, Le; Ghosh, Shrestha; Zheng, Huiling; Zhou, Zhongjun

    2013-01-01

    A de novo G608G mutation in LMNA gene leads to Hutchinson-Gilford progeria syndrome. Mice lacking the prelamin A-processing metalloprotease, Zmpste24, recapitulate many of the progeroid features of Hutchinson-Gilford progeria syndrome. Here we show that A-type lamins interact with SUV39H1, and prelamin A/progerin exhibits enhanced binding capacity to SUV39H1, protecting it from proteasomal degradation and, consequently, increasing H3K9me3 levels. Depletion of Suv39h1 reduces H3K9me3 levels, restores DNA repair capacity and delays senescence in progeroid cells. Remarkably, loss of Suv39h1 in Zmpste24(-/-) mice delays body weight loss, increases bone mineral density and extends lifespan by ∼60%. Thus, increased H3K9me3 levels, possibly mediated by enhanced Suv39h1 stability in the presence of prelamin A/progerin, compromise genome maintenance, which in turn contributes to accelerated senescence in laminopathy-based premature aging. Our study provides an explanation for epigenetic alterations in Hutchinson-Gilford progeria syndrome and a potential strategy for intervention by targeting SUV39H1-mediated heterochromatin remodelling.

  5. Advances in the study of Hutchinson-Gilford progeria syndrome%Hutchinson-Gilford早老症的研究进展

    Institute of Scientific and Technical Information of China (English)

    李燕辉; 吴白燕

    2006-01-01

    Hutchinson-Gilford早老症(HGPS)为一种极为罕见的遗传性疾病,发生率1/8000000,特征性表现为患儿以极快速度衰老,多数死于冠脉病变引起的心肌梗死或广泛动脉粥样硬化导致的卒中,平均寿命13岁.绝大多数HGPS病例病因为LMNA基因第11个外显子发生点突变(G608G),生成的突变lamin A由显性负效应造成细胞核结构和功能受损.目前该病已有几种动物模型,实验性治疗可以在体外将出泡的细胞核恢复正常.HGPS是研究衰老和心血管疾病机制的一个极好的模型.

  6. Progeria with post-streptococcal glomerulonephritis: a rare case report with differential diagnosis.

    Science.gov (United States)

    Sebastian, Alphy A; Ahsan, Auswaf K

    2013-02-01

    Hutchinson-Gilford progeria syndrome is a rare autosomal dominant disorder associated with skin fragility. It is characterized by craniofacial disproportion, delayed dentition, micrognathia, and plucked bird appearance. The genetic defect is mainly de nova mutation in the lamin A gene. This report describes a 16-year-old patient with classical features of progeria along with post-streptococcal glomerulonephritis. The symptoms of hepatomegaly were also present in the patient. The differential diagnoses of this lesion are also discussed in detail in this literature.

  7. Progeria

    Directory of Open Access Journals (Sweden)

    Kaur Charandeep

    2000-01-01

    Full Text Available A case of progeria is being reported in a 7-year old boy. He had characteristic facies, short stature, alopecia, high pitched voice, coxa valga and sclerodermatous changes in skin.

  8. Progeria Research Foundation, Inc.

    Science.gov (United States)

    About Progeria Progeria 101/FAQ The Connection to Other Diseases The Science Behind Progeria The FTI Drug Lonafarnib For School Reports About ... Profile Our Brochure and Logo Quick Facts Chapters Progeria en espanol Meet the Kids Life According to ...

  9. Progeria and the early aging in children: a case report.

    Science.gov (United States)

    Carvalho, Vania O; Celli, Adriane; Bancke Laverde, Bruno Leonardo; Cunico, Caroline; Santos Piedade, Guilherme; Lucas de Mello, Manuela; Beirao Junior, Paulo Sergio

    2016-02-17

    The Hutchinson-Gilford syndrome or progeria is a rare autosomal dominant syndrome characterized by premature aging and involvement of internal systems, such as the circulatory and locomotor. The diagnosis is essentially clinical and the manifestations become more evident from the first year of life. Long term outcome data from Progeria Research Foundation clinical trials have demonstrated an increase in survival in recent years. Even though new trials are ongoing, the recognition of this syndrome is essential to prevent cardiovascular and cerebrovascular complications. A patient, initially asymptomatic, who developed characteristic signs of the syndrome at the age of 6 months is reported. She was referred for evaluation only when she was two years and eleven months old. The diagnosis of Hutchinson-Gilford syndrome was suspected owing to clinical characteristics. The diagnosis was confirmed by genetic testing. A mutation c.1824C> T in exon 11 of the LMNA gene was detected. She was registered in the Progeria Research Foundation and was invited to participate in the weighing and supplementation program. She was included in the lonafarnib protocol study. This medication is a farnesyl transferase inhibitor that prevents the production of progerina and slows cardiovascular and neurological complications of the syndrome. This case highlights the importance of diagnosing progeria patients because they may be referred to the Progeria Research Foundation, which offers genetic screening and inclusion in clinical and therapeutic follow-up protocols without any costs. Progeria trials and research may also contribute to new drug developments related to prevention of aging and atherosclerosis in the near future.

  10. Progeria

    OpenAIRE

    Raval Ranjan; Bhatt Bhavin; Billiomoria Frenny

    1992-01-01

    An 8-year-old boy presented with clinical manifestations of progeria. He had senile looks, scanty scalp hair, stunted growth, and wrinkled skin with loss of subcutaneous fat. Sclerodermatous changes were found on both thighs and pelvic region, which was confirmed by histopathology.

  11. Progeria

    Directory of Open Access Journals (Sweden)

    Raval Ranjan

    1992-01-01

    Full Text Available An 8-year-old boy presented with clinical manifestations of progeria. He had senile looks, scanty scalp hair, stunted growth, and wrinkled skin with loss of subcutaneous fat. Sclerodermatous changes were found on both thighs and pelvic region, which was confirmed by histopathology.

  12. The two-faced progeria gene and its implications in aging and metabolism.

    Science.gov (United States)

    Chatzispyrou, Iliana A; Houtkooper, Riekelt H

    2014-05-01

    Premature aging syndromes have gained much attention, not only because of their devastating symptoms but also because they might hold a key to some of the mechanisms underlying aging. The Hutchinson-Gilford progeria syndrome (HGPS) is caused by a mutation in the LMNA gene, which normally produces lamins A and C through alternative splicing. Due to this mutation, HGPS patients express an incompletely processed form of lamin A called progerin. In this issue of EMBO Reports, the Tazi group demonstrates how mice expressing different LMNA isoforms present opposite phenotypes in longevity, fat storage and mitochondrial function.

  13. Progeria: Translational insights from cell biology

    Science.gov (United States)

    Gordon, Leslie B.; Cao, Kan

    2012-01-01

    Cell biologists love to think outside the box, pursuing many surprising twists and unexpected turns in their quest to unravel the mysteries of how cells work. But can cell biologists think outside the bench? We are certain that they can, and clearly some already do. To encourage more cell biologists to venture into the realm of translational research on a regular basis, we would like to share a handful of the many lessons that we have learned in our effort to develop experimental treatments for Hutchinson-Gilford progeria syndrome (HGPS), an endeavor that many view as a “poster child” for how basic cell biology can be translated to the clinic. PMID:23027899

  14. Progeria: a rare genetic premature ageing disorder.

    Science.gov (United States)

    Sinha, Jitendra Kumar; Ghosh, Shampa; Raghunath, Manchala

    2014-05-01

    Progeria is characterized by clinical features that mimic premature ageing. Although the mutation responsible for this syndrome has been deciphered, the mechanism of its action remains elusive. Progeria research has gained momentum particularly in the last two decades because of the possibility of revealing evidences about the ageing process in normal and other pathophysiological conditions. Various experimental models, both in vivo and in vitro, have been developed in an effort to understand the cellular and molecular basis of a number of clinically heterogeneous rare genetic disorders that come under the umbrella of progeroid syndromes (PSs). As per the latest clinical trial reports, Lonafarnib, a farnesyltranferase inhibitor, is a potent 'drug of hope' for Hutchinson-Gilford progeria syndrome (HGPS) and has been successful in facilitating weight gain and improving cardiovascular and skeletal pathologies in progeroid children. This can be considered as the dawn of a new era in progeria research and thus, an apt time to review the research developments in this area highlighting the molecular aspects, experimental models, promising drugs in trial and their implications to gain a better understanding of PSs.

  15. Progeria: A rare genetic premature ageing disorder

    Directory of Open Access Journals (Sweden)

    Jitendra Kumar Sinha

    2014-01-01

    Full Text Available Progeria is characterized by clinical features that mimic premature ageing. Although the mutation responsible for this syndrome has been deciphered, the mechanism of its action remains elusive. Progeria research has gained momentum particularly in the last two decades because of the possibility of revealing evidences about the ageing process in normal and other pathophysiological conditions. Various experimental models, both in vivo and in vitro, have been developed in an effort to understand the cellular and molecular basis of a number of clinically heterogeneous rare genetic disorders that come under the umbrella of progeroid syndromes (PSs. As per the latest clinical trial reports, Lonafarnib, a farnesyltranferase inhibitor, is a potent ′drug of hope′ for Hutchinson-Gilford progeria syndrome (HGPS and has been successful in facilitating weight gain and improving cardiovascular and skeletal pathologies in progeroid children. This can be considered as the dawn of a new era in progeria research and thus, an apt time to review the research developments in this area highlighting the molecular aspects, experimental models, promising drugs in trial and their implications to gain a better understanding of PSs.

  16. Neonatal progeria: increased ratio of progerin to lamin A leads to progeria of the newborn.

    Science.gov (United States)

    Reunert, Janine; Wentzell, Rüdiger; Walter, Michael; Jakubiczka, Sibylle; Zenker, Martin; Brune, Thomas; Rust, Stephan; Marquardt, Thorsten

    2012-09-01

    Hutchinson-Gilford progeria syndrome (HGPS) is an important model disease for premature ageing. Affected children appear healthy at birth, but develop the first symptoms during their first year of life. They die at an average age of 13 years, mostly because of myocardial infarction or stroke. Classical progeria is caused by the heterozygous point mutation c.1824C>T in the LMNA gene, which activates a cryptic splice site. The affected protein cannot be processed correctly to mature lamin A, but is modified into a farnesylated protein truncated by 50 amino acids (progerin). Three more variations in LMNA result in the same mutant protein, but different grades of disease severity. We describe a patient with the heterozygous LMNA mutation c.1821G>A, leading to neonatal progeria with death in the first year of life. Intracellular lamin A was downregulated in the patient's fibroblasts and the ratio of progerin to lamin A was increased when compared with HGPS. It is suggestive that the ratio of farnesylated protein to mature lamin A determines the disease severity in progeria.

  17. Progeria, the nucleolus and farnesyltransferase inhibitors.

    Science.gov (United States)

    Mehta, Ishita S; Bridger, Joanna M; Kill, Ian R

    2010-02-01

    HGPS (Hutchinson-Gilford progeria syndrome) is a rare genetic disease affecting children causing them to age and die prematurely. The disease is typically due to a point mutation in the coding sequence for the nuclear intermediate-type filament protein lamin A and gives rise to a dominant-negative splice variant named progerin. Accumulation of progerin within nuclei causes disruption to nuclear structure, causes and premature replicative senescence and increases apoptosis. Now it appears that accumulation of progerin may have more widespread effects than previously thought since the demonstration that the presence and distribution of some nucleolar proteins are also adversely affected in progeria cells. One of the major breakthroughs both in the lamin field and for this syndrome is that many of the cellular defects observed in HGPS patient cells and model systems can be restored after treatment with a class of compounds known as FTIs (farnesyltransferase inhibitors). Indeed, it is demonstrated that FTI-277 is able to completely restore nucleolar antigen localization in treated progeria cells. This is encouraging news for the HGPS patients who are currently undergoing clinical trials with FTI treatment.

  18. Dedifferentiation rescues senescence of progeria cells but only while pluripotent

    Science.gov (United States)

    2011-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a genetic disease in which children develop pathologies associated with old age. HGPS is caused by a mutation in the LMNA gene, resulting in the formation of a dominant negative form of the intermediate filament, nuclear structural protein lamin A, termed progerin. Expression of progerin alters the nuclear architecture and heterochromatin, affecting cell cycle progression and genomic stability. Two groups recently reported the successful generation and characterization of induced pluripotent stem cells (iPSCs) from HGPS fibroblasts. Remarkably, progerin expression and senescence phenotypes are lost in iPSCs but not in differentiated progeny. These new HGPS iPSCs are valuable for characterizing the role of progerin in driving HGPS and aging and for screening therapeutic strategies to prevent or delay cell senescence. PMID:21639955

  19. Aging Study, Hints from Hutchinson-Gilford Progeria Syndrome%Hutchinson-Gilford早老症在衰老研究中的意义

    Institute of Scientific and Technical Information of China (English)

    宋昱; 郭翯; 郑璐; 陈琳; 黄昱

    2009-01-01

    Hutchinson-Gilford早老症是一种散发的常染体显性遗传病,是研究人类正常衰老理想的疾病模型.其发病机制在于核纤层蛋白A的基因发生突变,使其翻译产物缺少了50个氨基酸而变成早老蛋白,该蛋白质在细胞内积累,导致细胞增殖异常、端粒缩短、基因表达调控异常、基因组不稳定等,这些表现与正常衰老有诸多相似之处.正常衰老细胞中同样发现早老蛋白的存在,且随年龄增长而积累.本文比较了HGPS与正常衰老在表型上的异同,综述了HGPS加速衰老的分子机制研究进展,并着重介绍了HGPS研究成果对衰老研究的借鉴意义.%time. By comparing and contrasting the phenotype of HGPS with that of normal aging, we summarize the research progress in the molec-ular mechanism of HGPS, and focus on the results from HGPS which can be used on aging research.

  20. Progeria Research Foundation Diagnostic Testing Program

    Science.gov (United States)

    About Progeria Progeria 101/FAQ The Connection to Other Diseases The Science Behind Progeria The FTI Drug Lonafarnib For School Reports About ... Profile Our Brochure and Logo Quick Facts Chapters Progeria en espanol Meet the Kids Life According to ...

  1. An inherited LMNA gene mutation in atypical Progeria syndrome.

    Science.gov (United States)

    Doubaj, Yassamine; De Sandre-Giovannoli, Annachiara; Vera, Esteves-Vieira; Navarro, Claire Laure; Elalaoui, Siham Chafai; Tajir, Mariam; Lévy, Nicolas; Sefiani, Abdelaziz

    2012-11-01

    Hutchinson-Gilford Progeria syndrome (HGPS) is a rare genetic disorder, characterized by several clinical features that begin in early childhood, recalling an accelerated aging process. The diagnosis of HGPS is based on the recognition of common clinical features and detection of the recurrent heterozygous c.1824C>T (p.Gly608Gly) mutation within exon 11 in the Lamin A/C encoding gene (LMNA). Besides "typical HGPS," several "atypical progeria" syndromes (APS) have been described, in a clinical spectrum ranging from mandibuloacral dysplasia to atypical Werner syndrome. These patients's clinical features include progeroid manifestations, such as short stature, prominent nose, premature graying of hair, partial alopecia, skin atrophy, lipodystrophy, skeletal anomalies, such as mandibular hypoplasia and acroosteolyses, and in some cases severe atherosclerosis with metabolic complications. APS are due in several cases to de novo heterozygous LMNA mutations other than the p.Gly608Gly, or due to homozygous BAFN1 mutations in Nestor-Guillermo Progeria syndrome (NGPS). We report here and discuss the observation of a non-consanguineous Moroccan patient presenting with atypical progeria. The molecular studies showed the heterozygous mutation c.412G>A (p.Glu138Lys) of the LMNA gene. This mutation, previously reported as a de novo mutation, was inherited from the apparently healthy father who showed a somatic cell mosaicism.

  2. Disease: H00601 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available H00601 Hutchinson-Gilford progeria syndrome Hutchinson-Gilford progeria syndrome (H...lez JM, Pla D, Perez-Sala D, Andres V A-type lamins and Hutchinson-Gilford progeria syndrome: pathogenesis a...nd therapy. Front Biosci (Schol Ed) 3:1133-46 (2011) PMID:15479179 (description, gene) Pollex RL, Hegele RA Hutchinson-Gilford progeria syndrome. Clin Genet 66:375-81 (2004) ...

  3. Stem cell aging in adult progeria.

    Science.gov (United States)

    Cheung, Hoi-Hung; Pei, Duanqing; Chan, Wai-Yee

    2015-01-01

    Aging is considered an irreversible biological process and also a major risk factor for a spectrum of geriatric diseases. Advanced age-related decline in physiological functions, such as neurodegeneration, development of cardiovascular disease, endocrine and metabolic dysfunction, and neoplastic transformation, has become the focus in aging research. Natural aging is not regarded as a programmed process. However, accelerated aging due to inherited genetic defects in patients of progeria is programmed and resembles many aspects of natural aging. Among several premature aging syndromes, Werner syndrome (WS) and Hutchinson-Gilford progeria syndrome (HGPS) are two broadly investigated diseases. In this review, we discuss how stem cell aging in WS helps us understand the biology of aging. We also discuss briefly how the altered epigenetic landscape in aged cells can be reversed to a "juvenile" state. Lastly, we explore the potential application of the latest genomic editing technique for stem cell-based therapy and regenerative medicine in the context of aging.

  4. LMNA-Associated Cardiocutaneous Progeria: a Novel Autosomal Dominant Premature Aging Syndrome with Late Onset

    Science.gov (United States)

    Kane, Megan S.; Lindsay, Mark E.; Judge, Daniel P.; Barrowman, Jemima; Rhys, Colette Ap; Simonson, Lisa; Dietz, Harry C.; Michaelis, Susan

    2013-01-01

    Hutchinson-Gilford Progeria Syndrome (HGPS) is a well-characterized premature aging disorder caused by mutations in LMNA, the gene encoding the nuclear scaffold proteins lamin A and C. In HGPS and related progerias, processing of prelamin A is blocked at a critical step mediated by the zinc metalloprotease ZMPSTE24. Emerging evidence indicates that LMNA-linked progerias can be grouped into two classes: 1) the processing-deficient, early onset “typical” progerias (e.g. HGPS), and 2) the processing-proficient “atypical” progeria syndromes (APS) that are later in onset. Here we describe a novel progeria syndrome with prominent cutaneous and cardiovascular manifestations belonging to the second class. We suggest the name LMNA-associated cardiocutaneous progeria syndrome (LCPS) for this disorder. Affected patients are normal at birth but undergo progressive cutaneous changes in childhood and die in middle age of cardiovascular complications, including accelerated atherosclerosis, calcific valve disease, and cardiomyopathy. In addition, the proband demonstrated cancer susceptibility, a phenotype rarely described for LMNA-based progeria disorders. The LMNA mutation that causes LCPS is a heterozygous missense mutation resulting in an amino acid substitution (D300G) in the coiled-coil domain of lamin A/C. In skin fibroblasts isolated from the proband, the processing and levels of lamin A and C are normal. However, nuclear morphology is aberrant and rescued by treatment with farnesyltransferase inhibitors (FTIs), as is also the case for HGPS and other laminopathies. Our findings advance knowledge of human LMNA progeria syndromes, and raise the possibility that typical and atypical progerias may converge upon a common mechanism to cause premature aging disease. PMID:23666920

  5. LMNA-associated cardiocutaneous progeria: an inherited autosomal dominant premature aging syndrome with late onset.

    Science.gov (United States)

    Kane, Megan S; Lindsay, Mark E; Judge, Daniel P; Barrowman, Jemima; Ap Rhys, Colette; Simonson, Lisa; Dietz, Harry C; Michaelis, Susan

    2013-07-01

    Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disorder caused by mutations in LMNA, which encodes the nuclear scaffold proteins lamin A and C. In HGPS and related progerias, processing of prelamin A is blocked at a critical step mediated by the zinc metalloprotease ZMPSTE24. LMNA-linked progerias can be grouped into two classes: (1) the processing-deficient, early onset "typical" progerias (e.g., HGPS), and (2) the processing-proficient "atypical" progeria syndromes (APS) that are later in onset. Here we describe a previously unrecognized progeria syndrome with prominent cutaneous and cardiovascular manifestations belonging to the second class. We suggest the name LMNA-associated cardiocutaneous progeria syndrome (LCPS) for this disorder. Affected patients are normal at birth but undergo progressive cutaneous changes in childhood and die in middle age of cardiovascular complications, including accelerated atherosclerosis, calcific valve disease, and cardiomyopathy. In addition, the proband demonstrated cancer susceptibility, a phenotype rarely described for LMNA-based progeria disorders. The LMNA mutation that caused LCPS in this family is a heterozygous c.899A>G (p.D300G) mutation predicted to alter the coiled-coil domain of lamin A/C. In skin fibroblasts isolated from the proband, the processing and levels of lamin A and C are normal. However, nuclear morphology is aberrant and rescued by treatment with farnesyltransferase inhibitors, as is also the case for HGPS and other laminopathies. Our findings advance knowledge of human LMNA progeria syndromes, and raise the possibility that typical and atypical progerias may converge upon a common mechanism to cause premature aging disease.

  6. Targeting isoprenylcysteine methylation ameliorates disease in a mouse model of progeria.

    Science.gov (United States)

    Ibrahim, Mohamed X; Sayin, Volkan I; Akula, Murali K; Liu, Meng; Fong, Loren G; Young, Stephen G; Bergo, Martin O

    2013-06-14

    Several progeroid disorders, including Hutchinson-Gilford progeria syndrome (HGPS) and restrictive dermopathy (ZMPSTE24 deficiency), arise when a farnesylated and methylated form of prelamin A accumulates at the nuclear envelope. Here, we found that a hypomorphic allele of isoprenylcysteine carboxyl methyltransferase (ICMT) increased body weight, normalized grip strength, and prevented bone fractures and death in Zmpste24-deficient mice. The reduced ICMT activity caused prelamin A mislocalization within the nucleus and triggered prelamin A-dependent activation of AKT-mammalian target of rapamycin (mTOR) signaling, which abolished the premature senescence of Zmpste24-deficient fibroblasts. ICMT inhibition increased AKT-mTOR signaling and proliferation and delayed senescence in human HGPS fibroblasts but did not reduce the levels of misshapen nuclei in mouse and human cells. Thus, targeting ICMT might be useful for treating prelamin A-associated progeroid disorders.

  7. Cell autonomous and systemic factors in progeria development.

    Science.gov (United States)

    Osorio, Fernando G; Ugalde, Alejandro P; Mariño, Guillermo; Puente, Xose S; Freije, José M P; López-Otín, Carlos

    2011-12-01

    Progeroid laminopathies are accelerated aging syndromes caused by defects in nuclear envelope proteins. Accordingly, mutations in the LMNA gene and functionally related genes have been described to cause HGPS (Hutchinson-Gilford progeria syndrome), MAD (mandibuloacral dysplasia) or RD (restrictive dermopathy). Functional studies with animal and cellular models of these syndromes have facilitated the identification of the molecular alterations and regulatory pathways involved in progeria development. We have recently described a novel regulatory pathway involving miR-29 and p53 tumour suppressor which has provided valuable information on the molecular components orchestrating the response to nuclear damage stress. Furthermore, by using progeroid mice deficient in ZMPSTE24 (zinc metalloprotease STE24 homologue) involved in lamin A maturation, we have demonstrated that, besides these abnormal cellular responses to stress, dysregulation of the somatotropic axis is responsible for some of the alterations associated with progeria. Consistent with these observations, pharmacological restoration of the somatotroph axis in these mice delays the onset of their progeroid features, significantly extending their lifespan and supporting the importance of systemic alterations in progeria progression. Finally, we have very recently identified a novel progeroid syndrome with distinctive features from HGPS and MAD, which we have designated NGPS (Néstor-Guillermo progeria syndrome) (OMIM #614008). This disorder is caused by a mutation in BANF1, a gene encoding a protein with essential functions in the assembly of the nuclear envelope, further illustrating the importance of the nuclear lamina integrity for human health and providing additional support to the study of progeroid syndromes as a valuable source of information on human aging.

  8. Speeding up the clock: The past, present and future of progeria.

    Science.gov (United States)

    Swahari, Vijay; Nakamura, Ayumi

    2016-01-01

    Progeria is a devastating disorder in which patients exhibit signs of premature aging. The most well-known progeroid syndromes include Hutchinson-Gilford Progeria Syndrome (HGPS) and Werner Syndrome (WS). While HGPS and WS are rare, they often result in severe age-associated complications starting in the early developmental period or after the pubertal growth spurt during adolescence, respectively. In addition, patients with HGPS ultimately die of diseases normally seen in the elderly population, with stroke and myocardial infarction as the leading causes of death. Many WS patients develop similar cardiovascular complications but also have an increased predisposition to developing multiple rare malignancies. These premature aging disorders, as well as animal and cell culture models that recapitulate these diseases, have provided insight into the genetics and cellular pathways that underlie these human conditions and have also uncovered possible mechanisms behind normal aging. Here we discuss the history, the types of progeria, and the various pathophysiological mechanisms that drive these diseases. We also address recent medical advances and treatment modalities for patients with progeria.

  9. Estimation of vessel age and early diagnose of atherosclerosis in progeria syndrome by using echo-tracking.

    Science.gov (United States)

    Várady, E; Feher, E; Levai, A; Battyany, I

    2010-01-01

    The stiffness of the arteries normally increases with age. Radiofrequency echo-tracking is a non-invasive ultrasound method which is able to detect the stiffness of the arteries, represented by the beta stiffness index. The estimation of biological age of vessels is possible on the basis of the normal age-group specific beta stiffness values. The beta stiffness index becomes higher in early stages of atherosclerosis as well, before any visible morphological changes. Hutchinson-Gilford progeria syndrome (HGPS) is rare genetic disorder resulting in accelerated aging including appearance of progressive atherosclerosis at an early age which determines the quality and term of life of these patients. Determination of vascular age and early diagnosis of atherosclerosis seems crucial. According to our knowledge, the estimation of vascular age detected with radiofrequency echo-tracking in HGPS patients, in contrast to the normal age-specific beta stiffness values, has not been published yet.

  10. Néstor-Guillermo progeria syndrome: a novel premature aging condition with early onset and chronic development caused by BANF1 mutations.

    Science.gov (United States)

    Cabanillas, Rubén; Cadiñanos, Juan; Villameytide, José A F; Pérez, Mercedes; Longo, Jesús; Richard, José M; Alvarez, Rebeca; Durán, Noelia S; Illán, Rafael; González, Daniel J; López-Otín, Carlos

    2011-11-01

    Progeria syndromes are rare disorders that involve premature aging. Mutations in BANF1 have been recently reported to cause a new hereditary progeroid syndrome that we now propose to call the Néstor-Guillermo progeria syndrome (NGPS). We describe herein the clinical features of the first two NGPS patients, who phenocopy features of classic progerias (i.e., Hutchinson-Gilford progeria syndrome or mandibuloacral dysplasia), such as aged appearance, growth retardation, decreased subcutaneous fat, thin limbs, and stiff joints. However, these NGPS patients have a distinctive phenotype. In their early adulthood (32 and 24 years of age), they have no signs of cardiovascular impairment, diabetes mellitus, or hypertriglyceridemia. In contrast, they suffer profound skeletal abnormalities that affect their quality of life. The observed differences are of utmost importance to patients and their families and palliation of osseous manifestations is a priority, given their relatively long lifespan. We define NGPS as a chronic progeria because of its slow clinical course and relatively long survival, despite its early onset. Understanding the differences between progeria syndromes might contribute to the development of treatment strategies for common skeletal conditions, as well as aging itself.

  11. Assessing the efficacy of protein farnesyltransferase inhibitors in mouse models of progeria.

    Science.gov (United States)

    Yang, Shao H; Chang, Sandy Y; Andres, Douglas A; Spielmann, H Peter; Young, Stephen G; Fong, Loren G

    2010-02-01

    Hutchinson-Gilford progeria syndrome (HGPS) is caused by the accumulation of a farnesylated form of prelamin A (progerin). Previously, we showed that blocking protein farnesylation with a farnesyltransferase inhibitor (FTI) ameliorates the disease phenotypes in mouse model of HGPS (Lmna(HG/+)). However, the interpretation of the FTI treatment studies is open to question in light of recent studies showing that mice expressing a nonfarnesylated version of progerin (Lmna(nHG/+)) develop progeria-like disease phenotypes. The fact that Lmna(nHG/+) mice manifest disease raised the possibility that the beneficial effects of an FTI in Lmna(HG/+) mice were not due to the effects of the drug on the farnesylation of progerin, but may have been due to unanticipated secondary effects of the drug on other farnesylated proteins. To address this issue, we compared the ability of an FTI to improve progeria-like disease phenotypes in both Lmna(HG/+) and Lmna(nHG/+) mice. In Lmna(HG/+) mice, the FTI reduced disease phenotypes in a highly significant manner, but the drug had no effect in Lmna(nHG/+) mice. The failure of the FTI to ameliorate disease in Lmna(nHG/+) mice supports the idea that the beneficial effects of an FTI in Lmna(HG/+) mice are due to the effect of drug on the farnesylation of progerin.

  12. Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria.

    Science.gov (United States)

    Xiong, Zheng-Mei; Choi, Ji Young; Wang, Kun; Zhang, Haoyue; Tariq, Zeshan; Wu, Di; Ko, Eunae; LaDana, Christina; Sesaki, Hiromi; Cao, Kan

    2016-04-01

    Hutchinson-Gilford progeria syndrome (HGPS), a fatal premature aging disease, is caused by a single-nucleotide mutation in the LMNA gene. Previous reports have focused on nuclear phenotypes in HGPS cells, yet the potential contribution of the mitochondria, a key player in normal aging, remains unclear. Using high-resolution microscopy analysis, we demonstrated a significantly increased fraction of swollen and fragmented mitochondria and a marked reduction in mitochondrial mobility in HGPS fibroblast cells. Notably, the expression of PGC-1α, a central regulator of mitochondrial biogenesis, was inhibited by progerin. To rescue mitochondrial defects, we treated HGPS cells with a mitochondrial-targeting antioxidant methylene blue (MB). Our analysis indicated that MB treatment not only alleviated the mitochondrial defects but also rescued the hallmark nuclear abnormalities in HGPS cells. Additional analysis suggested that MB treatment released progerin from the nuclear membrane, rescued perinuclear heterochromatin loss and corrected misregulated gene expression in HGPS cells. Together, these results demonstrate a role of mitochondrial dysfunction in developing the premature aging phenotypes in HGPS cells and suggest MB as a promising therapeutic approach for HGPS.

  13. Molecular insights into the premature aging disease progeria.

    Science.gov (United States)

    Vidak, Sandra; Foisner, Roland

    2016-04-01

    Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare premature aging disease presenting many features resembling the normal aging process. HGPS patients die before the age of 20 years due to cardiovascular problems and heart failure. HGPS is linked to mutations in the LMNA gene encoding the intermediate filament protein lamin A. Lamin A is a major component of the nuclear lamina, a scaffold structure at the nuclear envelope that defines mechanochemical properties of the nucleus and is involved in chromatin organization and epigenetic regulation. Lamin A is also present in the nuclear interior where it fulfills lamina-independent functions in cell signaling and gene regulation. The most common LMNA mutation linked to HGPS leads to mis-splicing of the LMNA mRNA and produces a mutant lamin A protein called progerin that tightly associates with the inner nuclear membrane and affects the dynamic properties of lamins. Progerin expression impairs many important cellular processes providing insight into potential disease mechanisms. These include changes in mechanosignaling, altered chromatin organization and impaired genome stability, and changes in signaling pathways, leading to impaired regulation of adult stem cells, defective extracellular matrix production and premature cell senescence. In this review, we discuss these pathways and their potential contribution to the disease pathologies as well as therapeutic approaches used in preclinical and clinical tests.

  14. Permanent farnesylation of lamin A mutants linked to progeria impairs its phosphorylation at serine 22 during interphase.

    Science.gov (United States)

    Moiseeva, Olga; Lopes-Paciencia, Stéphane; Huot, Geneviève; Lessard, Frédéric; Ferbeyre, Gerardo

    2016-02-01

    Mutants of lamin A cause diseases including the Hutchinson-Gilford progeria syndrome (HGPS) characterized by premature aging. Lamin A undergoes a series of processing reactions, including farnesylation and proteolytic cleavage of the farnesylated C-terminal domain. The role of cleavage is unknown but mutations that affect this reaction lead to progeria. Here we show that interphase serine 22 phosphorylation of endogenous mutant lamin A (progerin) is defective in cells from HGPS patients. This defect can be mimicked by expressing progerin in human cells and prevented by inhibition of farnesylation. Furthermore, serine 22 phosphorylation of non-farnesylated progerin was enhanced by a mutation that disrupts lamin A head to tail interactions. The phosphorylation of lamin A or non-farnesylated progerin was associated to the formation of spherical intranuclear lamin A droplets that accumulate protein kinases of the CDK family capable of phosphorylating lamin A at serine 22. CDK inhibitors compromised the turnover of progerin, accelerated senescence of HGPS cells and reversed the effects of FTI on progerin levels. We discuss a model of progeria where faulty serine 22 phosphorylation compromises phase separation of lamin A polymers, leading to accumulation of functionally impaired lamin A structures.

  15. Skeletal muscle contractile function and neuromuscular performance in Zmpste24 -/- mice, a murine model of human progeria.

    Science.gov (United States)

    Greising, Sarah M; Call, Jarrod A; Lund, Troy C; Blazar, Bruce R; Tolar, Jakub; Lowe, Dawn A

    2012-08-01

    Human progeroid syndromes and premature aging mouse models present as segmental, accelerated aging because some tissues and not others are affected. Skeletal muscle is detrimentally changed by normal aging but whether it is an affected tissue in progeria has not been resolved. We hypothesized that mice which mimic Hutchinson-Gilford progeria syndrome would exhibit age-related alterations of skeletal muscle. Zmpste24 (-/-) and Zmpste24 (+/+) littermates were assessed for skeletal muscle functions, histo-morphological characteristics, and ankle joint mechanics. Twenty-four-hour active time, ambulation, grip strength, and whole body tension were evaluated as markers of neuromuscular performance, each of which was at least 33% lower in Zmpste24 (-/-) mice compared with littermates (p normal. Ankle range of motion was 70% lower and plantar- and dorsiflexion passive torques were nearly 3-fold greater in Zmpste24 (-/-) than Zmpste24 (+/+) mice (p ≤ 0.01). The combined factors of muscle atrophy, collagen accumulation, and perturbed joint mechanics likely contributed to poor neuromuscular performance and selective muscle weakness displayed by Zmpste24 (-/-)mice. In summary, these characteristics are similar to those of aged mice indicating accelerated aging of skeletal muscle in progeria.

  16. Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria

    Science.gov (United States)

    Cenni, V.; Capanni, C.; Columbaro, M.; Ortolani, M.; D'Apice, M.R.; Novelli, G.; Fini, M.; Marmiroli, S.; Scarano, E.; Maraldi, N.M.; Squarzoni, S.; Prencipe, S.; Lattanzi, G.

    2011-01-01

    Farnesylated prelamin A is a processing intermediate produced in the lamin A maturation pathway. Accumulation of a truncated farnesylated prelamin A form, called progerin, is a hallmark of the severe premature ageing syndrome, Hutchinson-Gilford progeria. Progerin elicits toxic effects in cells, leading to chromatin damage and cellular senescence and ultimately causes skin and endothelial defects, bone resorption, lipodystrophy and accelerated ageing. Knowledge of the mechanism underlying prelamin A turnover is critical for the development of clinically effective protein inhibitors that can avoid accumulation to toxic levels without impairing lamin A/C expression, which is essential for normal biological functions. Little is known about specific molecules that may target farnesylated prelamin A to elicit protein degradation. Here, we report the discovery of rapamycin as a novel inhibitor of progerin, which dramatically and selectively decreases protein levels through a mechanism involving autophagic degradation. Rapamycin treatment of progeria cells lowers progerin, as well as wild-type prelamin A levels, and rescues the chromatin phenotype of cultured fibroblasts, including histone methylation status and BAF and LAP2α distribution patterns. Importantly, rapamycin treatment does not affect lamin C protein levels, but increases the relative expression of the prelamin A endoprotease ZMPSTE24. Thus, rapamycin, an antibiotic belonging to the class of macrolides, previously found to increase longevity in mouse models, can serve as a therapeutic tool, to eliminate progerin, avoid farnesylated prelamin A accumulation, and restore chromatin dynamics in progeroid laminopathies. PMID:22297442

  17. Defective nuclear import of Tpr in Progeria reflects the Ran sensitivity of large cargo transport.

    Science.gov (United States)

    Snow, Chelsi J; Dar, Ashraf; Dutta, Anindya; Kehlenbach, Ralph H; Paschal, Bryce M

    2013-05-13

    The RanGTPase acts as a master regulator of nucleocytoplasmic transport by controlling assembly and disassembly of nuclear transport complexes. RanGTP is required in the nucleus to release nuclear localization signal (NLS)-containing cargo from import receptors, and, under steady-state conditions, Ran is highly concentrated in the nucleus. We previously showed the nuclear/cytoplasmic Ran distribution is disrupted in Hutchinson-Gilford Progeria syndrome (HGPS) fibroblasts that express the Progerin form of lamin A, causing a major defect in nuclear import of the protein, translocated promoter region (Tpr). In this paper, we show that Tpr import was mediated by the most abundant import receptor, KPNA2, which binds the bipartite NLS in Tpr with nanomolar affinity. Analyses including NLS swapping revealed Progerin did not cause global inhibition of nuclear import. Rather, Progerin inhibited Tpr import because transport of large protein cargoes was sensitive to changes in the Ran nuclear/cytoplasmic distribution that occurred in HGPS. We propose that defective import of large protein complexes with important roles in nuclear function may contribute to disease-associated phenotypes in Progeria.

  18. In vitro pathological modelling using patient-specific induced pluripotent stem cells: the case of progeria.

    Science.gov (United States)

    Nissan, Xavier; Blondel, Sophie; Peschanski, Marc

    2011-12-01

    Progeria, also known as HGPS (Hutchinson-Gilford progeria syndrome), is a rare fatal genetic disease characterized by an appearance of accelerated aging in children. This syndrome is typically caused by mutations in codon 608 (C1804T) of the gene encoding lamins A and C, LMNA, leading to the production of a truncated form of the protein called progerin. Owing to their unique potential to self-renew and to differentiate into any cell types of the organism, pluripotent stem cells offer a unique tool to study molecular and cellular mechanisms related to this global and systemic disease. Recent studies have exploited this potential by generating human induced pluripotent stem cells from HGPS patients' fibroblasts displaying several phenotypic defects characteristic of HGPS such as nuclear abnormalities, progerin expression, altered DNA-repair mechanisms and premature senescence. Altogether, these findings provide new insights on the use of pluripotent stem cells for pathological modelling and may open original therapeutic perspectives for diseases that lack pre-clinical in vitro human models, such as HGPS.

  19. Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria.

    Science.gov (United States)

    Cenni, V; Capanni, C; Columbaro, M; Ortolani, M; D'Apice, M R; Novelli, G; Fini, M; Marmiroli, S; Scarano, E; Maraldi, N M; Squarzoni, S; Prencipe, S; Lattanzi, G

    2011-10-19

    Farnesylated prelamin A is a processing intermediate produced in the lamin A maturation pathway. Accumulation of a truncated farnesylated prelamin A form, called progerin, is a hallmark of the severe premature ageing syndrome, Hutchinson-Gilford progeria. Progerin elicits toxic effects in cells, leading to chromatin damage and cellular senescence and ultimately causes skin and endothelial defects, bone resorption, lipodystrophy and accelerated ageing. Knowledge of the mechanism underlying prelamin A turnover is critical for the development of clinically effective protein inhibitors that can avoid accumulation to toxic levels without impairing lamin A/C expression, which is essential for normal biological functions. Little is known about specific molecules that may target farnesylated prelamin A to elicit protein degradation. Here, we report the discovery of rapamycin as a novel inhibitor of progerin, which dramatically and selectively decreases protein levels through a mechanism involving autophagic degradation. Rapamycin treatment of progeria cells lowers progerin, as well as wild-type prelamin A levels, and rescues the chromatin phenotype of cultured fibroblasts, including histone methylation status and BAF and LAP2alpha distribution patterns. Importantly, rapamycin treatment does not affect lamin C protein levels, but increases the relative expression of the prelamin A endoprotease ZMPSTE24. Thus, rapamycin, an antibiotic belonging to the class of macrolides, previously found to increase longevity in mouse models, can serve as a therapeutic tool, to eliminate progerin, avoid farnesylated prelamin A accumulation, and restore chromatin dynamics in progeroid laminopathies.

  20. Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria

    Directory of Open Access Journals (Sweden)

    V. Cenni

    2011-10-01

    Full Text Available Farnesylated prelamin A is a processing intermediate produced in the lamin A maturation pathway. Accumulation of a truncated farnesylated prelamin A form, called progerin, is a hallmark of the severe premature ageing syndrome, Hutchinson-Gilford progeria. Progerin elicits toxic effects in cells, leading to chromatin damage and cellular senescence and ultimately causes skin and endothelial defects, bone resorption, lipodystrophy and accelerated ageing. Knowledge of the mechanism underlying prelamin A turnover is critical for the development of clinically effective protein inhibitors that can avoid accumulation to toxic levels without impairing lamin A/C expression, which is essential for normal biological functions. Little is known about specific molecules that may target farnesylated prelamin A to elicit protein degradation. Here, we report the discovery of rapamycin as a novel inhibitor of progerin, which dramatically and selectively decreases protein levels through a mechanism involving autophagic degradation. Rapamycin treatment of progeria cells lowers progerin, as well as wild-type prelamin A levels, and rescues the chromatin phenotype of cultured fibroblasts, including histone methylation status and BAF and LAP2alpha distribution patterns. Importantly, rapamycin treatment does not affect lamin C protein levels, but increases the relative expression of the prelamin A endoprotease ZMPSTE24. Thus, rapamycin, an antibiotic belonging to the class of macrolides, previously found to increase longevity in mouse models, can serve as a therapeutic tool, to eliminate progerin, avoid farnesylated prelamin A accumulation, and restore chromatin dynamics in progeroid laminopathies.

  1. 罕见突变引起的早老症1例及文献回顾%Hutchinson-Gilford progeria syndrome caused by rare mutation: a case report and literature review

    Institute of Scientific and Technical Information of China (English)

    彭斌; 郭圆圆; 肖生祥; 耿松梅

    2014-01-01

    报告1例早老症.患儿男,2个月.1个月时开始出现躯干及四肢皮肤硬化、双眼突出、面部皮肤菲薄、头皮静脉显露、哭声尖细、关节僵硬和生长受限,随访过程中出现脱发.基因分析显示核纤层蛋白A基因(LMNA)突变(c.1968+1G>A).根据临床表现和基因分析结果,诊断为早老症.该位点突变引起的早老症为国内首例报告.

  2. p.Pro4Arg mutation in LMNA gene: a new atypical progeria phenotype without metabolism abnormalities.

    Science.gov (United States)

    Guo, Hong; Luo, Na; Hao, Fei; Bai, Yun

    2014-08-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a typical presenile disorder, with mutation in the LMNA gene. Besides HGPS, mutations in LMNA gene have also been reported in atypical progeroid syndrome (APS). The objective of the study was to investigate the phenotype and molecular basis of APS in a Chinese family. LMNA gene mutations were also reviewed to identify the phenotypic and pathogenic differences among APS. Two siblings in a non-consanguineous Chinese family with atypical progeria were reported. The clinical features were observed, including presenile manifestations such as bird-like facial appearance, generalized lipodystrophy involving the extremities and mottled hyperpigmentation on the trunk and extremities. A heterozygous mutation c.11C>G (p.Pro4Arg) of the LMNA gene was detected in the two patients. 28 different variants of the LMNA gene have been reported in APS families, spreading over almost all the 12 exons of the LMNA gene with some hot-spot regions. This is the first detailed description of an APS family without metabolism abnormalities. APS patients share most of the clinical features, but there may be some distinct features in different ethnic groups.

  3. Mechanisms controlling the smooth muscle cell death in progeria via down-regulation of poly(ADP-ribose) polymerase 1.

    Science.gov (United States)

    Zhang, Haoyue; Xiong, Zheng-Mei; Cao, Kan

    2014-06-03

    Hutchinson-Gilford progeria syndrome (HGPS) is a severe human premature aging disorder caused by a lamin A mutant named progerin. Death occurs at a mean age of 13 y from cardiovascular problems. Previous studies revealed loss of vascular smooth muscle cells (SMCs) in the media of large arteries in a patient with HGPS and two mouse models, suggesting a causal connection between the SMC loss and cardiovascular malfunction. However, the mechanisms of how progerin leads to massive SMC loss are unknown. In this study, using SMCs differentiated from HGPS induced pluripotent stem cells, we show that HGPS SMCs exhibit a profound proliferative defect, which is primarily caused by caspase-independent cell death. Importantly, progerin accumulation stimulates a powerful suppression of PARP1 and consequently triggers an activation of the error-prone nonhomologous end joining response. As a result, most HGPS SMCs exhibit prolonged mitosis and die of mitotic catastrophe. This study demonstrates a critical role of PARP1 in mediating SMC loss in patients with HGPS and elucidates a molecular pathway underlying the progressive SMC loss in progeria.

  4. Genomic instability and DNA damage responses in progeria arising from defective maturation of prelamin A.

    Science.gov (United States)

    Musich, Phillip R; Zou, Yue

    2009-01-01

    Progeria syndromes have in common a premature aging phenotype and increased genome instability. The susceptibility to DNA damage arises from a compromised repair system, either in the repair proteins themselves or in the DNA damage response pathways. The most severe progerias stem from mutations affecting lamin A production, a filamentous protein of the nuclear lamina. Hutchinson-Gilford progeria syndrome (HGPS) patients are heterozygous for aLMNA gene mutation while Restrictive Dermopathy (RD) individuals have a homozygous deficiency in the processing protease Zmpste24. These mutations generate the mutant lamin A proteins progerin and FC-lamina A, respectively, which cause nuclear deformations and chromatin perturbations. Genome instability is observed even though genome maintenance and repair genes appear normal. The unresolved question is what features of the DNA damage response pathways are deficient in HGPS and RD cells. Here we review and discuss recent findings which resolve some mechanistic details of how the accumulation of progerin/FC-lamin A proteins may disrupt DNA damage response pathways in HGPS and RD cells. As the mutant lamin proteins accumulate they sequester replication and repair factors, leading to stalled replication forks which collapse into DNA double-strand beaks (DSBs). In a reaction unique to HGPS and RD cells these accessible DSB termini bind Xeroderma pigmentosum group A (XPA) protein which excludes normal binding by DNA DSB repair proteins. The bound XPA also signals activation of ATM and ATR, arresting cell cycle progression, leading to arrested growth. In addition, the effective sequestration of XPA at these DSB damage sites makes HGPS and RD cells more sensitive to ultraviolet light and other mutagens normally repaired by the nucleotide excision repair pathway of which XPA is a necessary and specific component.

  5. A pathway linking oxidative stress and the Ran GTPase system in progeria.

    Science.gov (United States)

    Datta, Sutirtha; Snow, Chelsi J; Paschal, Bryce M

    2014-04-01

    Maintaining the Ran GTPase at a proper concentration in the nucleus is important for nucleocytoplasmic transport. Previously we found that nuclear levels of Ran are reduced in cells from patients with Hutchinson-Gilford progeria syndrome (HGPS), a disease caused by constitutive attachment of a mutant form of lamin A (termed progerin) to the nuclear membrane. Here we explore the relationship between progerin, the Ran GTPase, and oxidative stress. Stable attachment of progerin to the nuclear membrane disrupts the Ran gradient and results in cytoplasmic localization of Ubc9, a Ran-dependent import cargo. Ran and Ubc9 disruption can be induced reversibly with H2O2. CHO cells preadapted to oxidative stress resist the effects of progerin on Ran and Ubc9. Given that HGPS-patient fibroblasts display elevated ROS, these data suggest that progerin inhibits nuclear transport via oxidative stress. A drug that inhibits pre-lamin A cleavage mimics the effects of progerin by disrupting the Ran gradient, but the effects on Ran are observed before a substantial ROS increase. Moreover, reducing the nuclear concentration of Ran is sufficient to induce ROS irrespective of progerin. We speculate that oxidative stress caused by progerin may occur upstream or downstream of Ran, depending on the cell type and physiological setting.

  6. Absence of progeria-like disease phenotypes in knock-in mice expressing a non-farnesylated version of progerin.

    Science.gov (United States)

    Yang, Shao H; Chang, Sandy Y; Ren, Shuxun; Wang, Yibin; Andres, Douglas A; Spielmann, H Peter; Fong, Loren G; Young, Stephen G

    2011-02-01

    Hutchinson-Gilford progeria syndrome (HGPS) is caused by a mutant prelamin A, progerin, that terminates with a farnesylcysteine. HGPS knock-in mice (Lmna(HG/+)) develop severe progeria-like disease phenotypes. These phenotypes can be ameliorated with a protein farnesyltransferase inhibitor (FTI), suggesting that progerin's farnesyl lipid is important for disease pathogenesis and raising the possibility that FTIs could be useful for treating humans with HGPS. Subsequent studies showed that mice expressing non-farnesylated progerin (Lmna(nHG/+) mice, in which progerin's carboxyl-terminal -CSIM motif was changed to -SSIM) also develop severe progeria, raising doubts about whether any treatment targeting protein prenylation would be particularly effective. We suspected that those doubts might be premature and hypothesized that the persistent disease in Lmna(nHG/+) mice could be an unanticipated consequence of the cysteine-to-serine substitution that was used to eliminate farnesylation. To test this hypothesis, we generated a second knock-in allele yielding non-farnesylated progerin (Lmna(csmHG)) in which the carboxyl-terminal -CSIM motif was changed to -CSM. We then compared disease phenotypes in mice harboring the Lmna(nHG) or Lmna(csmHG) allele. As expected, Lmna(nHG/+) and Lmna(nHG/nHG) mice developed severe progeria-like disease phenotypes, including osteolytic lesions and rib fractures, osteoporosis, slow growth and reduced survival. In contrast, Lmna(csmHG/+) and Lmna(csmHG/csmHG) mice exhibited no bone disease and displayed entirely normal body weights and survival. The frequencies of misshapen cell nuclei were lower in Lmna(csmHG/+) and Lmna(csmHG/csmHG) fibroblasts. These studies show that the ability of non-farnesylated progerin to elicit disease depends on the carboxyl-terminal mutation used to eliminate protein prenylation.

  7. Mutation analysis of the LMNA gene in a child with Hutchinson-Gifford progeria syndrome%Hutchinson-Gilford早老综合征LMNA基因突变研究

    Institute of Scientific and Technical Information of China (English)

    阳芳; 李乾; 郑利雄; 冯思航; 房思宁; 姚勇丰

    2014-01-01

    目的 报告1例Hutchinson-Gilford早老综合征,并进行分子遗传学诊断.方法 提取1例Hutchinson-Gilford早老综合征患儿及其父母外周血DNA,对LMNA基因1 1号外显子和侧翼序列进行测序,并以150例无关系健康人作为对照.结果 患者男,12月龄.出现躯干部紧张如硬皮病样改变、脱发,头皮静脉明显9个月.身高和体重低于同龄儿童平均值2个标准差.头部皮肤菲薄,头皮静脉清晰可见.躯干皮肤紧张变硬有光泽,干燥,少许细小脱屑,皮肤有斑点状色素加深和色素减退夹杂,鹅卵石样的皮肤硬化肥厚,下肢有皮下脂肪凹陷.X线片示指骨末端吸收.患儿LMNA基因11号外显子c.1824C>T杂合点突变(dbSNP:m58596362),父母及健康人对照均未检测到该位点突变.结论 LMNA基因1 1号外显子的c.1824C>T突变为该例Hutchinson-Gilford早老综合征的发病原因.%Objective To report a case of Hutchinson-Gilford progeria syndrome,and to make a molecular genetic diagnosis.Methods Peripheral blood samples were collected from a 12-month-old child with HutchinsonGilford progeria syndrome,his parents,and 150 unrelated healthy controls.DNA was extracted from these samples,and PCR was performed to amplify exon 11 of the LMNA gene and its flanking sequence followed by sequencing.Results The patient presented with scleroderma-like tight skin on the trunk,hair loss and prominent scalp veins for 9 months,whose body height and weight were two standard deviations below the mean.Physical examination showed thin skin and prominent superficial veins over the scalp.The skin over the trunk was tight,hard,shiny and dry with a small number of tiny scales,mottled pigmentation and hypopigmentation,induration and hypertrophy giving a cobblestone-like appearance.The subcutaneous fat was diminished on the lower limbs.Skeletal X-ray examination of the left hand revealed phalangeal acroosteolysis.A known heterozygous mutation c.1824C > T (dbSNP:rs58596362

  8. Genetics Home Reference: Werner syndrome

    Science.gov (United States)

    ... for This Condition Adult premature aging syndrome Adult Progeria Werner's Syndrome Werners Syndrome WS Related Information How ... BK, Monnat RJ Jr. Werner and Hutchinson-Gilford progeria syndromes: mechanistic basis of human progeroid diseases. Nat ...

  9. Proliferation of progeria cells is enhanced by lamina-associated polypeptide 2α (LAP2α) through expression of extracellular matrix proteins.

    Science.gov (United States)

    Vidak, Sandra; Kubben, Nard; Dechat, Thomas; Foisner, Roland

    2015-10-01

    Lamina-associated polypeptide 2α (LAP2α) localizes throughout the nucleoplasm and interacts with the fraction of lamins A/C that is not associated with the peripheral nuclear lamina. The LAP2α-lamin A/C complex negatively affects cell proliferation. Lamins A/C are encoded by LMNA, a single heterozygous mutation of which causes Hutchinson-Gilford progeria syndrome (HGPS). This mutation generates the lamin A variant progerin, which we show here leads to loss of LAP2α and nucleoplasmic lamins A/C, impaired proliferation, and down-regulation of extracellular matrix components. Surprisingly, contrary to wild-type cells, ectopic expression of LAP2α in cells expressing progerin restores proliferation and extracellular matrix expression but not the levels of nucleoplasmic lamins A/C. We conclude that, in addition to its cell cycle-inhibiting function with lamins A/C, LAP2α can also regulate extracellular matrix components independently of lamins A/C, which may help explain the proliferation-promoting function of LAP2α in cells expressing progerin.

  10. Enhanced SRSF5 Protein Expression Reinforces Lamin A mRNA Production in HeLa Cells and Fibroblasts of Progeria Patients.

    Science.gov (United States)

    Vautrot, Valentin; Aigueperse, Christelle; Oillo-Blanloeil, Florence; Hupont, Sébastien; Stevenin, James; Branlant, Christiane; Behm-Ansmant, Isabelle

    2016-03-01

    The Hutchinson Gilford Progeria Syndrome (HGPS) is a rare genetic disease leading to accelerated aging. Three mutations of the LMNA gene leading to HGPS were identified. The more frequent ones, c.1824C>T and c.1822G>A, enhance the use of the intron 11 progerin 5'splice site (5'SS) instead of the LMNA 5'SS, leading to the production of the truncated dominant negative progerin. The less frequent c.1868C>G mutation creates a novel 5'SS (LAΔ35 5'SS), inducing the production of another truncated LMNA protein (LAΔ35). Our data show that the progerin 5'SS is used at low yield in the absence of HGPS mutation, whereas utilization of the LAΔ35 5'SS is dependent upon the presence of the c.1868C>G mutation. In the perspective to correct HGPS splicing defects, we investigated whether SR proteins can modify the relative yields of utilization of intron 11 5'SSs. By in cellulo and in vitro assays, we identified SRSF5 as a direct key regulator increasing the utilization of the LMNA 5'SS in the presence of the HGPS mutations. Enhanced SRSF5 expression in dermal fibroblasts of HGPS patients as well as PDGF-BB stimulation of these cells decreased the utilization of the progerin 5'SS, and improves nuclear morphology, opening new therapeutic perspectives for premature aging.

  11. Coronary artery disease in a Werner syndrome-like form of progeria characterized by low levels of progerin, a splice variant of lamin A.

    Science.gov (United States)

    Hisama, Fuki M; Lessel, Davor; Leistritz, Dru; Friedrich, Katrin; McBride, Kim L; Pastore, Matthew T; Gottesman, Gary S; Saha, Bidisha; Martin, George M; Kubisch, Christian; Oshima, Junko

    2011-12-01

    Classical Hutchinson-Gilford progeria syndrome (HGPS) is caused by LMNA mutations that generate an alternatively spliced form of lamin A, termed progerin. HGPS patients present in early childhood with atherosclerosis and striking features of accelerated aging. We report on two pedigrees of adult-onset coronary artery disease with progeroid features, who were referred to our International Registry of Werner Syndrome (WS) because of clinical features consistent with the diagnosis. No mutations were identified in the WRN gene that is responsible for WS, among these patients. Instead, we found two novel heterozygous mutations at the junction of exon 10 and intron 11 of the LMNA gene. These mutations resulted in the production of progerin at a level substantially lower than that of HGPS. Our findings indicate that LMNA mutations may result in coronary artery disease presenting in the fourth to sixth decades along with short stature and a progeroid appearance resembling WS. The absence of early-onset cataracts in this setting should suggest the diagnosis of progeroid laminopathy. This study illustrates the evolving genotype-phenotype relationship between the amount of progerin produced and the age of onset among the spectrum of restrictive dermopathy, HGPS, and atypical forms of WS.

  12. The accumulation of un-repairable DNA damage in laminopathy progeria fibroblasts is caused by ROS generation and is prevented by treatment with N-acetyl cysteine.

    Science.gov (United States)

    Richards, Shane A; Muter, Joanne; Ritchie, Pamela; Lattanzi, Giovanna; Hutchison, Christopher J

    2011-10-15

    Fibroblasts from patients with the severe laminopathy diseases, restrictive dermopathy (RD) and Hutchinson Gilford progeria syndrome (HGPS), are characterized by poor growth in culture, the presence of abnormally shaped nuclei and the accumulation of DNA double-strand breaks (DSB). Here we show that the accumulation of DSB and poor growth of the fibroblasts but not the presence of abnormally shaped nuclei are caused by elevated levels of reactive oxygen species (ROS) and greater sensitivity to oxidative stress. Basal levels of ROS and sensitivity to H(2)O(2) were compared in fibroblasts from normal, RD and HGPS individuals using fluorescence activated cell sorting-based assays. Basal levels of ROS and stimulated levels of ROS were both 5-fold higher in the progeria fibroblasts. Elevated levels of ROS were correlated with lower proliferation indices but not with the presence of abnormally shaped nuclei. DSB induced by etoposide were repaired efficiently in normal, RD and HGPS fibroblasts. In contrast, DSB induced by ROS were repaired efficiently in normal fibroblasts, but in RD and HGPS fibroblasts many ROS-induced DSB were un-repairable. The accumulation of ROS-induced DSB appeared to cause the poor growth of RD and HGPS fibroblasts, since culture in the presence of the ROS scavenger N-acetyl cysteine (NAC) reduced the basal levels of DSB, eliminated un-repairable ROS-induced DSB and greatly improved population-doubling times. Our findings suggest that un-repaired ROS-induced DSB contribute significantly to the RD and HGPS phenotypes and that inclusion of NAC in a combinatorial therapy might prove beneficial to HGPS patients.

  13. Accumulation of prelamin A compromises NF-κB-regulated B-lymphopoiesis in a progeria mouse model

    Science.gov (United States)

    2013-01-01

    Background Alteration in the immune system is one of the most profound aspects of aging. Progressive changes in the number of B lymphocyte progenitors during aging have been reported but the underlying mechanisms are still elusive. A heterozygous G608G mutation in the LMNA gene leads to a deletion of 50 amino acids in lamin A protein, termed progerin, and is the predominant cause of Hutchinson-Gilford progeria syndrome (HGPS). Lack of Zmpste24, a metalloproteinase responsible for prelamin A processing, leads to progeroid features resembling HGPS. Therefore Zmpste24-deficient mice provide an ideal mouse model to study the impact of lamin A and (premature) aging on the aging-related decline of B lymphopoiesis. Results Analysis of bone marrow (BM) nucleated cells revealed a decline of early B cell progenitors in Zmpste24−/− mice. BM transplantation in a congenic strain completely rescued the defects in B lymphopoiesis, indicating that the decline in B cell progenitors in Zmpste24−/− mice is attributable to defective BM microenvironments rather than to cell-intrinsic defects. Further investigation revealed downregulation of a set of important early B lymphopoiesis factors in Zmpste24−/− bone marrow stromal cells (BMSCs), such as Vcam-1, SDF-1α, Flt3L and TSLP, and most of them are under transcriptional control of NF-κB signaling. Though TNFα stimulates IκBα degradation and NF-κB nuclear translocation in Zmpste24−/− BMSCs, NF-κB fails to stimulate IκBα re-expression, which mediates a negative feedback loop of NF-κB signaling in wild-type BMSCs. Conclusions Our data demonstrate a cell-extrinsic defect of B cell development in a progeroid mouse model and a critical role for lamin A in the regulation of NF-κB signaling and cytokines that are essential for lymphopoiesis. PMID:24764515

  14. Progeria 101/FAQ

    Science.gov (United States)

    ... Progeria, but also may shed light on the phenomenon of aging and cardiovascular disease.” v “Recurrent de ... Statistics Is Progeria passed down from parent to child? HGPS is not usually passed down in families. ...

  15. Physical Therapy and Occupational Therapy in Progeria

    Science.gov (United States)

    Physical Therapy and Occupational Therapy in Progeria Information for Families and Caretakers from The Progeria Research Foundation Written ... accelerated aging in children. Children with Progeria need Physical Therapy (PT) and Occupational Therapy (OT) as often as ...

  16. Labor Market Progeria.

    Science.gov (United States)

    Rodeheaver, Dean

    1990-01-01

    Social ambivalence toward women's roles, sexuality, appearance, and aging combine with social standards of attractiveness to create both age and sex discrimination in the workplace. The life expectancy of presentability is shorter among women than men, thus creating an accelerated aging process termed labor market progeria. (SK)

  17. Progeria 101/FAQ

    Science.gov (United States)

    ... Statistics Is Progeria passed down from parent to child? HGPS is not usually passed down in families. The gene change is almost always a chance occurrence that is extremely rare. Children with other types of “progeroid” syndromes which are not HGPS may have diseases that ...

  18. Mechanisms of cardiovascular disease in accelerated aging syndromes.

    Science.gov (United States)

    Capell, Brian C; Collins, Francis S; Nabel, Elizabeth G

    2007-07-06

    In the past several years, remarkable progress has been made in the understanding of the mechanisms of premature aging. These rare, genetic conditions offer valuable insights into the normal aging process and the complex biology of cardiovascular disease. Many of these advances have been made in the most dramatic of these disorders, Hutchinson-Gilford progeria syndrome. Although characterized by features of normal aging such as alopecia, skin wrinkling, and osteoporosis, patients with Hutchinson-Gilford progeria syndrome are affected by accelerated, premature arteriosclerotic disease that leads to heart attacks and strokes at a mean age of 13 years. In this review, we highlight recent advances in the biology of premature aging uncovered in Hutchinson-Gilford progeria syndrome and other accelerated aging syndromes, advances that provide insight into the mechanisms of cardiovascular diseases ranging from atherosclerosis to arrhythmias.

  19. Reprogramming aging and progeria.

    Science.gov (United States)

    Freije, José M P; López-Otín, Carlos

    2012-12-01

    The aging rate of an organism depends on the ratio of tissue degeneration to tissue repair. As a consequence, molecular alterations that tip this balance toward degeneration cause accelerated aging. Conversely, interventions can be pursued to reduce tissue degeneration or to increase tissue repair with the aim of delaying the onset of age-associated manifestations. Recent studies on the biology of stem cells in aging have revealed the influence of systemic factors on their functionality and demonstrated the feasibility of reprogramming aged and progeroid cells. These results illustrate the reversibility of some aspects of the aging process and encourage the search for new anti-aging and anti-progeria interventions.

  20. Progeria syndrome: A case report

    Directory of Open Access Journals (Sweden)

    Rastogi Rajul

    2008-01-01

    Full Text Available Progeria is a rare and peculiar combination of dwarfism and premature aging. The incidence is one in several million births. It occurs sporadically and is probably an autosomal recessive syndrome. Though the clinical presentation is usually typical, conventional radiological and biochemical investigations help in confirming the diagnosis. We present a rare case of progeria with most of the radiological features as a pictorial essay.

  1. Schizophrenia as segmental progeria

    Science.gov (United States)

    Papanastasiou, Evangelos; Gaughran, Fiona; Smith, Shubulade

    2011-01-01

    Schizophrenia is associated with a variety of physical manifestations (i.e. metabolic, neurological) and despite psychotropic medication being blamed for some of these (in particular obesity and diabetes), there is evidence that schizophrenia itself confers an increased risk of physical disease and early death. The observation that schizophrenia and progeroid syndromes share common clinical features and molecular profiles gives rise to the hypothesis that schizophrenia could be conceptualized as a whole body disorder, namely a segmental progeria. Mammalian cells employ the mechanisms of cellular senescence and apoptosis (programmed cell death) as a means to control inevitable DNA damage and cancer. Exacerbation of those processes is associated with accelerated ageing and schizophrenia and this warrants further investigation into possible underlying biological mechanisms, such as epigenetic control of the genome. PMID:22048679

  2. Dangerous Entrapment for NRF2.

    Science.gov (United States)

    Gorbunova, Vera; Rezazadeh, Sarallah; Seluanov, Andrei

    2016-06-02

    Progerin, a mutated lamin A, causes the severe premature-aging syndrome Hutchinson-Gilford progeria (HGPS). Kubben et al. present a driving mechanism for HGPS involving trapping of NRF2 at the nuclear periphery by progerin. This local restriction results in impaired NRF2 signaling and chronic oxidative stress.

  3. Experiment list: SRX200051 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available 98.0,3.9,1297 GSM1023625: LaminA ChIP, HGPS, p16, INPUT, rep1; Homo sapiens; ChIP-Seq source_name=patient forearm skin biopsy..., input || disease status=Hutchinson-Gilford progeria syndrome || tissue=forearm skin biopsy

  4. Experiment list: SRX200043 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available 97.1,7.0,1190 GSM1023617: H3K27me3 ChIP, HGPS, p14, INPUT; Homo sapiens; ChIP-Seq source_name=patient forearm skin biopsy..., input || disease status=Hutchinson-Gilford progeria syndrome || tissue=forearm skin biopsy ||

  5. Experiment list: SRX200052 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available 4 GSM1023626: LaminA ChIP, HGPS, p16, rep2; Homo sapiens; ChIP-Seq source_name=patient forearm skin biopsy, ...lamin ChIP || disease status=Hutchinson-Gilford progeria syndrome || tissue=forearm skin biopsy || cell type

  6. Experiment list: SRX200045 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available 97.6,4.5,1339 GSM1023619: H3K27me3 ChIP, HGPS, p17, INPUT; Homo sapiens; ChIP-Seq source_name=patient forearm skin biopsy..., input || disease status=Hutchinson-Gilford progeria syndrome || tissue=forearm skin biopsy ||

  7. Experiment list: SRX200044 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available M1023618: H3K27me3 ChIP, HGPS, p17; Homo sapiens; ChIP-Seq source_name=patient forearm skin biopsy, H3K27me3... ChIP || disease status=Hutchinson-Gilford progeria syndrome || tissue=forearm skin biopsy || cell type=fibr

  8. Experiment list: SRX200042 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available 1023616: H3K27me3 ChIP, HGPS, p14; Homo sapiens; ChIP-Seq source_name=patient forearm skin biopsy, H3K27me3 ...ChIP || disease status=Hutchinson-Gilford progeria syndrome || tissue=forearm skin biopsy || cell type=fibro

  9. Experiment list: SRX200050 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available GSM1023624: LaminA ChIP, HGPS, p16, rep1; Homo sapiens; ChIP-Seq source_name=patient forearm skin biopsy, l...amin ChIP || disease status=Hutchinson-Gilford progeria syndrome || tissue=forearm skin biopsy || cell type=

  10. Experiment list: SRX200053 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available 97.8,3.9,968 GSM1023627: LaminA ChIP, HGPS, p16, INPUT, rep2; Homo sapiens; ChIP-Seq source_name=patient forearm skin biopsy..., input || disease status=Hutchinson-Gilford progeria syndrome || tissue=forearm skin biopsy

  11. Progeria, rapamycin and normal aging: recent breakthrough

    Science.gov (United States)

    Blagosklonny, Mikhail V.

    2011-01-01

    A recent discovery that rapamycin suppresses a pro-senescent phenotype in progeric cells not only suggests a non-toxic therapy for progeria but also implies its similarity with normal aging. For one, rapamycin is also known to suppress aging of regular human cells. Here I discuss four potential scenarios, comparing progeria with both normal and accelerated aging. This reveals further indications of rapamycin both for accelerated aging in obese and for progeria. PMID:21743107

  12. Progeria, rapamycin and normal aging: recent breakthrough

    OpenAIRE

    Blagosklonny, Mikhail V.

    2011-01-01

    A recent discovery that rapamycin suppresses a pro-senescent phenotype in progeric cells not only suggests a non-toxic therapy for progeria but also implies its similarity with normal aging. For one, rapamycin is also known to suppress aging of regular human cells. Here I discuss four potential scenarios, comparing progeria with both normal and accelerated aging. This reveals further indications of rapamycin both for accelerated aging in obese and for progeria.

  13. Progeria, rapamycin and normal aging: recent breakthrough.

    Science.gov (United States)

    Blagosklonny, Mikhail V

    2011-07-01

    A recent discovery that rapamycin suppresses a pro-senescent phenotype in progeric cells not only suggests a non-toxic therapy for progeria but also implies its similarity with normal aging. For one, rapamycin is also known to suppress aging of regular human cells. Here I discuss four potential scenarios, comparing progeria with both normal and accelerated aging. This reveals further indications of rapamycin both for accelerated aging in obese and for progeria.

  14. Progeria: A rare genetic premature ageing disorder

    OpenAIRE

    Jitendra Kumar Sinha; Shampa Ghosh; Manchala Raghunath

    2014-01-01

    Progeria is characterized by clinical features that mimic premature ageing. Although the mutation responsible for this syndrome has been deciphered, the mechanism of its action remains elusive. Progeria research has gained momentum particularly in the last two decades because of the possibility of revealing evidences about the ageing process in normal and other pathophysiological conditions. Various experimental models, both in vivo and in vitro, have been developed in an effort to understand...

  15. Progeria syndrome with cardiac complications.

    Science.gov (United States)

    Ilyas, Saadia; Ilyas, Hajira; Hameed, Abdul; Ilyas, Muhammad

    2013-09-01

    A case report of 6-year-old boy with progeria syndrome, with marked cardiac complications is presented. The boy had cardiorespiratory failure. Discoloured purpuric skin patches, alopecia, prominent forehead, protuberant eyes, flattened nasal cartilage, malformed mandible, hypodentition, and deformed rigid fingers and toes were observed on examination. The boy was unable to speak. A sclerotic systolic murmur was audible over the mitral and aortic areas. Chest x-rays showed cardiac enlargement and the electrocardiogram (ECG) showed giant peaked P waves (right atrial hypertrophy) and right ventricular hypertrophy. Atherosclerotic dilated ascending aorta, thickened sclerotic aortic, mitral, and tricuspid valves with increased echo texture, left and right atrial and right ventricular dilatation, reduced left ventricular cavity, and thickened speckled atrial and ventricular septa were observed on echocardiography.

  16. Immortalization of Werner syndrome and progeria fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Saito, H.; Moses, R.E. (Baylor College of Medicine, Houston, TX (USA))

    1991-02-01

    Human fibroblast cells from two different progeroid syndromes, Werner syndrome (WS) and progeria, were established as immortalized cell lines by transfection with plasmid DNA containing the SV40 early region. The lineage of each immortalized cell line was confirmed by VNTR analysis. Each of the immortalized cell lines maintained its original phenotype of slow growth. DNA repair ability of these cells was also studied by measuring sensitivity to killing by uv or the DNA-damaging drugs methyl methansulfonate, bleomycin, and cis-dichlorodiamine platinum. The results showed that both WS and progeria cells have normal sensitivity to these agents.

  17. Mandibulo-acral dysplasia

    Energy Technology Data Exchange (ETDEWEB)

    Hoeffel, J.C.; Mainard, L. [Dept. of Radiology, Children' s Hospital, Vandoeuvre (France); Chastagner, P. [Dept. of Medicine, Children' s Hospital, Vandoeuvre (France); Hoeffel, C.C. [UFR Faculte de Medecine Cochin, Paris (France)

    2000-11-01

    We report on a 7 year-old-girl with mandibulo-acral dysplasia. When she was 3 years of age it mimicked scleroderma because of skin atrophy and later on a Hutchinson-Gilford progeria syndrome (HGP). Acro-mandibular dysplasia was diagnosed because of facial hypoplasia and mandibular hypoplasia. The bilateral proximal mid-humeral notch seen in this case is unusual. (orig.)

  18. The curious case of ageing

    OpenAIRE

    Dilip Gude; Aslam Abbas; MAW Zubair

    2013-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare hereditary disease characterized by multisystem involvement. Although the patients may sport normal intelligence, the disease takes a considerable toll both physically and psychologically resulting in a debilitating state. It may also be compounded by catastrophic/fatal events of accelerated atherosclerosis such as stroke and myocardial infarction. We discuss our experience with HGPS and review the literature.

  19. The curious case of ageing

    Directory of Open Access Journals (Sweden)

    Dilip Gude

    2013-01-01

    Full Text Available Hutchinson-Gilford progeria syndrome (HGPS is an extremely rare hereditary disease characterized by multisystem involvement. Although the patients may sport normal intelligence, the disease takes a considerable toll both physically and psychologically resulting in a debilitating state. It may also be compounded by catastrophic/fatal events of accelerated atherosclerosis such as stroke and myocardial infarction. We discuss our experience with HGPS and review the literature.

  20. Progeria: a paradigm for translational medicine.

    Science.gov (United States)

    Gordon, Leslie B; Rothman, Frank G; López-Otín, Carlos; Misteli, Tom

    2014-01-30

    Rare diseases are powerful windows into biological processes and can serve as models for the development of therapeutic strategies. The progress made on the premature aging disorder Progeria is a shining example of the impact that studies of rare diseases can have. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Neonatal progeria: increased ratio of progerin to lamin A leads to progeria of the newborn

    Science.gov (United States)

    Reunert, Janine; Wentzell, Rüdiger; Walter, Michael; Jakubiczka, Sibylle; Zenker, Martin; Brune, Thomas; Rust, Stephan; Marquardt, Thorsten

    2012-01-01

    Hutchinson–Gilford progeria syndrome (HGPS) is an important model disease for premature ageing. Affected children appear healthy at birth, but develop the first symptoms during their first year of life. They die at an average age of 13 years, mostly because of myocardial infarction or stroke. Classical progeria is caused by the heterozygous point mutation c.1824C>T in the LMNA gene, which activates a cryptic splice site. The affected protein cannot be processed correctly to mature lamin A, but is modified into a farnesylated protein truncated by 50 amino acids (progerin). Three more variations in LMNA result in the same mutant protein, but different grades of disease severity. We describe a patient with the heterozygous LMNA mutation c.1821G>A, leading to neonatal progeria with death in the first year of life. Intracellular lamin A was downregulated in the patient's fibroblasts and the ratio of progerin to lamin A was increased when compared with HGPS. It is suggestive that the ratio of farnesylated protein to mature lamin A determines the disease severity in progeria. PMID:22419169

  2. Decreased repair of gamma damaged DNA in progeria

    Energy Technology Data Exchange (ETDEWEB)

    Rainbow, A.J.; Howes, M.

    1977-01-01

    A sensitive host-cell reactivation technique was used to examine the DNA repair ability of fibroblasts from two patients with classical progeria. Fibroblasts were infected with either non-irradiated or gamma-irradiated adenovirus type 2 and at 48 hrs after infection cells were examined for the presence of viral structural antigens using immunofluorescent staining. The production of viral structural antigens was considerably reduced in the progeria lines as compared to normal fibroblasts when gamma-irradiated virus was used, indicating a defect in the repair of gamma ray damaged DNA in the progeria cells.

  3. Recherche des mécanismes impliqués dans les dérégulations de l'épissage alternatif à l'origine de la progéria et étude du rôle de l'étape d'épissage dans les changements globaux d'expression des gènes en réaction au choc thermique

    OpenAIRE

    Vautrot, Valentin

    2013-01-01

    The Hutchinson-Gilford syndrome, also called progeria, is a rare genetic disease, characterized by symptoms that can be assimilated to accelerated natural ageing. Mutations that cause progeria affect the LMNA gene, which codes the lamin A that plays a major role in the shaping, maintenance and resistance of the nucleus. These mutations lead to the activation of alternative or cryptic 5' splice sites located within the exon 11 of LMNA pre-mRNA upstream from the normal 5' splice site. Our work ...

  4. Stem cell aging in adult progeria

    Directory of Open Access Journals (Sweden)

    Hoi-Hung Cheung

    2015-01-01

    Full Text Available Aging is considered an irreversible biological process and also a major risk factor for a spectrum of geriatric diseases. Advanced age-related decline in physiological functions, such as neurodegeneration, development of cardiovascular disease, endocrine and metabolic dysfunction, and neoplastic transformation, has become the focus in aging research. Natural aging is not regarded as a programmed process. However, accelerated aging due to inherited genetic defects in patients of progeria is programmed and resembles many aspects of natural aging. Among several premature aging syndromes, Werner syndrome (WS and Hutchinson–Gilford progeria syndrome (HGPS are two broadly investigated diseases. In this review, we discuss how stem cell aging in WS helps us understand the biology of aging. We also discuss briefly how the altered epigenetic landscape in aged cells can be reversed to a “juvenile” state. Lastly, we explore the potential application of the latest genomic editing technique for stem cell-based therapy and regenerative medicine in the context of aging.

  5. 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.

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

    Science.gov (United States)

    Raghu, T Y; Venkatesulu, G A; Kantharaj, G R; Suresh, T; Veeresh, V; Hanumanthappa, Y

    2001-01-01

    Progeria is an autosomal dominant, premature aging syndrome. Six and three year old female siblings had sclerodermatous 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.

  7. Skeletal abnormalities of acrogeria, a progeroid syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Ho, A.; White, S.J.; Rasmussen, J.E.

    1987-08-01

    We report the skeletal abnormalities in a 4 1/2-year-old boy with acrogeria, a progeroid syndrome of premature aging of the skin without the involvement of internal organs seen in Hutchinson-Gilford progeria syndrome. Acro-osteolysis of the distal phalanges, delayed cranial suture closure with wormian bones, linear lucent defects of the metaphyses, and antegonial notching of the mandible are the predominant skeletal features of the disorder. The skeletal features described in 21 other reported cases of acrogeria are summarized.

  8. Altered Nuclear Functions in Progeroid Syndromes: a Paradigm for Aging Research

    Directory of Open Access Journals (Sweden)

    Baomin Li

    2009-01-01

    Full Text Available Syndromes of accelerated aging could provide an entry point for identifying and dissecting the cellular pathways that are involved in the development of age-related pathologies in the general population. However, their usefulness for aging research has been controversial, as it has been argued that these diseases do not faithfully reflect the process of natural aging. Here we review recent findings on the molecular basis of two progeroid diseases, Werner syndrome (WS and Hutchinson-Gilford progeria syndrome (HGPS, and highlight functional connections to cellular processes that may contribute to normal aging.

  9. Cell aging caused by prelamin A mutation%突变前核纤层蛋白A对细胞衰老的作用

    Institute of Scientific and Technical Information of China (English)

    王君文; 刘新光; 周中军

    2008-01-01

    早老症(Hutchinson-Gilford progeria syndrome,HGPS)是一种极其罕见的遗传性疾病,它是由LMNA基因突变引起的,产生一个截短的lamin A 蛋白称为 progerin.核纤层蛋白异常A加工积累的 progerin 能够破坏核纤层的支架功能,替代正常蛋白质与其配体结合,导致细胞核畸形和早老表型.

  10. Investigation of age-related changes in LMNA splicing and expression of progerin in human skeletal muscles

    OpenAIRE

    Luo, Yue-Bei; Mitrpant, Chalermchai; Johnsen, Russell D; Fabian, Victoria A; Fletcher, Sue; Mastaglia, Frank L.; Steve D Wilton

    2013-01-01

    Age-related changes in splice-forms of LMNA, which encodes the nuclear lamina proteins lamin A/C, have not been investigated in skeletal muscle. In the rare premature ageing disease, Hutchinson-Gilford progeria syndrome (HGPS), de novo point mutations in LMNA activate a cryptic splice site in exon 11, resulting in a 150 base deletion in LMNA mRNA and accumulation of a truncated protein isoform, progerin. The LMNA Δ150 progerin transcript has also been found in trace quantities in tissues of h...

  11. Altered nuclear functions in progeroid syndromes: a paradigm for aging research.

    Science.gov (United States)

    Li, Baomin; Jog, Sonali; Candelario, Jose; Reddy, Sita; Comai, Lucio

    2009-12-16

    Syndromes of accelerated aging could provide an entry point for identifying and dissecting the cellular pathways that are involved in the development of age-related pathologies in the general population. However, their usefulness for aging research has been controversial, as it has been argued that these diseases do not faithfully reflect the process of natural aging. Here we review recent findings on the molecular basis of two progeroid diseases, Werner syndrome (WS) and Hutchinson-Gilford progeria syndrome (HGPS), and highlight functional connections to cellular processes that may contribute to normal aging.

  12. Premature aging syndrome.

    Science.gov (United States)

    Coppedè, Fabio

    2012-01-01

    Hutchinson-Gilford progeria syndrome and Werner syndrome are two of the best characterized human progeroid diseases with clinical features mimicking physiological aging at an early age. Both disorders have been the focus of intense research in recent years since they might provide insights into the pathology of normal human aging. The chapter contains a detailed description of the clinical features of both disorders and then it focuses on the genetics, the resulting biochemical alterations at the protein level and the most recent findings and hypotheses concerning the molecular basis of the premature aging phenotypes. A description of available diagnostic and therapeutic approaches is included.

  13. A case of progeria syndrome treated as VIP patient

    Directory of Open Access Journals (Sweden)

    Seema Mahant, Mahant PD, C.M. Reddy

    2014-11-01

    Full Text Available Progeria is rare autosomal recessive genetic disease with an incidence of about one in eight million. He was 16 years old boy lying on the couch. He was short stature thin with minimal subcutaneous tissue, skin was thin and fragile with loss of hair over scalp, eyebrows and eyelashes, and his face was dismorphic with prominent eyes, beaked nose, small jaw and large cranium with visible veins over it. His voice was thin and high pitched. Overall, this gives them an extremely aged nearly 70 -80 years old man look. The patient was a known case of progeria syndrome and he was treated as a VIP patient by all faculty members and staff, though he belongs low socioeconomic status, no political issue with them. But still he was a VIP.

  14. Biomechanical Strain Exacerbates Inflammation on a Progeria-on-a-Chip Model

    NARCIS (Netherlands)

    Ribas, J.; Zhang, Y.S.; Pitrez, P.R.; Leijten, Jeroen Christianus Hermanus; Miscuglio, M.; Rouwkema, Jeroen; Dokmeci, M.R.; Nissan, X.; Ferreira, L.; Khademhosseini, A.

    2017-01-01

    A progeria-on-a-chip model is engineered to recapitulate the biomechanical dynamics of vascular disease and aging. The model shows an exacerbated injury response to strain and is rescued by pharmacological treatments. The progeria-on-a-chip is expected to drive the discovery of new drugs and to eluc

  15. Biomechanical Strain Exacerbates Inflammation on a Progeria-on-a-Chip Model

    NARCIS (Netherlands)

    Ribas, J.; Zhang, Y.S.; Pitrez, P.R.; Leijten, J.C.H.; Miscuglio, M.; Rouwkema, J.; Dokmeci, M.R.; Nissan, X.; Ferreira, L.; Khademhosseini, A.

    2017-01-01

    A progeria-on-a-chip model is engineered to recapitulate the biomechanical dynamics of vascular disease and aging. The model shows an exacerbated injury response to strain and is rescued by pharmacological treatments. The progeria-on-a-chip is expected to drive the discovery of new drugs and to eluc

  16. Low and high expressing alleles of the LMNA gene: implications for laminopathy disease development.

    Directory of Open Access Journals (Sweden)

    Sofía Rodríguez

    Full Text Available Today, there are at least a dozen different genetic disorders caused by mutations within the LMNA gene, and collectively, they are named laminopathies. Interestingly, the same mutation can cause phenotypes with different severities or even different disorders and might, in some cases, be asymptomatic. We hypothesized that one possible contributing mechanism for this phenotypic variability could be the existence of high and low expressing alleles in the LMNA locus. To investigate this hypothesis, we developed an allele-specific absolute quantification method for lamin A and lamin C transcripts using the polymorphic rs4641(C/TLMNA coding SNP. The contribution of each allele to the total transcript level was investigated in nine informative human primary dermal fibroblast cultures from Hutchinson-Gilford progeria syndrome (HGPS and unaffected controls. Our results show differential expression of the two alleles. The C allele is more frequently expressed and accounts for ∼70% of the lamin A and lamin C transcripts. Analysis of samples from six patients with Hutchinson-Gilford progeria syndrome showed that the c.1824C>T, p.G608G mutation is located in both the C and the T allele, which might account for the variability in phenotype seen among HGPS patients. Our method should be useful for further studies of human samples with mutations in the LMNA gene and to increase the understanding of the link between genotype and phenotype in laminopathies.

  17. Differential expression of A-type and B-type lamins during hair cycling.

    Directory of Open Access Journals (Sweden)

    Mubashir Hanif

    Full Text Available Multiple genetic disorders caused by mutations that affect the proteins lamin A and C show strong skin phenotypes. These disorders include the premature aging disorders Hutchinson-Gilford progeria syndrome and mandibuloacral dysplasia, as well as restrictive dermopathy. Prior studies have shown that the lamin A/C and B proteins are expressed in skin, but little is known about their normal expression in the different skin cell-types and during the hair cycle. Our immunohistochemical staining for lamins A/C and B in wild-type mice revealed strong expression in the basal cell layer of the epidermis, the outer root sheath, and the dermal papilla during all stages of the hair cycle. Lower expression of both lamins A/C and B was seen in suprabasal cells of the epidermis, in the hypodermis, and in the bulb of catagen follicles. In addition, we have utilized a previously described mouse model of Hutchinson-Gilford progeria syndrome and show here that the expression of progerin does not result in pronounced effects on hair cycling or the expression of lamin B.

  18. Hutchinson – Gilford progeria syndrome: A rare case report

    Science.gov (United States)

    Kashyap, Subhash; Shanker, Vinay; Sharma, Neeraj

    2014-01-01

    Hutchinson – Gilford Progeria Syndrome is a rare genetic disorder characterized by premature aging involving the skin, bones, heart, and blood vessels. We report a three-year-old boy with clinical manifestations characteristic of this syndrome. He had a characteristic “plucked-bird” appearance, prominent eyes and scalp veins, senile look, loss of scalp hair, eyebrows, and eyelashes, stunted growth, and mottled pigmentation with sclerodermatous changes over the trunk and lower limbs. Radiological changes and decreased high-density lipoprotein (HDL) levels were also characteristic of the syndrome. This interesting case is reported for its rarity. PMID:25396134

  19. Adaptive stress response in segmental progeria resembles long-lived dwarfism and calorie restriction in mice

    NARCIS (Netherlands)

    H.W.M. van de Ven (Marieke); J.-O. Andressoo (Jaan-Olle); V.B. Holcomb (Valerie); M.M. von Lindern (Marieke); W.M.C. Jong (Willeke); C.I. de Zeeuw (Chris); Y. Suh (Yousin); P. Hasty (Paul); J.H.J. Hoeijmakers (Jan); G.T.J. van der Horst (Gijsbertus); J.R. Mitchell (James)

    2006-01-01

    textabstractHow congenital defects causing genome instability can result in the pleiotropic symptoms reminiscent of aging but in a segmental and accelerated fashion remains largely unknown. Most segmental progerias are associated with accelerated fibroblast senescence, suggesting that cellular senes

  20. Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson–Gilford progeria syndrome

    National Research Council Canada - National Science Library

    Leslie B. Gordon; Monica E. Kleinman; David T. Miller; Donna S. Neuberg; Anita Giobbie-Hurder; Marie Gerhard-Herman; Leslie B. Smoot; Catherine M. Gordon; Robert Cleveland; Brian D. Snyder; Brian Fligor; W. Robert Bishop; Paul Statkevich; Amy Regen; Andrew Sonis; Susan Riley; Christine Ploski; Annette Correia; Nicolle Quinn; Nicole J. Ullrich; Ara Nazarian; Marilyn G. Liang; Susanna Y. Huh; Armin Schwartzman; Mark W. Kieran

    2012-01-01

    Hutchinson–Gilford progeria syndrome (HGPS) is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA that produces the farnesylated aberrant lamin A protein, progerin...

  1. Adaptive stress response in segmental progeria resembles long-lived dwarfism and calorie restriction in mice

    NARCIS (Netherlands)

    H.W.M. van de Ven (Marieke); J.-O. Andressoo (Jaan-Olle); V.B. Holcomb (Valerie); M.M. von Lindern (Marieke); W.M.C. Jong (Willeke); C.I. de Zeeuw (Chris); Y. Suh (Yousin); P. Hasty (Paul); J.H.J. Hoeijmakers (Jan); G.T.J. van der Horst (Gijsbertus); J.R. Mitchell (James)

    2006-01-01

    textabstractHow congenital defects causing genome instability can result in the pleiotropic symptoms reminiscent of aging but in a segmental and accelerated fashion remains largely unknown. Most segmental progerias are associated with accelerated fibroblast senescence, suggesting that cellular senes

  2. Adaptive stress response in segmental progeria resembles long-lived dwarfism and calorie restriction in mice

    NARCIS (Netherlands)

    H.W.M. van de Ven (Marieke); J.-O. Andressoo (Jaan-Olle); V.B. Holcomb (Valerie); M.M. von Lindern (Marieke); W.M.C. Jong (Willeke); C.I. de Zeeuw (Chris); Y. Suh (Yousin); P. Hasty (Paul); J.H.J. Hoeijmakers (Jan); G.T.J. van der Horst (Gijsbertus); J.R. Mitchell (James)

    2006-01-01

    textabstractHow congenital defects causing genome instability can result in the pleiotropic symptoms reminiscent of aging but in a segmental and accelerated fashion remains largely unknown. Most segmental progerias are associated with accelerated fibroblast senescence, suggesting that cellular

  3. In silico analysis of Progeria: A genetic disease and natural cardiovascular disorders preventive compounds

    OpenAIRE

    Shraddha Mulange; Satish Kulkarni; Vaishali Wadekar; L H Kamble

    2016-01-01

    Progeria (also known as "Hutchinson–Gilford progeria syndrome"(HGPS) is an extremely rare, severe, genetic condition wherein symptoms resembling aspects of aging are manifested at an early age. The basic objective of this study is how is it responsible for faster ageing than normal? The study of its bioinformatics aspect explaining where the mutation occurs in normal LMNA gene to form mutated Progerin. We explain its sequential and structural aspects in domain and motif. Structural visualizat...

  4. From old organisms to new molecules: integrative biology and therapeutic targets in accelerated human ageing.

    Science.gov (United States)

    Cox, L S; Faragher, R G A

    2007-10-01

    Understanding the basic biology of human ageing is a key milestone in attempting to ameliorate the deleterious consequences of old age. This is an urgent research priority given the global demographic shift towards an ageing population. Although some molecular pathways that have been proposed to contribute to ageing have been discovered using classical biochemistry and genetics, the complex, polygenic and stochastic nature of ageing is such that the process as a whole is not immediately amenable to biochemical analysis. Thus, attempts have been made to elucidate the causes of monogenic progeroid disorders that recapitulate some, if not all, features of normal ageing in the hope that this may contribute to our understanding of normal human ageing. Two canonical progeroid disorders are Werner's syndrome and Hutchinson-Gilford progeroid syndrome (also known as progeria). Because such disorders are essentially phenocopies of ageing, rather than ageing itself, advances made in understanding their pathogenesis must always be contextualised within theories proposed to help explain how the normal process operates. One such possible ageing mechanism is described by the cell senescence hypothesis of ageing. Here, we discuss this hypothesis and demonstrate that it provides a plausible explanation for many of the ageing phenotypes seen in Werner's syndrome and Hutchinson-Gilford progeriod syndrome. The recent exciting advances made in potential therapies for these two syndromes are also reviewed.

  5. Prelamin A causes progeria through cell-extrinsic mechanisms and prevents cancer invasion

    Science.gov (United States)

    de la Rosa, Jorge; Freije, José M. P.; Cabanillas, Rubén; Osorio, Fernando G.; Fraga, Mario F.; Fernández-García, M. Soledad; Rad, Roland; Fanjul, Víctor; Ugalde, Alejandro P.; Liang, Qi; Prosser, Haydn M.; Bradley, Allan; Cadiñanos, Juan; López-Otín, Carlos

    2013-01-01

    Defining the relationship between ageing and cancer is a crucial but challenging task. Mice deficient in Zmpste24, a metalloproteinase mutated in human progeria and involved in nuclear prelamin A maturation, recapitulate multiple features of ageing. However, their short lifespan and serious cell-intrinsic and cell-extrinsic alterations restrict the application and interpretation of carcinogenesis protocols. Here we present Zmpste24 mosaic mice that lack these limitations. Zmpste24 mosaic mice develop normally and keep similar proportions of Zmpste24-deficient (prelamin A accumulating) and Zmpste24-proficient (mature lamin A containing) cells throughout life, revealing that cell-extrinsic mechanisms are preeminent for progeria development. Moreover, prelamin A accumulation does not impair tumour initiation and growth, but it decreases the incidence of infiltrating oral carcinomas. Accordingly, silencing of ZMPSTE24 reduces human cancer cell invasiveness. Our results support the potential of cell-based and systemic therapies for progeria and highlight ZMPSTE24 as a new anticancer target. PMID:23917225

  6. Prelamin A causes progeria through cell-extrinsic mechanisms and prevents cancer invasion.

    Science.gov (United States)

    de la Rosa, Jorge; Freije, José M P; Cabanillas, Rubén; Osorio, Fernando G; Fraga, Mario F; Fernández-García, M Soledad; Rad, Roland; Fanjul, Víctor; Ugalde, Alejandro P; Liang, Qi; Prosser, Haydn M; Bradley, Allan; Cadiñanos, Juan; López-Otín, Carlos

    2013-01-01

    Defining the relationship between ageing and cancer is a crucial but challenging task. Mice deficient in Zmpste24, a metalloproteinase mutated in human progeria and involved in nuclear prelamin A maturation, recapitulate multiple features of ageing. However, their short lifespan and serious cell-intrinsic and cell-extrinsic alterations restrict the application and interpretation of carcinogenesis protocols. Here we present Zmpste24 mosaic mice that lack these limitations. Zmpste24 mosaic mice develop normally and keep similar proportions of Zmpste24-deficient (prelamin A-accumulating) and Zmpste24-proficient (mature lamin A-containing) cells throughout life, revealing that cell-extrinsic mechanisms are preeminent for progeria development. Moreover, prelamin A accumulation does not impair tumour initiation and growth, but it decreases the incidence of infiltrating oral carcinomas. Accordingly, silencing of ZMPSTE24 reduces human cancer cell invasiveness. Our results support the potential of cell-based and systemic therapies for progeria and highlight ZMPSTE24 as a new anticancer target.

  7. Leg ulcer in Werner syndrome (adult progeria): a case report.

    Science.gov (United States)

    Fumo, Giuseppe; Pau, Monica; Patta, Federico; Aste, Nicola; Atzori, Laura

    2013-03-15

    Werner syndrome (WS; MIM#277700) or adult progeria, is a rare disease, associated with mutations of a single gene (RECQL2 or WRN), located on chromosome 8 (8p12). It codes a DNA-helicase, whose defects cause genomic instability. The highest incidences are reported in Japan and Sardinia (Italy). On this major island of the Mediterranean Basin, the WS cases have been observed in the northern areas. The authors describe the apparently first case reported in southern Sardinia, a 51-year-old woman, who was born in and resides in the province of Cagliari. She presented with a 9-year history of an intractable leg ulcer and other characteristic symptoms, including "bird-like" face, high-pitched voice, premature greying, short stature, abdominal obesity in contrast with thin body type, scleroderma-like legs, decreased muscle mass, diabetes, atherosclerosis, and premature menopause. A specialized genetic Institute of Research (IRCCS-IDI, Rome) confirmed the clinical diagnosis. There is no cure or specific treatment and patients must be periodically screened for an increased risk of cardiovascular and cerebrovascular disease and malignancies. Among the many findings, leg ulcers significantly affect the patient's quality of life. This problem may send the patient to the dermatologist, who finally suspects the diagnosis. Poor response to medical treatment may require aggressive repeated surgery, with poor or temporary results.

  8. Sulforaphane enhances progerin clearance in Hutchinson–Gilford progeria fibroblasts

    Science.gov (United States)

    Gabriel, Diana; Roedl, Daniela; Gordon, Leslie B; Djabali, Karima

    2015-01-01

    Hutchinson–Gilford progeria syndrome (HGPS, OMIM 176670) is a rare multisystem childhood premature aging disorder linked to mutations in the LMNA gene. The most common HGPS mutation is found at position G608G within exon 11 of the LMNA gene. This mutation results in the deletion of 50 amino acids at the carboxyl-terminal tail of prelamin A, and the truncated protein is called progerin. Progerin only undergoes a subset of the normal post-translational modifications and remains permanently farnesylated. Several attempts to rescue the normal cellular phenotype with farnesyltransferase inhibitors (FTIs) and other compounds have resulted in partial cellular recovery. Using proteomics, we report here that progerin induces changes in the composition of the HGPS nuclear proteome, including alterations to several components of the protein degradation pathways. Consequently, proteasome activity and autophagy are impaired in HGPS cells. To restore protein clearance in HGPS cells, we treated HGPS cultures with sulforaphane (SFN), an antioxidant derived from cruciferous vegetables. We determined that SFN stimulates proteasome activity and autophagy in normal and HGPS fibroblast cultures. Specifically, SFN enhances progerin clearance by autophagy and reverses the phenotypic changes that are the hallmarks of HGPS. Therefore, SFN is a promising therapeutic avenue for children with HGPS. PMID:25510262

  9. Rescue of progeria in trichothiodystrophy by homozygous lethal Xpd alleles.

    Directory of Open Access Journals (Sweden)

    Jaan-Olle Andressoo

    2006-10-01

    Full Text Available Although compound heterozygosity, or the presence of two different mutant alleles of the same gene, is common in human recessive disease, its potential to impact disease outcome has not been well documented. This is most likely because of the inherent difficulty in distinguishing specific biallelic effects from differences in environment or genetic background. We addressed the potential of different recessive alleles to contribute to the enigmatic pleiotropy associated with XPD recessive disorders in compound heterozygous mouse models. Alterations in this essential helicase, with functions in both DNA repair and basal transcription, result in diverse pathologies ranging from elevated UV sensitivity and cancer predisposition to accelerated segmental progeria. We report a variety of biallelic effects on organismal phenotype attributable to combinations of recessive Xpd alleles, including the following: (i the ability of homozygous lethal Xpd alleles to ameliorate a variety of disease symptoms when their essential basal transcription function is supplied by a different disease-causing allele, (ii differential developmental and tissue-specific functions of distinct Xpd allele products, and (iii interallelic complementation, a phenomenon rarely reported at clinically relevant loci in mammals. Our data suggest a re-evaluation of the contribution of "null" alleles to XPD disorders and highlight the potential of combinations of recessive alleles to affect both normal and pathological phenotypic plasticity in mammals.

  10. An Xpd mouse model for the combined xeroderma pigmentosum/Cockayne syndrome exhibiting both cancer predisposition and segmental progeria.

    NARCIS (Netherlands)

    Andressoo, Jaan-Olle; Mitchell, James R; Wit, Jan de; Hoogstraten, Deborah; Volker, Marcel; Toussaint, Wendy; Speksnijder, Ewoud; Beems, Rudolf B; Steeg, Harry van; Jans, Judith; Zeeuw, Chris I de; Jaspers, Nicolaas G J; Raams, Anja; Lehmann, Alan R; Vermeulen, Wim; Hoeijmakers, Jan H J; Horst, Gijsbertus T J van der

    2006-01-01

    Inborn defects in nucleotide excision DNA repair (NER) can paradoxically result in elevated cancer incidence (xeroderma pigmentosum [XP]) or segmental progeria without cancer predisposition (Cockayne syndrome [CS] and trichothiodystrophy [TTD]). We report generation of a knockin mouse model for the

  11. An Xpd mouse model for the combined xeroderma pigmentosum/Cockayne syndrome exhibiting both cancer predisposition and segmental progeria.

    NARCIS (Netherlands)

    Andressoo, Jaan-Olle; Mitchell, James R; Wit, Jan de; Hoogstraten, Deborah; Volker, Marcel; Toussaint, Wendy; Speksnijder, Ewoud; Beems, Rudolf B; Steeg, Harry van; Jans, Judith; Zeeuw, Chris I de; Jaspers, Nicolaas G J; Raams, Anja; Lehmann, Alan R; Vermeulen, Wim; Hoeijmakers, Jan H J; Horst, Gijsbertus T J van der

    2006-01-01

    Inborn defects in nucleotide excision DNA repair (NER) can paradoxically result in elevated cancer incidence (xeroderma pigmentosum [XP]) or segmental progeria without cancer predisposition (Cockayne syndrome [CS] and trichothiodystrophy [TTD]). We report generation of a knockin mouse model for the

  12. Roles of the nucleoporin Tpr in cancer and aging.

    Science.gov (United States)

    Snow, Chelsi J; Paschal, Bryce M

    2014-01-01

    Tpr is a prominent architectural component of the nuclear pore complex that forms the basket-like structure on the nucleoplasmic side of the pore. Tpr, which stands for translocated promoter region, was originally described in the context of oncogenic fusions with the receptor tyrosine kinases Met, TRK, and Raf. Tpr has been since implicated in a variety of nuclear functions, including nuclear transport, chromatin organization, regulation of transcription, and mitosis. More recently, Tpr function has been linked to events including p53 signaling and premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS). Here we provide an overview of the various processes that involve Tpr, and discuss how the levels and localization of a single protein can affect diverse pathways in the cell.

  13. A High Throughput Phenotypic Screening reveals compounds that counteract premature osteogenic differentiation of HGPS iPS-derived mesenchymal stem cells

    Science.gov (United States)

    Lo Cicero, Alessandra; Jaskowiak, Anne-Laure; Egesipe, Anne-Laure; Tournois, Johana; Brinon, Benjamin; Pitrez, Patricia R.; Ferreira, Lino; de Sandre-Giovannoli, Annachiara; Levy, Nicolas; Nissan, Xavier

    2016-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare fatal genetic disorder that causes systemic accelerated aging in children. Thanks to the pluripotency and self-renewal properties of induced pluripotent stem cells (iPSC), HGPS iPSC-based modeling opens up the possibility of access to different relevant cell types for pharmacological approaches. In this study, 2800 small molecules were explored using high-throughput screening, looking for compounds that could potentially reduce the alkaline phosphatase activity of HGPS mesenchymal stem cells (MSCs) committed into osteogenic differentiation. Results revealed seven compounds that normalized the osteogenic differentiation process and, among these, all-trans retinoic acid and 13-cis-retinoic acid, that also decreased progerin expression. This study highlights the potential of high-throughput drug screening using HGPS iPS-derived cells, in order to find therapeutic compounds for HGPS and, potentially, for other aging-related disorders. PMID:27739443

  14. Autophagy and aging: new lessons from progeroid mice.

    Science.gov (United States)

    Mariño, Guillermo; López-Otín, Carlos

    2008-08-01

    It is widely-assumed that the autophagic activity of living cells decreases with age and probably contributes to the accumulation of damaged macromolecules and organelles during aging. Over the last few years, the study of segmental progeroid syndromes in which certain aspects of aging are manifested precociously or in exacerbated form, has increased our knowledge of the molecular basis of aging. We have recently reported the unexpected finding that distinct progeroid murine models exhibit an extensive basal activation of autophagy instead of the characteristic decline in this process occurring during normal aging. Further studies on Zmpste24-null progeroid mice, which are a reliable model of human Hutchinson-Gilford progeria, have revealed that the observed autophagic increase is associated with a series of metabolic alterations resembling those occurring under calorie restriction or in other situations reported to prolong lifespan. Here, we analyze these unexpected findings and discuss their possible implications for the development of premature aging.

  15. Lamin A-dependent nuclear defects in human aging.

    Science.gov (United States)

    Scaffidi, Paola; Misteli, Tom

    2006-05-19

    Mutations in the nuclear structural protein lamin A cause the premature aging syndrome Hutchinson-Gilford progeria (HGPS). Whether lamin A plays any role in normal aging is unknown. We show that the same molecular mechanism responsible for HGPS is active in healthy cells. Cell nuclei from old individuals acquire defects similar to those of HGPS patient cells, including changes in histone modifications and increased DNA damage. Age-related nuclear defects are caused by sporadic use, in healthy individuals, of the same cryptic splice site in lamin A whose constitutive activation causes HGPS. Inhibition of this splice site reverses the nuclear defects associated with aging. These observations implicate lamin A in physiological aging.

  16. Gene-rich chromosomal regions are preferentially localized in the lamin B deficient nuclear blebs of atypical progeria cells.

    Science.gov (United States)

    Bercht Pfleghaar, Katrin; Taimen, Pekka; Butin-Israeli, Veronika; Shimi, Takeshi; Langer-Freitag, Sabine; Markaki, Yolanda; Goldman, Anne E; Wehnert, Manfred; Goldman, Robert D

    2015-01-01

    More than 20 mutations in the gene encoding A-type lamins (LMNA) cause progeria, a rare premature aging disorder. The major pathognomonic hallmarks of progeria cells are seen as nuclear deformations or blebs that are related to the redistribution of A- and B-type lamins within the nuclear lamina. However, the functional significance of these progeria-associated blebs remains unknown. We have carried out an analysis of the structural and functional consequences of progeria-associated nuclear blebs in dermal fibroblasts from a progeria patient carrying a rare point mutation p.S143F (C428T) in lamin A/C. These blebs form microdomains that are devoid of major structural components of the nuclear envelope (NE)/lamina including B-type lamins and nuclear pore complexes (NPCs) and are enriched in A-type lamins. Using laser capture microdissection and comparative genomic hybridization (CGH) analyses, we show that, while these domains are devoid of centromeric heterochromatin and gene-poor regions of chromosomes, they are enriched in gene-rich chromosomal regions. The active form of RNA polymerase II is also greatly enriched in blebs as well as nascent RNA but the nuclear co-activator SKIP is significantly reduced in blebs compared to other transcription factors. Our results suggest that the p.S143F progeria mutation has a severe impact not only on the structure of the lamina but also on the organization of interphase chromatin domains and transcription. These structural defects are likely to contribute to gene expression changes reported in progeria and other types of laminopathies.

  17. Partial lipodystrophy with severe insulin resistance and adult progeria Werner syndrome.

    OpenAIRE

    Donadille, Bruno; D'Anella, Pascal; Auclair, Martine; Uhrhammer, Nancy; Sorel, Marc; Grigorescu, Romulus; Ouzounian, Sophie; Cambonie, Gilles; Boulot, Pierre; Laforêt, Pascal; Carbonne, Bruno; Christin-Maitre, Sophie; Bignon, Yves-Jean; Vigouroux, Corinne

    2013-01-01

    International audience; BACKGROUND: Laminopathies, due to mutations in LMNA, encoding A type-lamins, can lead to premature ageing and/or lipodystrophic syndromes, showing that these diseases could have close physiopathological relationships. We show here that lipodystrophy and extreme insulin resistance can also reveal the adult progeria Werner syndrome linked to mutations in WRN, encoding a RecQ DNA helicase. METHODS: We analysed the clinical and biological features of two women, aged 32 and...

  18. DNA-damage accumulation and replicative arrest in Hutchinson–Gilford progeria syndrome

    Science.gov (United States)

    Musich, Phillip R.; Zou, Yue

    2013-01-01

    A common feature of progeria syndromes is a premature aging phenotype and an enhanced accumulation of DNA damage arising from a compromised repair system. HGPS (Hutchinson–Gilford progeria syndrome) is a severe form of progeria in which patients accumulate progerin, a mutant lamin A protein derived from a splicing variant of the lamin A/C gene (LMNA). Progerin causes chromatin perturbations which result in the formation of DSBs (double-strand breaks) and abnormal DDR (DNA-damage response). In the present article, we review recent findings which resolve some mechanistic details of how progerin may disrupt DDR pathways in HGPS cells. We propose that progerin accumulation results in disruption of functions of some replication and repair factors, causing the mislocalization of XPA (xeroderma pigmentosum group A) protein to the replication forks, replication fork stalling and, subsequently, DNA DSBs. The binding of XPA to the stalled forks excludes normal binding by repair proteins, leading to DSB accumulation, which activates ATM (ataxia telangiectasia mutated) and ATR (ATM- and Rad3-related) checkpoints, and arresting cell-cycle progression. PMID:22103522

  19. Association of progerin-interactive partner proteins with lamina proteins:Mel18 is associated with emerin in HGPS%Progerin作用的伴侣蛋白和核纤层蛋白问的相互作用:在早老症中Mel18与emerin的相互作用

    Institute of Scientific and Technical Information of China (English)

    Wei-na JU; W. Ted BROWN; Nanbert ZHONG

    2009-01-01

    Objective :The Hutchinson-Gilford progeria syndrome (HGPS or progeria) is a childhood disorder with features of premature aging and is caused by mutations in the lamin A gene resulting in the production of an abnormal protein, termed progerin. To investigate the underlying pathogenic mecha-nism, we studied the nuclear co-localization and association of progerin interactive partner proteins (PIPPs) with lamina proteins. Methods:Both wild-type (WT) and progeria fibroblasts were studied by various methods including eonfocal microscopy, immunopreeipitation and Western blot. Results:All PIPPs discovered so-far co-localized with lamin A/C. In addition, the PIPPs were selectively associated with lamina proteins. An increased immunofluorescent staining signal was found for Mel18 in HGPS as com-pared to WT cells. An association of Me118 with emerin was observed in HGPS, but not in WT cells.Conclusion: Based on these findings, we propose that PIPPs, along with associated lamina proteins may form a pathogenic progerin-containing protein complex.

  20. LMNA mutations in progeroid syndromes.

    Science.gov (United States)

    Huang, Shurong; Kennedy, Brian K; Oshima, Junko

    2005-01-01

    Segmental progeroid syndromes are disorders in which affected individuals. present various features that suggest accelerated ageing. The two best-known examples are Hutchinson-Gilford progeria syndrome (HGPS, 'Progeria of childhood') and Werner syndrome (WS, 'Progeria of the adult'). A novel, recurrent de novo mutation in the LMNA gene, responsible for the majority of HGPS cases, results in an in-frame deletion of 50 amino acids, including endoproteolytic sites required for processing of prelamin A to mature lamin A protein. Another mutation results in a 35 amino acid in-frame deletion with a milder HGPS phenotype. WRN, the gene responsible for the majority of WS cases, encodes a multifunctional nuclear protein with exonuclease and helicase activities and may participate in optimizing DNA repair/recombination. A subset of WS patients do not show mutations at the WRN locus (atypical WS), but show heterozygous amino acid substitutions in the heptad repeat region of lamin A. Structural analysis suggests that mutations in atypical WS may interfere with protein-protein interactions. When compared to WRN-mutant WS, LMNA-mutant atypical WS patients appear to show earlier onset and possibly more severe ageing-related symptoms.

  1. Accelerated aging syndromes, are they relevant to normal human aging?

    Science.gov (United States)

    Dreesen, Oliver; Stewart, Colin L

    2011-09-01

    Hutchinson-Gilford Progeria (HGPS) and Werner syndromes are diseases that clinically resemble some aspects of accelerated aging. HGPS is caused by mutations in theLMNA gene resulting in post-translational processing defects that trigger Progeria in children. Werner syndrome, arising from mutations in the WRN helicase gene, causes premature aging in young adults. What are the molecular mechanism(s) underlying these disorders and what aspects of the diseases resemble physiological human aging? Much of what we know stems from the study of patient derived fibroblasts with both mutations resulting in increased DNA damage, primarily at telomeres. However, in vivo patients with Werner's develop arteriosclerosis, among other pathologies. In HGPS patients, including iPS derived cells from HGPS patients, as well as some mouse models for Progeria, vascular smooth muscle (VSM) appears to be among the most severely affected tissues. Defective Lamin processing, associated with DNA damage, is present in VSM from old individuals, indicating processing defects may be a factor in normal aging. Whether persistent DNA damage, particularly at telomeres, is the root cause for these pathologies remains to be established, since not all progeroid Lmna mutations result in DNA damage and genome instability.

  2. Hutchinson–Gilford progeria syndrome with severe calcific aortic valve stenosis

    Science.gov (United States)

    Hanumanthappa, Natesh B; Madhusudan, Ganigara; Mahimarangaiah, Jayaranganath; Manjunath, Cholenahally N

    2011-01-01

    Hutchinson–Gilford progeria syndrome (HGPS) is a rare premature aging syndrome that results from mutation in the Laminin A gene. This case report of a 12-year-old girl with HGPS is presented for the rarity of the syndrome and the classical clinical features that were observed in the patient. All patients with this condition should undergo early and periodic evaluation for cardiovascular diseases. However, the prognosis is poor and management is mainly conservative. There is no proven therapy available. Mortality in this uniformly fatal condition is primarily due to myocardial infarction, strokes or congestive cardiac failure between ages 7 and 21 years due to the rapidly progressive arteriosclerosis involving the large vessels. PMID:21976890

  3. Extradural hematoma surgery in a child with Hutchinson–Gilford progeria syndrome: Perioperative concerns

    Science.gov (United States)

    Hansda, Upendra; Agarwal, Jyotsna; Patra, Chitralekha; Ganjoo, Pragati

    2013-01-01

    Hutchinson–Gilford progeria syndrome (HGPS) is a very rare genetic disorder characterized by premature ageing, severe growth failure, and very early onset atherosclerosis. Psychologically and emotionally child-like, these patients suffer from physiological changes of old age. Early and progressive atherosclerosis of intra-cranial vessels in HGPS patients, along with a thin skin and fragile vessels, make these patients susceptible to intra-cranial hematomas following relatively trivial injuries and to severe intra-cranial disease. Anesthetizing HGPS patients for surgery can be challenging due to the presence of a possible difficult airway, multi-system derangements, and associated skin, bone and joint disease. We report here one such child with HGPS who underwent craniotomy and evacuation of an extradural hematoma that developed after minor head trauma. Securing his airway during surgery was difficult. PMID:24082942

  4. Resveratrol rescues SIRT1-dependent adult stem cell decline and alleviates progeroid features in laminopathy-based progeria.

    Science.gov (United States)

    Liu, Baohua; Ghosh, Shrestha; Yang, Xi; Zheng, Huiling; Liu, Xinguang; Wang, Zimei; Jin, Guoxiang; Zheng, Bojian; Kennedy, Brian K; Suh, Yousin; Kaeberlein, Matt; Tryggvason, Karl; Zhou, Zhongjun

    2012-12-05

    Abnormal splicing of LMNA gene or aberrant processing of prelamin A results in progeroid syndrome. Here we show that lamin A interacts with and activates SIRT1. SIRT1 exhibits reduced association with nuclear matrix (NM) and decreased deacetylase activity in the presence of progerin or prelamin A, leading to rapid depletion of adult stem cells (ASCs) in Zmpste24(-/-) mice. Resveratrol enhances the binding between SIRT1 and A-type lamins to increases its deacetylase activity. Resveratrol treatment rescues ASC decline, slows down body weight loss, improves trabecular bone structure and mineral density, and significantly extends the life span in Zmpste24(-/-) mice. Our data demonstrate lamin A as an activator of SIRT1 and provide a mechanistic explanation for the activation of SIRT1 by resveratrol. The link between conserved SIRT1 longevity pathway and progeria suggests a stem cell-based and SIRT1 pathway-dependent therapeutic strategy for progeria.

  5. Depleting the methyltransferase Suv39h1 improves DNA repair and extends lifespan in a progeria mouse model

    Science.gov (United States)

    Liu, Baohua; Wang, Zimei; Zhang, Le; Ghosh, Shrestha; Zheng, Huiling; Zhou, Zhongjun

    2013-01-01

    A de novo G608G mutation in LMNA gene leads to Hutchinson–Gilford progeria syndrome. Mice lacking the prelamin A-processing metalloprotease, Zmpste24, recapitulate many of the progeroid features of Hutchinson–Gilford progeria syndrome. Here we show that A-type lamins interact with SUV39H1, and prelamin A/progerin exhibits enhanced binding capacity to SUV39H1, protecting it from proteasomal degradation and, consequently, increasing H3K9me3 levels. Depletion of Suv39h1 reduces H3K9me3 levels, restores DNA repair capacity and delays senescence in progeroid cells. Remarkably, loss of Suv39h1 in Zmpste24−/− mice delays body weight loss, increases bone mineral density and extends lifespan by ∼60%. Thus, increased H3K9me3 levels, possibly mediated by enhanced Suv39h1 stability in the presence of prelamin A/progerin, compromise genome maintenance, which in turn contributes to accelerated senescence in laminopathy-based premature aging. Our study provides an explanation for epigenetic alterations in Hutchinson–Gilford progeria syndrome and a potential strategy for intervention by targeting SUV39H1-mediated heterochromatin remodelling. PMID:23695662

  6. Age-Dependent Loss of MMP-3 in Hutchinson–Gilford Progeria Syndrome

    Science.gov (United States)

    Harten, Ingrid A.; Zahr, Rima S.; Lemire, Joan M.; Machan, Jason T.; Moses, Marsha A.; Doiron, Robert J.; Curatolo, Adam S.; Rothman, Frank G.; Wight, Thomas N.; Toole, Bryan P.

    2011-01-01

    Hutchinson–Gilford progeria syndrome (HGPS) is a rare, progressive segmental premature aging disease that includes scleroderma-like skin, progressive joint contracture, and atherosclerosis. Affected individuals die prematurely of heart attacks or strokes. Extracellular matrix dysregulation is implicated as a factor in disease progression. We analyzed messenger RNA and protein levels for matrix metalloproteinases (MMPs)-2,-3, and -9 in HGPS primary human dermal fibroblasts using real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and gelatin zymography. MMP-3 messenger RNA and protein levels decreased significantly with increasing donor age in HGPS fibroblasts but not in controls. MMP-2 messenger RNA also showed a donor age–dependent decrease in HGPS fibroblasts, but levels of secreted protein were unchanged. MMP-9 was similar in HGPS and control cultures. The decreased MMP-3 may represent a shift in the inherent extracellular matrix–degrading proteolytic balance in favor of matrix deposition in HGPS. This metalloproteinase has the potential to serve as a biomarker of therapeutic efficacy when assessing treatments for HGPS. PMID:21852285

  7. Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson–Gilford progeria syndrome

    Science.gov (United States)

    Gordon, Leslie B.; Kleinman, Monica E.; Miller, David T.; Neuberg, Donna S.; Giobbie-Hurder, Anita; Gerhard-Herman, Marie; Smoot, Leslie B.; Gordon, Catherine M.; Cleveland, Robert; Snyder, Brian D.; Fligor, Brian; Bishop, W. Robert; Statkevich, Paul; Regen, Amy; Sonis, Andrew; Riley, Susan; Ploski, Christine; Correia, Annette; Quinn, Nicolle; Ullrich, Nicole J.; Nazarian, Ara; Liang, Marilyn G.; Huh, Susanna Y.; Schwartzman, Armin; Kieran, Mark W.

    2012-01-01

    Hutchinson–Gilford progeria syndrome (HGPS) is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA that produces the farnesylated aberrant lamin A protein, progerin. This multisystem disorder causes failure to thrive and accelerated atherosclerosis leading to early death. Farnesyltransferase inhibitors have ameliorated disease phenotypes in preclinical studies. Twenty-five patients with HGPS received the farnesyltransferase inhibitor lonafarnib for a minimum of 2 y. Primary outcome success was predefined as a 50% increase over pretherapy in estimated annual rate of weight gain, or change from pretherapy weight loss to statistically significant on-study weight gain. Nine patients experienced a ≥50% increase, six experienced a ≥50% decrease, and 10 remained stable with respect to rate of weight gain. Secondary outcomes included decreases in arterial pulse wave velocity and carotid artery echodensity and increases in skeletal rigidity and sensorineural hearing within patient subgroups. All patients improved in one or more of these outcomes. Results from this clinical treatment trial for children with HGPS provide preliminary evidence that lonafarnib may improve vascular stiffness, bone structure, and audiological status. PMID:23012407

  8. Different prelamin A forms accumulate in human fibroblasts: a study in experimental models and progeria

    Directory of Open Access Journals (Sweden)

    S Dominici

    2009-08-01

    Full Text Available Lamin A is a component of the nuclear lamina mutated in a group of human inherited disorders known as laminopathies. Among laminopathies, progeroid syndromes and lipodystrophies feature accumulation of prelamin A, the precursor protein which, in normal cells, undergoes a multi-step processing to yield mature lamin A. It is of utmost importance to characterize the prelamin A form accumulated in each laminopathy, since existing evidence shows that drugs acting on protein processing can improve some pathological aspects.We report that two antibodies raised against differently modified prelamin A peptides show a clear specificity to full-length prelamin A or carboxymethylated farnesylated prelamin A, respectively. Using these antibodies, we demonstrated that inhibition of the prelamin A endoprotease ZMPSTE24 mostly elicits accumulation of full-length prelamin A in its farnesylated form, while loss of the prelamin A cleavage site causes accumulation of carboxymethylated prelamin A in progeria cells. These results suggest a major role of ZMPSTE24 in the first prelamin A cleavage step.

  9. Sporadic premature aging in a Japanese monkey: a primate model for progeria.

    Directory of Open Access Journals (Sweden)

    Takao Oishi

    Full Text Available In our institute, we have recently found a child Japanese monkey who is characterized by deep wrinkles of the skin and cataract of bilateral eyes. Numbers of analyses were performed to identify symptoms representing different aspects of aging. In this monkey, the cell cycle of fibroblasts at early passage was significantly extended as compared to a normal control. Moreover, both the appearance of senescent cells and the deficiency in DNA repair were observed. Also, pathological examination showed that this monkey has poikiloderma with superficial telangiectasia, and biochemical assay confirmed that levels of HbA1c and urinary hyaluronan were higher than those of other (child, adult, and aged monkey groups. Of particular interest was that our MRI analysis revealed expansion of the cerebral sulci and lateral ventricles probably due to shrinkage of the cerebral cortex and the hippocampus. In addition, the conduction velocity of a peripheral sensory but not motor nerve was lower than in adult and child monkeys, and as low as in aged monkeys. However, we could not detect any individual-unique mutations of known genes responsible for major progeroid syndromes. The present results indicate that the monkey suffers from a kind of progeria that is not necessarily typical to human progeroid syndromes.

  10. Different prelamin A forms accumulate in human fibroblasts: a study in experimental models and progeria

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    G Lattanzi

    2009-03-01

    Full Text Available Lamin A is a component of the nuclear lamina mutated in a group of human inherited disorders known as laminopathies. Among laminopathies, progeroid syndromes and lipodystrophies feature accumulation of prelamin A, the precursor protein which, in normal cells, undergoes a multi-step processing to yield mature lamin A. It is of utmost importance to characterize the prelamin A form accumulated in each laminopathy, since existing evidence shows that drugs acting on protein processing can improve some pathological aspects.We report that two antibodies raised against differently modified prelamin A peptides show a clear specificity to full-length prelamin A or carboxymethylated farnesylated prelamin A, respectively. Using these antibodies, we demonstrated that inhibition of the prelamin A endoprotease ZMPSTE24 mostly elicits accumulation of full-length prelamin A in its farnesylated form, while loss of the prelamin A cleavage site causes accumulation of carboxymethylated prelamin A in progeria cells. These results suggest a major role of ZMPSTE24 in the first prelamin A cleavage step.

  11. Sporadic premature aging in a Japanese monkey: a primate model for progeria.

    Science.gov (United States)

    Oishi, Takao; Imai, Hiroo; Go, Yasuhiro; Imamura, Masanori; Hirai, Hirohisa; Takada, Masahiko

    2014-01-01

    In our institute, we have recently found a child Japanese monkey who is characterized by deep wrinkles of the skin and cataract of bilateral eyes. Numbers of analyses were performed to identify symptoms representing different aspects of aging. In this monkey, the cell cycle of fibroblasts at early passage was significantly extended as compared to a normal control. Moreover, both the appearance of senescent cells and the deficiency in DNA repair were observed. Also, pathological examination showed that this monkey has poikiloderma with superficial telangiectasia, and biochemical assay confirmed that levels of HbA1c and urinary hyaluronan were higher than those of other (child, adult, and aged) monkey groups. Of particular interest was that our MRI analysis revealed expansion of the cerebral sulci and lateral ventricles probably due to shrinkage of the cerebral cortex and the hippocampus. In addition, the conduction velocity of a peripheral sensory but not motor nerve was lower than in adult and child monkeys, and as low as in aged monkeys. However, we could not detect any individual-unique mutations of known genes responsible for major progeroid syndromes. The present results indicate that the monkey suffers from a kind of progeria that is not necessarily typical to human progeroid syndromes.

  12. Global Reorganization of the Nuclear Landscape in Senescent Cells

    Directory of Open Access Journals (Sweden)

    Tamir Chandra

    2015-02-01

    Full Text Available Cellular senescence has been implicated in tumor suppression, development, and aging and is accompanied by large-scale chromatin rearrangements, forming senescence-associated heterochromatic foci (SAHF. However, how the chromatin is reorganized during SAHF formation is poorly understood. Furthermore, heterochromatin formation in senescence appears to contrast with loss of heterochromatin in Hutchinson-Gilford progeria. We mapped architectural changes in genome organization in cellular senescence using Hi-C. Unexpectedly, we find a dramatic sequence- and lamin-dependent loss of local interactions in heterochromatin. This change in local connectivity resolves the paradox of opposing chromatin changes in senescence and progeria. In addition, we observe a senescence-specific spatial clustering of heterochromatic regions, suggesting a unique second step required for SAHF formation. Comparison of embryonic stem cells (ESCs, somatic cells, and senescent cells shows a unidirectional loss in local chromatin connectivity, suggesting that senescence is an endpoint of the continuous nuclear remodelling process during differentiation.

  13. NF-κB activation impairs somatic cell reprogramming in ageing.

    Science.gov (United States)

    Soria-Valles, Clara; Osorio, Fernando G; Gutiérrez-Fernández, Ana; De Los Angeles, Alejandro; Bueno, Clara; Menéndez, Pablo; Martín-Subero, José I; Daley, George Q; Freije, José M P; López-Otín, Carlos

    2015-08-01

    Ageing constitutes a critical impediment to somatic cell reprogramming. We have explored the regulatory mechanisms that constitute age-associated barriers, through derivation of induced pluripotent stem cells (iPSCs) from individuals with premature or physiological ageing. We demonstrate that NF-κB activation blocks the generation of iPSCs in ageing. We also show that NF-κB repression occurs during cell reprogramming towards a pluripotent state. Conversely, ageing-associated NF-κB hyperactivation impairs the generation of iPSCs by eliciting the reprogramming repressor DOT1L, which reinforces senescence signals and downregulates pluripotency genes. Genetic and pharmacological NF-κB inhibitory strategies significantly increase the reprogramming efficiency of fibroblasts from Néstor-Guillermo progeria syndrome and Hutchinson-Gilford progeria syndrome patients, as well as from normal aged donors. Finally, we demonstrate that DOT1L inhibition in vivo extends lifespan and ameliorates the accelerated ageing phenotype of progeroid mice, supporting the interest of studying age-associated molecular impairments to identify targets of rejuvenation strategies.

  14. Global reorganization of the nuclear landscape in senescent cells.

    Science.gov (United States)

    Chandra, Tamir; Ewels, Philip Andrew; Schoenfelder, Stefan; Furlan-Magaril, Mayra; Wingett, Steven William; Kirschner, Kristina; Thuret, Jean-Yves; Andrews, Simon; Fraser, Peter; Reik, Wolf

    2015-02-03

    Cellular senescence has been implicated in tumor suppression, development, and aging and is accompanied by large-scale chromatin rearrangements, forming senescence-associated heterochromatic foci (SAHF). However, how the chromatin is reorganized during SAHF formation is poorly understood. Furthermore, heterochromatin formation in senescence appears to contrast with loss of heterochromatin in Hutchinson-Gilford progeria. We mapped architectural changes in genome organization in cellular senescence using Hi-C. Unexpectedly, we find a dramatic sequence- and lamin-dependent loss of local interactions in heterochromatin. This change in local connectivity resolves the paradox of opposing chromatin changes in senescence and progeria. In addition, we observe a senescence-specific spatial clustering of heterochromatic regions, suggesting a unique second step required for SAHF formation. Comparison of embryonic stem cells (ESCs), somatic cells, and senescent cells shows a unidirectional loss in local chromatin connectivity, suggesting that senescence is an endpoint of the continuous nuclear remodelling process during differentiation. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  15. Defective ATM-Kap-1-mediated chromatin remodeling impairs DNA repair and accelerates senescence in progeria mouse model.

    Science.gov (United States)

    Liu, Baohua; Wang, Zimei; Ghosh, Shrestha; Zhou, Zhongjun

    2013-04-01

    ATM-mediated phosphorylation of KAP-1 triggers chromatin remodeling and facilitates the loading and retention of repair proteins at DNA lesions. Mouse embryonic fibroblasts (MEFs) derived from Zmpste24(-/-) mice undergo early senescence, attributable to delayed recruitment of DNA repair proteins. Here, we show that ATM-Kap-1 signaling is compromised in Zmpste24(-/-) MEFs, leading to defective DNA damage-induced chromatin remodeling. Knocking down Kap-1 rescues impaired chromatin remodeling, defective DNA repair and early senescence in Zmpste24(-/-) MEFs. Thus, ATM-Kap-1-mediated chromatin remodeling plays a critical role in premature aging, carrying significant implications for progeria therapy.

  16. Adaptive stress response in segmental progeria resembles long-lived dwarfism and calorie restriction in mice.

    Directory of Open Access Journals (Sweden)

    Marieke van de Ven

    2006-12-01

    Full Text Available How congenital defects causing genome instability can result in the pleiotropic symptoms reminiscent of aging but in a segmental and accelerated fashion remains largely unknown. Most segmental progerias are associated with accelerated fibroblast senescence, suggesting that cellular senescence is a likely contributing mechanism. Contrary to expectations, neither accelerated senescence nor acute oxidative stress hypersensitivity was detected in primary fibroblast or erythroblast cultures from multiple progeroid mouse models for defects in the nucleotide excision DNA repair pathway, which share premature aging features including postnatal growth retardation, cerebellar ataxia, and death before weaning. Instead, we report a prominent phenotypic overlap with long-lived dwarfism and calorie restriction during postnatal development (2 wk of age, including reduced size, reduced body temperature, hypoglycemia, and perturbation of the growth hormone/insulin-like growth factor 1 neuroendocrine axis. These symptoms were also present at 2 wk of age in a novel progeroid nucleotide excision repair-deficient mouse model (XPD(G602D/R722W/XPA(-/- that survived weaning with high penetrance. However, despite persistent cachectic dwarfism, blood glucose and serum insulin-like growth factor 1 levels returned to normal by 10 wk, with hypoglycemia reappearing near premature death at 5 mo of age. These data strongly suggest changes in energy metabolism as part of an adaptive response during the stressful period of postnatal growth. Interestingly, a similar perturbation of the postnatal growth axis was not detected in another progeroid mouse model, the double-strand DNA break repair deficient Ku80(-/- mouse. Specific (but not all types of genome instability may thus engage a conserved response to stress that evolved to cope with environmental pressures such as food shortage.

  17. Adaptive stress response in segmental progeria resembles long-lived dwarfism and calorie restriction in mice.

    Science.gov (United States)

    van de Ven, Marieke; Andressoo, Jaan-Olle; Holcomb, Valerie B; von Lindern, Marieke; Jong, Willeke M C; De Zeeuw, Chris I; Suh, Yousin; Hasty, Paul; Hoeijmakers, Jan H J; van der Horst, Gijsbertus T J; Mitchell, James R

    2006-12-15

    How congenital defects causing genome instability can result in the pleiotropic symptoms reminiscent of aging but in a segmental and accelerated fashion remains largely unknown. Most segmental progerias are associated with accelerated fibroblast senescence, suggesting that cellular senescence is a likely contributing mechanism. Contrary to expectations, neither accelerated senescence nor acute oxidative stress hypersensitivity was detected in primary fibroblast or erythroblast cultures from multiple progeroid mouse models for defects in the nucleotide excision DNA repair pathway, which share premature aging features including postnatal growth retardation, cerebellar ataxia, and death before weaning. Instead, we report a prominent phenotypic overlap with long-lived dwarfism and calorie restriction during postnatal development (2 wk of age), including reduced size, reduced body temperature, hypoglycemia, and perturbation of the growth hormone/insulin-like growth factor 1 neuroendocrine axis. These symptoms were also present at 2 wk of age in a novel progeroid nucleotide excision repair-deficient mouse model (XPD(G602D/R722W)/XPA(-/-)) that survived weaning with high penetrance. However, despite persistent cachectic dwarfism, blood glucose and serum insulin-like growth factor 1 levels returned to normal by 10 wk, with hypoglycemia reappearing near premature death at 5 mo of age. These data strongly suggest changes in energy metabolism as part of an adaptive response during the stressful period of postnatal growth. Interestingly, a similar perturbation of the postnatal growth axis was not detected in another progeroid mouse model, the double-strand DNA break repair deficient Ku80(-/-) mouse. Specific (but not all) types of genome instability may thus engage a conserved response to stress that evolved to cope with environmental pressures such as food shortage.

  18. Adaptive Stress Response in Segmental Progeria Resembles Long-Lived Dwarfism and Calorie Restriction in Mice

    Science.gov (United States)

    Holcomb, Valerie B; von Lindern, Marieke; Jong, Willeke M. C; Zeeuw, Chris I. De; Suh, Yousin; Hasty, Paul; Hoeijmakers, Jan H. J; van der Horst, Gijsbertus T. J; Mitchell, James R

    2006-01-01

    How congenital defects causing genome instability can result in the pleiotropic symptoms reminiscent of aging but in a segmental and accelerated fashion remains largely unknown. Most segmental progerias are associated with accelerated fibroblast senescence, suggesting that cellular senescence is a likely contributing mechanism. Contrary to expectations, neither accelerated senescence nor acute oxidative stress hypersensitivity was detected in primary fibroblast or erythroblast cultures from multiple progeroid mouse models for defects in the nucleotide excision DNA repair pathway, which share premature aging features including postnatal growth retardation, cerebellar ataxia, and death before weaning. Instead, we report a prominent phenotypic overlap with long-lived dwarfism and calorie restriction during postnatal development (2 wk of age), including reduced size, reduced body temperature, hypoglycemia, and perturbation of the growth hormone/insulin-like growth factor 1 neuroendocrine axis. These symptoms were also present at 2 wk of age in a novel progeroid nucleotide excision repair-deficient mouse model (XPDG602D/R722W/XPA−/−) that survived weaning with high penetrance. However, despite persistent cachectic dwarfism, blood glucose and serum insulin-like growth factor 1 levels returned to normal by 10 wk, with hypoglycemia reappearing near premature death at 5 mo of age. These data strongly suggest changes in energy metabolism as part of an adaptive response during the stressful period of postnatal growth. Interestingly, a similar perturbation of the postnatal growth axis was not detected in another progeroid mouse model, the double-strand DNA break repair deficient Ku80 −/− mouse. Specific (but not all) types of genome instability may thus engage a conserved response to stress that evolved to cope with environmental pressures such as food shortage. PMID:17173483

  19. Muscle-derived stem/progenitor cell dysfunction limits healthspan and lifespan in a murine progeria model

    Science.gov (United States)

    Lavasani, Mitra; Robinson, Andria R.; Lu, Aiping; Song, Minjung; Feduska, Joseph M.; Ahani, Bahar; Tilstra, Jeremy S.; Feldman, Chelsea H.; Robbins, Paul D.; Niedernhofer, Laura J.; Huard, Johnny

    2012-01-01

    With ageing, there is a loss of adult stem cell function. However, there is no direct evidence that this has a causal role in ageing-related decline. We tested this using muscle-derived stem/progenitor cells (MDSPCs) in a murine progeria model. Here we show that MDSPCs from old and progeroid mice are defective in proliferation and multilineage differentiation. Intraperitoneal administration of MDSPCs, isolated from young wild-type mice, to progeroid mice confer significant lifespan and healthspan extension. The transplanted MDSPCs improve degenerative changes and vascularization in tissues where donor cells are not detected, suggesting that their therapeutic effect may be mediated by secreted factor(s). Indeed, young wild-type-MDSPCs rescue proliferation and differentiation defects of aged MDSPCs when co-cultured. These results establish that adult stem/progenitor cell dysfunction contributes to ageing-related degeneration and suggests a therapeutic potential of post-natal stem cells to extend health. PMID:22215083

  20. 早老症一例追踪观察及临床分析%Follow-up and clinical analysis of one case with progeria

    Institute of Scientific and Technical Information of China (English)

    陈丽; 张晓黎; 董明; 侯新国

    2004-01-01

    早老症,又称Hutchinson—Guilford综合征(Hutchinson—Guilford progeria syndrome,HGPS),是与自然老化不同的一种局部性老化性疾病,临床比较少见,国内报道仅十余例。本组于1998年11月门诊诊治一例并跟踪观察,现报道如下。

  1. Recent advances in understanding the role of lamins in health and disease [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Sita Reddy

    2016-10-01

    Full Text Available Lamins are major components of the nuclear lamina, a network of proteins that supports the nuclear envelope in metazoan cells. Over the past decade, biochemical studies have provided support for the view that lamins are not passive bystanders providing mechanical stability to the nucleus but play an active role in the organization of the genome and the function of fundamental nuclear processes. It has also become apparent that lamins are critical for human health, as a large number of mutations identified in the gene that encodes for A-type lamins are associated with tissue-specific and systemic genetic diseases, including the accelerated aging disorder known as Hutchinson-Gilford progeria syndrome. Recent years have witnessed great advances in our understanding of the role of lamins in the nucleus and the functional consequences of disease-associated A-type lamin mutations. Many of these findings have been presented in comprehensive reviews. In this mini-review, we discuss recent breakthroughs in the role of lamins in health and disease and what lies ahead in lamin research.

  2. New look at the role of progerin in skin aging

    Directory of Open Access Journals (Sweden)

    Anna Skoczyńska

    2015-02-01

    Full Text Available Current literature data indicate that progerin, which is a mutant of lamin A, may be one of several previously known physiological biomarkers of the aging process which begins at the age of 30. Lamins belong to the family of intermediate filaments type V and are an important component of the nuclear envelope (NE. The physiological processes of an alternative splicing of LMNA (lamin A/C gene and posttranslational processing result in the formation of different variants of this gene. Prelamin A is generated in cytosol and modified by respective enzymes. In the final step, 15-aa peptide is released at the C-terminus, resulting in mature lamin A. Point mutation of cytosine to thymine at position 1824 in exon 11 of LMNA gene causes a truncated form of lamin A, which is defined as progerin. In the course of time, progerin is mainly found in skin fibroblasts and reticular layers of terminally differentiated keratinocytes. Changes take place in the nucleus and they are similar to those observed in patients with Hutchinson-Gilford progeria syndrome and refer mainly to an increase in the amount of reactive oxygen species which reduce the level of antioxidant enzymes, DNA damage and histone modification. There are still pending studies on working out new anti-aging strategies and the skin is the main area of research. Biomimetic peptides (analogues of elafin are used in cosmetics to reduce the formation of progerin.

  3. Nuclear protein import is reduced in cells expressing nuclear envelopathy-causing lamin A mutants

    Energy Technology Data Exchange (ETDEWEB)

    Busch, Albert; Kiel, Tilman; Heupel, Wolfgang-M. [University of Wuerzburg, Institute of Anatomy and Cell Biology, Koellikerstrasse 6, 97070 Wuerzburg (Germany); Wehnert, Manfred [Institute of Human Genetics, University of Greifswald, Greifswald (Germany); Huebner, Stefan, E-mail: stefan.huebner@mail.uni-wuerzburg.de [University of Wuerzburg, Institute of Anatomy and Cell Biology, Koellikerstrasse 6, 97070 Wuerzburg (Germany)

    2009-08-15

    Lamins, which form the nuclear lamina, not only constitute an important determinant of nuclear architecture, but additionally play essential roles in many nuclear functions. Mutations in A-type lamins cause a wide range of human genetic disorders (laminopathies). The importance of lamin A (LaA) in the spatial arrangement of nuclear pore complexes (NPCs) prompted us to study the role of LaA mutants in nuclear protein transport. Two mutants, causing prenatal skin disease restrictive dermopathy (RD) and the premature aging disease Hutchinson Gilford progeria syndrome, were used for expression in HeLa cells to investigate their impact on the subcellular localization of NPC-associated proteins and nuclear protein import. Furthermore, dynamics of the LaA mutants within the nuclear lamina were studied. We observed affected localization of NPC-associated proteins, diminished lamina dynamics for both LaA mutants and reduced nuclear import of representative cargo molecules. Intriguingly, both LaA mutants displayed similar effects on nuclear morphology and functions, despite their differences in disease severity. Reduced nuclear protein import was also seen in RD fibroblasts and impaired lamina dynamics for the nucleoporin Nup153. Our data thus represent the first study of a direct link between LaA mutant expression and reduced nuclear protein import.

  4. Comparing lamin proteins post-translational relative stability using a 2A peptide-based system reveals elevated resistance of progerin to cellular degradation

    Science.gov (United States)

    Wu, Di; Zhang, Haoyue; Cao, Kan

    2016-01-01

    ABSTRACT Nuclear lamins are the major components of the nuclear lamina at the periphery of the nucleus, supporting the nuclear envelope and participating in many nuclear processes, including DNA replication, transcription and chromatin organization. A group of diseases, the laminopathies, is associated with mutations in lamin genes. One of the most striking cases is Hutchinson-Gilford progeria syndrome (HGPS) which is the consequence of a lamin A dominant negative mutant named progerin. Due to the abnormal presence of a permanent C-terminal farnesyl tail, progerin gradually accumulates on the nuclear membrane, perturbing a diversity of signalings and transcriptional events. The accumulation of progerin has led to the speculation that progerin possesses higher stability than the wild type lamin A protein. However, the low solubility of lamin proteins renders traditional immunoprecipitation-dependent methods such as pulse-chase analysis ineffective for comparing the relative stabilities of mutant and wild type lamins. Here, we employ a novel platform for inferring differences in lamin stability, which is based on normalization to a co-translated reporter protein following porcine teschovirus-1 2A peptide-mediated co-translational cleavage. The results obtained using this method support the notion that progerin is more stable than lamin A. Moreover, treatment of FTI reduces progerin relative stability to the level of wild type lamin A. PMID:27929926

  5. Lamin A Is an Endogenous SIRT6 Activator and Promotes SIRT6-Mediated DNA Repair

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    Shrestha Ghosh

    2015-11-01

    Full Text Available The nuclear lamins are essential for various molecular events in the nucleus, such as chromatin organization, DNA replication, and provision of mechanical support. A specific point mutation in the LMNA gene creates a truncated prelamin A termed progerin, causing Hutchinson-Gilford progeria syndrome (HGPS. SIRT6 deficiency leads to defective genomic maintenance and accelerated aging similar to HGPS, suggesting a potential link between lamin A and SIRT6. Here, we report that lamin A is an endogenous activator of SIRT6 and facilitates chromatin localization of SIRT6 upon DNA damage. Lamin A promotes SIRT6-dependent DNA-PKcs (DNA-PK catalytic subunit recruitment to chromatin, CtIP deacetylation, and PARP1 mono-ADP ribosylation in response to DNA damage. The presence of progerin jeopardizes SIRT6 activation and compromises SIRT6-mediated molecular events in response to DNA damage. These data reveal a critical role for lamin A in regulating SIRT6 activities, suggesting that defects in SIRT6 functions contribute to impaired DNA repair and accelerated aging in HGPS.

  6. Overexpression of Lamin B Receptor Results in Impaired Skin Differentiation.

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    Agustín Sola Carvajal

    Full Text Available Hutchinson-Gilford progeria syndrome (HGPS is a rare segmental progeroid disorder commonly caused by a point mutation in the LMNA gene that results in the increased activation of an intra-exonic splice site and the production of a truncated lamin A protein, named progerin. In our previous work, induced murine epidermal expression of this specific HGPS LMNA mutation showed impaired keratinocyte differentiation and upregulated lamin B receptor (LBR expression in suprabasal keratinocytes. Here, we have developed a novel transgenic animal model with induced overexpression of LBR in the interfollicular epidermis. LBR overexpression resulted in epidermal hypoplasia, along with the downregulation and mislocalization of keratin 10, suggesting impaired keratinocyte differentiation. Increased LBR expression in basal and suprabasal cells did not coincide with increased proliferation. Similar to our previous report of HGPS mice, analyses of γH2AX, a marker of DNA double-strand breaks, revealed an increased number of keratinocytes with multiple foci in LBR-overexpressing mice compared with wild-type mice. In addition, suprabasal LBR-positive cells showed densely condensed and peripherally localized chromatin. Our results show a moderate skin differentiation phenotype, which indicates that upregulation of LBR is not the sole contributor to the HGPS phenotype.

  7. Lamin A/C truncation in dilated cardiomyopathy with conduction disease

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    Huber Jill M

    2003-07-01

    Full Text Available Abstract Background Mutations in the gene encoding the nuclear membrane protein lamin A/C have been associated with at least 7 distinct diseases including autosomal dominant dilated cardiomyopathy with conduction system disease, autosomal dominant and recessive Emery Dreifuss Muscular Dystrophy, limb girdle muscular dystrophy type 1B, autosomal recessive type 2 Charcot Marie Tooth, mandibuloacral dysplasia, familial partial lipodystrophy and Hutchinson-Gilford progeria. Methods We used mutation detection to evaluate the lamin A/C gene in a 45 year-old woman with familial dilated cardiomyopathy and conduction system disease whose family has been well characterized for this phenotype 1. Results DNA from the proband was analyzed, and a novel 2 base-pair deletion c.908_909delCT in LMNA was identified. Conclusions Mutations in the gene encoding lamin A/C can lead to significant cardiac conduction system disease that can be successfully treated with pacemakers and/or defibrillators. Genetic screening can help assess risk for arrhythmia and need for device implantation.

  8. Low levels of the reverse transactivator fail to induce target transgene expression in vascular smooth muscle cells.

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    Nikenza Viceconte

    Full Text Available Hutchinson-Gilford progeria syndrome (HGPS is a genetic disease with multiple features that are suggestive of premature aging. Most patients with HGPS carry a mutation on one of their copies of the LMNA gene. The LMNA gene encodes the lamin A and lamin C proteins, which are the major proteins of the nuclear lamina. The organs of the cardiovascular system are amongst those that are most severely affected in HGPS, undergoing a progressive depletion of vascular smooth muscle cells, and most children with HGPS die in their early teens from cardio-vascular disease and other complications from atherosclerosis. In this study, we developed a transgenic mouse model based on the tet-ON system to increase the understanding of the molecular mechanisms leading to the most lethal aspect of HGPS. To induce the expression of the most common HGPS mutation, LMNA c.1824C>T; p.G608G, in the vascular smooth muscle cells of the aortic arch and thoracic aorta, we used the previously described reverse tetracycline-controlled transactivator, sm22α-rtTA. However, the expression of the reverse sm22α-transactivator was barely detectable in the arteries, and this low level of expression was not sufficient to induce the expression of the target human lamin A minigene. The results from this study are important because they suggest caution during the use of previously functional transgenic animal models and emphasize the importance of assessing transgene expression over time.

  9. Lamin A, farnesylation and aging

    Energy Technology Data Exchange (ETDEWEB)

    Reddy, Sita [Department of Biochemistry and Molecular Biology, Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 (United States); Comai, Lucio, E-mail: comai@usc.edu [Department of Molecular Microbiology and Immunology, Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 (United States)

    2012-01-01

    Lamin A is a component of the nuclear envelope that is synthesized as a precursor prelamin A molecule and then processed into mature lamin A through sequential steps of posttranslational modifications and proteolytic cleavages. Remarkably, over 400 distinct point mutations have been so far identified throughout the LMNA gene, which result in the development of at least ten distinct human disorders, collectively known as laminopathies, among which is the premature aging disease Hutchinson-Gilford progeria syndrome (HGPS). The majority of HGPS cases are associated with a single point mutation in the LMNA gene that causes the production of a permanently farnesylated mutant lamin A protein termed progerin. The mechanism by which progerin leads to premature aging and the classical HGPS disease phenotype as well as the relationship between this disorder and the onset of analogous symptoms during the lifespan of a normal individual are not well understood. Yet, recent studies have provided critical insights on the cellular processes that are affected by accumulation of progerin and have suggested that cellular alterations in the lamin A processing pathway leading to the accumulation of farnesylated prelamin A intermediates may play a role in the aging process in the general population. In this review we provide a short background on lamin A and its maturation pathway and discuss the current knowledge of how progerin or alterations in the prelamin A processing pathway are thought to influence cell function and contribute to human aging.

  10. A previously functional tetracycline-regulated transactivator fails to target gene expression to the bone

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    Schmidt Eva

    2011-08-01

    Full Text Available Abstract Background The tetracycline-controlled transactivator system is a powerful tool to control gene expression in vitro and to generate consistent and conditional transgenic in vivo model organisms. It has been widely used to study gene function and to explore pathological mechanisms involved in human diseases. The system permits the regulation of the expression of a target gene, both temporally and quantitatively, by the application of tetracycline or its derivative, doxycycline. In addition, it offers the possibility to restrict gene expression in a spatial fashion by utilizing tissue-specific promoters to drive the transactivator. Findings In this study, we report our problems using a reverse tetracycline-regulated transactivator (rtTA in a transgenic mouse model system for the bone-specific expression of the Hutchinson-Gilford progeria syndrome mutation. Even though prior studies have been successful utilizing the same rtTA, expression analysis of the transactivator revealed insufficient activity for regulating the transgene expression in our system. The absence of transactivator could not be ascribed to differences in genetic background because mice in a mixed genetic background and in congenic mouse lines showed similar results. Conclusions The purpose of this study is to report our negative experience with previously functional transactivator mice, to raise caution in the use of tet-based transgenic mouse lines and to reinforce the need for controls to ensure the stable functionality of generated tetracycline-controlled transactivators over time.

  11. Dynamics of lamin-A processing following precursor accumulation.

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    Qian Liu

    Full Text Available Lamin A (LaA is a component of the nuclear lamina, an intermediate filament meshwork that underlies the inner nuclear membrane (INM of the nuclear envelope (NE. Newly synthesized prelamin A (PreA undergoes extensive processing involving C-terminal farnesylation followed by proteolysis yielding non-farnesylated mature lamin A. Different inhibitors of these processing events are currently used therapeutically. Hutchinson-Gilford Progeria Syndrome (HGPS is most commonly caused by mutations leading to an accumulation of a farnesylated LaA isoform, prompting a clinical trial using farnesyltransferase inhibitors (FTI to reduce this modification. At therapeutic levels, HIV protease inhibitors (PI can unexpectedly inhibit the final processing step in PreA maturation. We have examined the dynamics of LaA processing and associated cellular effects during PI or FTI treatment and following inhibitor washout. While PI reversibility was rapid, with respect to both LaA maturation and associated cellular phenotype, recovery from FTI treatment was more gradual. FTI reversibility is influenced by both cell type and rate of proliferation. These results suggest a less static lamin network than has previously been observed.

  12. Mandibuloacral Dysplasia Caused by LMNA Mutations and Uniparental Disomy

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    Shaochun Bai

    2014-01-01

    Full Text Available Mandibuloacral dysplasia (MAD is a rare autosomal recessive disorder characterized by postnatal growth retardation, craniofacial anomalies, skeletal malformations, and mottled cutaneous pigmentation. Hutchinson-Gilford Progeria Syndrome (HGPS is characterized by the clinical features of accelerated aging in childhood. Both MAD and HGPS can be caused by mutations in the LMNA gene. In this study, we describe a 2-year-old boy with overlapping features of MAD and HGPS. Mutation analysis of the LMNA gene revealed a homozygous missense change, p.M540T, while only the mother carries the mutation. Uniparental disomy (UPD analysis for chromosome 1 showed the presence of maternal UPD. Markers in the 1q21.3–q22 region flanking the LMNA locus were isodisomic, while markers in the short arm and distal 1q region were heterodisomic. These results suggest that nondisjunction in maternal meiosis followed by loss of the paternal chromosome 1 during trisomy rescue might result in the UPD1 and homozygosity for the p.M540T mutation observed in this patient.

  13. Survey of radiosensitivity in a variety of human cell strains

    Energy Technology Data Exchange (ETDEWEB)

    Arlett, C.F.; Harcourt, S.A.

    1980-03-01

    Gamma-ray sensitivity for cell killing was assayed in 54 human cell strains, including some derived from individuals suffering from certain hereditary diseases. The overall range of Do values in this study was 38 to 180 rads, indicating a considerable range of variability in humans. The normal sensitivity was described by a range of Do values of 97 to 180 rads. All ten ataxia telangiectasia cell strains tested proved radiosensitive and gave a mean Do value of 57 +- 15 (S.E.) rads, and these represent the most radiosensitive human skin fibroblasts currently available. Representative cell strains from familial retinoblastoma, Fanconi's anemia, and Hutchinson-Gilford progeria occupied positions of intermediate sensitivity, as did one of two ataxia telangiectasia heterozygotes. Six xeroderma pigmentosum cell strains together with two Cockayne's syndrome cell strains (all known to be sensitive to ultraviolet light) fell into the normal range, indicating an absence of cross-sensitivity between ultraviolet light and gamma-irradiation.

  14. An Elastic Model of Blebbing in Nuclear Lamin Meshworks

    Science.gov (United States)

    Funkhouser, Chloe; Sknepnek, Rastko; Shimi, Takeshi; Goldman, Anne; Goldman, Robert; Olvera de La Cruz, Monica

    2013-03-01

    A two-component continuum elastic model is introduced to analyze a nuclear lamin meshwork, a structural element of the lamina of the nuclear envelope. The main component of the lamina is a meshwork of lamin protein filaments providing mechanical support to the nucleus and also playing a role in gene expression. Abnormalities in nuclear shape are associated with a variety of pathologies, including some forms of cancer and Hutchinson-Gilford progeria syndrome, and are often characterized by protruding structures termed nuclear blebs. Nuclear blebs are rich in A-type lamins and may be related to pathological gene expression. We apply the two-dimensional elastic shell model to determine which characteristics of the meshwork could be responsible for blebbing, including heterogeneities in the meshwork thickness and mesh size. We find that if one component of the lamin meshwork, rich in A-type lamins, has a tendency to form a larger mesh size than that rich in B-type lamins, this is sufficient to cause segregation of the lamin components and also to form blebs rich in A-type lamins. The model produces structures with comparable morphologies and mesh size distributions as the lamin meshworks of real, pathological nuclei. Funded by US DoE Award DEFG02-08ER46539 and by the DDR&E and AFOSR under Award FA9550-10-1-0167; simulations performed on NU Quest cluster

  15. Recent advances in understanding the role of lamins in health and disease

    Science.gov (United States)

    Reddy, Sita; Comai, Lucio

    2016-01-01

    Lamins are major components of the nuclear lamina, a network of proteins that supports the nuclear envelope in metazoan cells. Over the past decade, biochemical studies have provided support for the view that lamins are not passive bystanders providing mechanical stability to the nucleus but play an active role in the organization of the genome and the function of fundamental nuclear processes. It has also become apparent that lamins are critical for human health, as a large number of mutations identified in the gene that encodes for A-type lamins are associated with tissue-specific and systemic genetic diseases, including the accelerated aging disorder known as Hutchinson-Gilford progeria syndrome. Recent years have witnessed great advances in our understanding of the role of lamins in the nucleus and the functional consequences of disease-associated A-type lamin mutations. Many of these findings have been presented in comprehensive reviews. In this mini-review, we discuss recent breakthroughs in the role of lamins in health and disease and what lies ahead in lamin research. PMID:27803806

  16. Role of nuclear Lamin A/C in cardiomyocyte functions.

    Science.gov (United States)

    Carmosino, Monica; Torretta, Silvia; Procino, Giuseppe; Gerbino, Andrea; Forleo, Cinzia; Favale, Stefano; Svelto, Maria

    2014-10-01

    Lamin A/C is a structural protein of the nuclear envelope (NE) and cardiac involvement in Lamin A/C mutations was one of the first phenotypes to be reported in humans, suggesting a crucial role of this protein in the cardiomyocytes function. Mutations in LMNA gene cause a class of pathologies generically named 'Lamanopathies' mainly involving heart and skeletal muscles. Moreover, the well-known disease called Hutchinson-Gilford Progeria Syndrome due to extensive mutations in LMNA gene, in addition to the systemic phenotype of premature aging, is characterised by the death of patients at around 13 typically for a heart attack or stroke, suggesting again the heart as the main site sensitive to Lamin A/C disfunction. Indeed, the identification of the roles of the Lamin A/C in cardiomyocytes function is a key area of exploration. One of the primary biological roles recently conferred to Lamin A/C is to affect contractile cells lineage determination and senescence. Then, in differentiated adult cardiomyocytes both the 'structural' and 'gene expression hypothesis' could explain the role of Lamin A in the function of cardiomyocytes. In fact, recent advances in the field propose that the structural weakness/stiffness of the NE, regulated by Lamin A/C amount in NE, can 'consequently' alter gene expression. © 2014 Société Française des Microscopies and Société de Biologie Cellulaire de France. Published by John Wiley & Sons Ltd.

  17. Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction.

    Science.gov (United States)

    Lammerding, Jan; Schulze, P Christian; Takahashi, Tomosaburo; Kozlov, Serguei; Sullivan, Teresa; Kamm, Roger D; Stewart, Colin L; Lee, Richard T

    2004-02-01

    Mutations in the lamin A/C gene (LMNA) cause a variety of human diseases including Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy, and Hutchinson-Gilford progeria syndrome. The tissue-specific effects of lamin mutations are unclear, in part because the function of lamin A/C is incompletely defined, but the many muscle-specific phenotypes suggest that defective lamin A/C could increase cellular mechanical sensitivity. To investigate the role of lamin A/C in mechanotransduction, we subjected lamin A/C-deficient mouse embryo fibroblasts to mechanical strain and measured nuclear mechanical properties and strain-induced signaling. We found that Lmna-/- cells have increased nuclear deformation, defective mechanotransduction, and impaired viability under mechanical strain. NF-kappaB-regulated transcription in response to mechanical or cytokine stimulation was attenuated in Lmna-/- cells despite increased transcription factor binding. Lamin A/C deficiency is thus associated with both defective nuclear mechanics and impaired mechanically activated gene transcription. These findings suggest that the tissue-specific effects of lamin A/C mutations observed in the laminopathies may arise from varying degrees of impaired nuclear mechanics and transcriptional activation.

  18. The nuclear membrane and mechanotransduction: impaired nuclear mechanics and mechanotransduction in lamin A/C deficient cells.

    Science.gov (United States)

    Lammerding, Jan; Lee, Richard T

    2005-01-01

    Mutations in the lamin A/C gene cause a variety of human diseases including Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy and Hutchinson-Gilford progeria syndrome. The tissue specific effects of lamin mutations are unclear, in part because the function of lamin A/C is incompletely defined, but the many muscle specific phenotypes suggest that defective lamin A/C could increase cellular mechanical sensitivity. Lamin A/C deficient fibroblasts were subjected to mechanical strain to measure nuclear mechanical properties and strain-induced signalling. We found that lamin A/C deficient fibroblasts are characterized by impaired nuclear mechanics and mechanotransduction, reflected by increased nuclear deformations, increased nuclear fragility, attenuated expression of mechanosensitive genes, and impaired transcriptional activation, leading to impaired viability of mechanically strained cells. Lamins and other nuclear envelope proteins can thus affect several levels of the mechanotransduction cascade, altering nuclear and cytoskeletal mechanics as well as playing an important role in mechanically activated gene regulation. Individual mutations in the lamin A/C gene could potentially selectively interfere with any of these functions, explaining the tissue-specific effects observed in the laminopathies.

  19. Atomic force microscopy and lamins: A review study towards future, combined investigations.

    Science.gov (United States)

    Pecorari, Ilaria; Puzzi, Luca; Sbaizero, Orfeo

    2017-01-01

    In the last decades, atomic force microscopy (AFM) underwent a rapid and stunning development, especially for studying mechanical properties of biological samples. The numerous discoveries relying to this approach, have increased the credit of AFM as a versatile tool, and potentially eligible as a diagnostic equipment. Meanwhile, it has become strikingly evident that lamins are involved on the onset and development of certain diseases, including cancer, Hutchinson-Gilford progeria syndrome, cardiovascular pathologies, and muscular dystrophy. A new category of pathologies has been defined, the laminopathies, which are caused by mutations in the gene encoding for A-type lamins. As the majority of medical issues, lamins, and all their related aspects can be considered as a quite complex problem. Indeed, there are many facets to explore, and this definitely requires a multidisciplinary approach. One of the most intriguing aspects concerning lamins is their remarkable contribute to cells mechanics. Over the years, this has led to the speculation of the so-called "structural hypothesis", which attempts to elucidate the etiology and some features of the laminopathies. Among the various techniques tried to figure out the role of lamins in the cells mechanics, the AFM has been already successfully applied, proving its versatility. Therefore, the present work aims both to highlight the qualities of AFM and to review the most relevant knowledge about lamins, in order to promote the study of the latter, taking advantage from the former. Microsc. Res. Tech. 80:97-108, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  20. Lamin A deregulation in human mesenchymal stem cells promotes an impairment in their chondrogenic potential and imbalance in their response to oxidative stress.

    Science.gov (United States)

    Mateos, Jesús; De la Fuente, Alexandre; Lesende-Rodriguez, Iván; Fernández-Pernas, Pablo; Arufe, María C; Blanco, Francisco J

    2013-11-01

    In the present study, we examined the effect of the over-expression of LMNA, or its mutant form progerin (PG), on the mesoderm differentiation potential of mesenchymal stem cells (MSCs) from human umbilical cord (UC) stroma using a recently described differentiation model employing spheroid formation. Accumulation of lamin A (LMNA) was previously associated with the osteoarthritis (OA) chondrocyte phenotype. Mutations of this protein are linked to laminopathies and specifically to Hutchinson-Gilford Progeria Syndrome (HGPS), an accelerated aging disease. Some authors have proposed that a deregulation of LMNA affects the differentiation potential of stem cells. The chondrogenic potential is defective in PG-MSCs, although both PG and LMNA transduced MSCs, have an increase in hypertrophy markers during chondrogenic differentiation. Furthermore, both PG and LMNA-MSCs showed a decrease in manganese superoxide dismutase (MnSODM), an increase of mitochondrial MnSODM-dependent reactive oxygen species (ROS) and alterations in their migration capacity. Finally, defects in chondrogenesis are partially reversed by periodic incubation with ROS-scavenger agent that mimics MnSODM effect. Our results indicate that over-expression of LMNA or PG by lentiviral gene delivery leads to defects in chondrogenic differentiation potential partially due to an imbalance in oxidative stress.

  1. Quantitative assessment of lactate and progerin production in normal human cutaneous cells during normal ageing: effect of an Alaria esculenta extract.

    Science.gov (United States)

    Verdy, C; Branka, J-E; Mekideche, N

    2011-10-01

    Anti-ageing products are of a great importance in cosmetic fields. However, even if numerous strategies have been proposed to fight against skin ageing or to minimize its aesthetic impact since the beginning of the 'scientific cosmetology' era, the products basing their efficacy on the observation of pathological situations are rare. The most obvious pathology linked to the ageing of skin (notably) consists in the Hutchinson-Gilford Progeria Syndrome (HGPS), a rare disorder characterized by accelerated ageing and early death. In this disease the lamin A, a protein participating (with others lamins) in the formation of the nuclear lamina and implicated in nuclear stability, chromatin structure and gene expression, is present in a truncated version called progerin. In this study, we have examined the lactate and the progerin production of human normal cutaneous cells issued from subjects of different ages. Using a sensitive and specific progerin ELISA assay developed in house, we so provide the first quantitative demonstration of an increased progerin expression and lactate production in skin during ageing. Moreover, we have also demonstrated that in the selected experimental conditions, it was possible to down-regulate the progerin production of aged cells by using an algae extract. As this extract, an Alaria esculenta extract, could be used in cosmetic formulations, we suggest that a better understanding of the skin pathologies could be a useful tool in developing efficient active compounds, attractive for but not limited to cosmetic purposes.

  2. Phenotype-Dependent Coexpression Gene Clusters: Application to Normal and Premature Ageing.

    Science.gov (United States)

    Wang, Kun; Das, Avinash; Xiong, Zheng-Mei; Cao, Kan; Hannenhalli, Sridhar

    2015-01-01

    Hutchinson Gilford progeria syndrome (HGPS) is a rare genetic disease with symptoms of aging at a very early age. Its molecular basis is not entirely clear, although profound gene expression changes have been reported, and there are some known and other presumed overlaps with normal aging process. Identification of genes with agingor HGPS-associated expression changes is thus an important problem. However, standard regression approaches are currently unsuitable for this task due to limited sample sizes, thus motivating development of alternative approaches. Here, we report a novel iterative multiple regression approach that leverages co-expressed gene clusters to identify gene clusters whose expression co-varies with age and/or HGPS. We have applied our approach to novel RNA-seq profiles in fibroblast cell cultures at three different cellular ages, both from HGPS patients and normal samples. After establishing the robustness of our approach, we perform a comparative investigation of biological processes underlying normal aging and HGPS. Our results recapitulate previously known processes underlying aging as well as suggest numerous unique processes underlying aging and HGPS. The approach could also be useful in detecting phenotype-dependent co-expression gene clusters in other contexts with limited sample sizes.

  3. Insights into the role of immunosenescence during varicella zoster virus infection (shingles) in the aging cell model.

    Science.gov (United States)

    Kim, Ji-Ae; Park, Seul-Ki; Kumar, Mukesh; Lee, Chan-Hee; Shin, Ok Sarah

    2015-11-03

    Varicella zoster virus (VZV) is the etiological agent of shingles, a painful skin rash that affects a significant proportion of the elderly population. In the present study, we used two aging cell models, Hutchinson-Gilford progeria syndrome (HGPS) fibroblasts and stress or replicative senescence-induced normal human dermal fibroblasts (NHDFs), to investigate age-associated susceptibility to VZV infection. VZV infectivity titers were significantly associated with donor age in HGPS fibroblasts and senescence induction in NHDFs. High throughput RNA-sequencing (RNA-seq) analysis was performed to assess global and dynamic changes in the host transcriptomes of VZV-infected aging cells. Analysis of differentially expressed genes (DEGs) indicated that VZV infection in aged HGPS fibroblasts resembled that in senescent NHDFs, particularly in terms of genes associated with pattern recognition receptors in virus sensing network, providing novel insights into the mechanisms of senescence-associated susceptibility to VZV infection. Additionally, we identified stimulator of interferon genes (STING) as a potential VZV sensing receptor. Knockdown of STING expression resulted in increased viral replication in primary fibroblasts, whereas STING overexpression led to suppression of VZV plaque formation. In conclusion, our findings highlight the important role of immunosenescence following VZV infection and provide significant insights into the mechanisms underlying cellular sensing of VZV infection and the induction of immune responses in aged skin cells.

  4. Atherosclerosis in ancient humans, accelerated aging syndromes and normal aging: is lamin a protein a common link?

    Science.gov (United States)

    Miyamoto, Michael I; Djabali, Karima; Gordon, Leslie B

    2014-06-01

    Imaging studies of ancient human mummies have demonstrated the presence of vascular calcification that is consistent with the presence of atherosclerosis. These findings have stimulated interest in the underlying biological processes that might impart to humans an inherent predisposition to the development of atherosclerosis. Clues to these processes may possibly be found in accelerated aging syndromes, such as Hutchinson-Gilford progeria syndrome (HGPS), an ultra-rare disorder characterized by premature aging phenotypes, including very aggressive forms of atherosclerosis, occurring in childhood. The genetic defect in HGPS eventuates in the production of a mutant form of the nuclear structural protein lamin A, called progerin, which is thought to interfere with normal nuclear functioning. Progerin appears to be expressed in vascular cells, resulting in vessel wall cell loss and replacement by fibrous tissue, reducing vessel compliance and promoting calcification, leading to the vascular dysfunction and atherosclerosis seen in HGPS. Interestingly, vascular progerin is detectable in lower levels, in an age-related manner, in the general population, providing the basis for further study of the potential role of abnormal forms of lamin A in the atherosclerotic process of normal aging.

  5. Premature aging in mice activates a systemic metabolic response involving autophagy induction.

    Science.gov (United States)

    Mariño, Guillermo; Ugalde, Alejandro P; Salvador-Montoliu, Natalia; Varela, Ignacio; Quirós, Pedro M; Cadiñanos, Juan; van der Pluijm, Ingrid; Freije, José M P; López-Otín, Carlos

    2008-07-15

    Autophagy is a highly regulated intracellular process involved in the turnover of most cellular constituents and in the maintenance of cellular homeostasis. It is well-established that the basal autophagic activity of living cells decreases with age, thus contributing to the accumulation of damaged macromolecules during aging. Conversely, the activity of this catabolic pathway is required for lifespan extension in animal models such as Caenorhabditis elegans and Drosophila melanogaster. In this work, we describe the unexpected finding that Zmpste24-null mice, which show accelerated aging and are a reliable model of human Hutchinson-Gilford progeria, exhibit an extensive basal activation of autophagy instead of the characteristic decline in this process occurring during normal aging. We also show that this autophagic increase is associated with a series of changes in lipid and glucose metabolic pathways, which resemble those occurring in diverse situations reported to prolong lifespan. These Zmpste24(-/-) mice metabolic alterations are also linked to substantial changes in circulating blood parameters, such as leptin, glucose, insulin or adiponectin which in turn lead to peripheral LKB1-AMPK activation and mTOR inhibition. On the basis of these results, we propose that nuclear abnormalities causing premature aging in Zmpste24(-/-) mice trigger a metabolic response involving the activation of autophagy. However, the chronic activation of this catabolic pathway may turn an originally intended pro-survival strategy into a pro-aging mechanism and could contribute to the systemic degeneration and weakening observed in these progeroid mice.

  6. Investigation of age-related changes in LMNA splicing and expression of progerin in human skeletal muscles.

    Science.gov (United States)

    Luo, Yue-Bei; Mitrpant, Chalermchai; Johnsen, Russell D; Fabian, Victoria A; Fletcher, Sue; Mastaglia, Frank L; Wilton, Steve D

    2013-01-01

    Age-related changes in splice-forms of LMNA, which encodes the nuclear lamina proteins lamin A/C, have not been investigated in skeletal muscle. In the rare premature ageing disease, Hutchinson-Gilford progeria syndrome (HGPS), de novo point mutations in LMNA activate a cryptic splice site in exon 11, resulting in a 150 base deletion in LMNA mRNA and accumulation of a truncated protein isoform, progerin. The LMNA Δ150 progerin transcript has also been found in trace quantities in tissues of healthy people and its implication in 'natural' ageing has been proposed. We therefore investigated the expression of progerin and lamin A/C in normal human and mouse skeletal muscles of different ages. LMNA Δ150 was detected in most muscle samples from healthy individuals aged 16-71 years, but was not present in any mouse muscle samples up to the age of 18 months. Real time qPCR of human muscle samples showed that there was an age-related increase in both the full length lamin A and LMNA Δ150 transcripts, whereas their protein levels did not change significantly with age. These findings indicate that there is a basal level of mis-splicing during LMNA expression that does not change with ageing in human muscle, but at levels that do not result in increased aberrant protein. The significance of these findings in the pathophysiology of muscle ageing is uncertain and warrants further investigation.

  7. Longwave UV light induces the aging-associated progerin.

    Science.gov (United States)

    Takeuchi, Hirotaka; Rünger, Thomas M

    2013-07-01

    Premature aging in Hutchinson-Gilford progeria syndrome (HGPS) is caused by a mutation of the LMNA gene that activates a cryptic splice site. This results in expression of a truncated form of Lamin A, called progerin. Accumulation of progerin in the nuclei of HGPS cells impairs nuclear functions and causes abnormal nuclear morphology. Progerin accumulation has not only been described in HGPS, but also during normal intrinsic aging. We hypothesized that accumulation of progerin with abnormal nuclear shapes may also be accelerated by UV and with that contribute to photoaging of the skin. We exposed neonatal or aged cultured fibroblasts to single or repeated doses of longwave or shortwave UV (UVA or UVB) and found that UVA, but not UVB, induces progerin expression and HGPS-like abnormal nuclear shapes in all cells, but more in aged cells. The induction of progerin is mediated by UVA-induced oxidative damage and subsequent alternative splicing of the LMNA transcript, as progerin induction was suppressed by the singlet oxygen quencher sodium azide, and as mRNA expression of LMNA was not induced by UVA. These data suggest a previously unreported pathway of photoaging and support the concept that photoaging is at least in part a process of damage-accelerated intrinsic aging.

  8. Investigation of splicing changes and post-translational processing of LMNA in sporadic inclusion body myositis.

    Science.gov (United States)

    Luo, Yue-Bei; Mitrpant, Chalermchai; Johnsen, Russell; Fabian, Vicki; Needham, Merrilee; Fletcher, Sue; Wilton, Steve D; Mastaglia, Frank L

    2013-01-01

    Some features of sporadic inclusion body myositis (s-IBM) suggest that there is acceleration of the normal ageing process in muscle tissue. LMNA encodes the nuclear lamina proteins lamin A/C through alternative splicing, and aberrant splicing of exon 11 leads to the premature ageing disease, Hutchinson-Gilford progeria syndrome. Progerin, the pathogenic isoform expressed in HGPS tissues, has also been detected at low levels in tissues of normal individuals with aging. We therefore investigated the alternative splicing of LMNA gene transcripts, and the post-translational processing of prelamin A, in s-IBM and control muscle samples. Age-related low level expression of the progerin transcript was detected in both s-IBM and control muscles, but was not increased in s-IBM and there was no increase in progerin protein or demonstrable accumulation of intermediate prelamin isoforms in the s-IBM muscles. However, an age-related shift in the balance of splicing towards lamin A-related transcripts, which was present in normal muscles, was not found in s-IBM. Our findings indicate that while there are changes in the patterns of LMNA splicing in s-IBM muscle which are probably secondary to the underlying pathological process, it is unlikely that aberrant splicing of exon 11 or defective post-translational processing of prelamin A are involved in the pathogenesis of the disease.

  9. Global genome splicing analysis reveals an increased number of alternatively spliced genes with aging.

    Science.gov (United States)

    Rodríguez, Sofía A; Grochová, Diana; McKenna, Tomás; Borate, Bhavesh; Trivedi, Niraj S; Erdos, Michael R; Eriksson, Maria

    2016-04-01

    Alternative splicing (AS) is a key regulatory mechanism for the development of different tissues; however, not much is known about changes to alternative splicing during aging. Splicing events may become more frequent and widespread genome-wide as tissues age and the splicing machinery stringency decreases. Using skin, skeletal muscle, bone, thymus, and white adipose tissue from wild-type C57BL6/J male mice (4 and 18 months old), we examined the effect of age on splicing by AS analysis of the differential exon usage of the genome. The results identified a considerable number of AS genes in skeletal muscle, thymus, bone, and white adipose tissue between the different age groups (ranging from 27 to 246 AS genes corresponding to 0.3-3.2% of the total number of genes analyzed). For skin, skeletal muscle, and bone, we included a later age group (28 months old) that showed that the number of alternatively spliced genes increased with age in all three tissues (P aging disease Hutchinson-Gilford progeria syndrome was performed. The results show that expression of the mutant protein, progerin, is associated with an impaired developmental splicing. As progerin accumulates, the number of genes with AS increases compared to in wild-type skin. Our results indicate the existence of a mechanism for increased AS during aging in several tissues, emphasizing that AS has a more important role in the aging process than previously known.

  10. Nuclear lamins and neurobiology.

    Science.gov (United States)

    Young, Stephen G; Jung, Hea-Jin; Lee, John M; Fong, Loren G

    2014-08-01

    Much of the work on nuclear lamins during the past 15 years has focused on mutations in LMNA (the gene for prelamin A and lamin C) that cause particular muscular dystrophy, cardiomyopathy, partial lipodystrophy, and progeroid syndromes. These disorders, often called "laminopathies," mainly affect mesenchymal tissues (e.g., striated muscle, bone, and fibrous tissue). Recently, however, a series of papers have identified important roles for nuclear lamins in the central nervous system. Studies of knockout mice uncovered a key role for B-type lamins (lamins B1 and B2) in neuronal migration in the developing brain. Also, duplications of LMNB1 (the gene for lamin B1) have been shown to cause autosome-dominant leukodystrophy. Finally, recent studies have uncovered a peculiar pattern of nuclear lamin expression in the brain. Lamin C transcripts are present at high levels in the brain, but prelamin A expression levels are very low-due to regulation of prelamin A transcripts by microRNA 9. This form of prelamin A regulation likely explains why "prelamin A diseases" such as Hutchinson-Gilford progeria syndrome spare the central nervous system. In this review, we summarize recent progress in elucidating links between nuclear lamins and neurobiology.

  11. Mechanobiology and the microcirculation: cellular, nuclear and fluid mechanics.

    Science.gov (United States)

    Dahl, Kris Noel; Kalinowski, Agnieszka; Pekkan, Kerem

    2010-04-01

    Endothelial cells are stimulated by shear stress throughout the vasculature and respond with changes in gene expression and by morphological reorganization. Mechanical sensors of the cell are varied and include cell surface sensors that activate intracellular chemical signaling pathways. Here, possible mechanical sensors of the cell including reorganization of the cytoskeleton and the nucleus are discussed in relation to shear flow. A mutation in the nuclear structural protein lamin A, related to Hutchinson-Gilford progeria syndrome, is reviewed specifically as the mutation results in altered nuclear structure and stiffer nuclei; animal models also suggest significantly altered vascular structure. Nuclear and cellular deformation of endothelial cells in response to shear stress provides partial understanding of possible mechanical regulation in the microcirculation. Increasing sophistication of fluid flow simulations inside the vessel is also an emerging area relevant to the microcirculation as visualization in situ is difficult. This integrated approach to study--including medicine, molecular and cell biology, biophysics and engineering--provides a unique understanding of multi-scale interactions in the microcirculation.

  12. Promotion of tumor development in prostate cancer by progerin

    Directory of Open Access Journals (Sweden)

    Nie Daotai

    2010-11-01

    Full Text Available Abstract Progerin is a truncated form of lamin A. It is identified in patients with Hutchinson-Gilford progeria syndrome (HGPS, a disease characterized by accelerated aging. The contribution of progerin toward aging has been shown to be related to increased DNA damages. Since aging is one major risk factor for carcinogenesis, and genomic instability is a hallmark of malignant cancers, we investigated the expression of progerin in human cancer cells, and whether its expression contributes to carcinogenesis. Using RT-PCR and Western blotting, we detected the expression of progerin in prostate PC-3, DU145 and LNCaP cells at mRNA and protein levels. Ectopic progerin expression did not cause cellular senescence in PC-3 or MCF7 cells. PC-3 cells progerin transfectants were sensitized to DNA damage agent camptothecin (CPT; and persistent DNA damage responses were observed, which might be caused by progerin induced defective DNA damage repair. In addition, progerin transfectants were more tumorigenic in vivo than vector control cells. Our study for the first time describes the expression of progerin in a number of human cancer cell lines and its contributory role in tumorigenesis.

  13. Accelerated Telomere Shortening and Replicative Senescence in Human Fibroblasts Overexpressing Mutant and Wild Type Lamin A

    Science.gov (United States)

    Huang, Shurong; Risques, Rosa Ana; Martin, George M.; Rabinovitch, Peter S.; Oshima, Junko

    2008-01-01

    LMNA mutations are responsible for a variety of genetic disorders, including muscular dystrophy, lipodystrophy, and certain progeroid syndromes, notably Hutchinson-Gilford Progeria. Although a number of clinical features of these disorders are suggestive of accelerated aging, it is not known whether cells derived from these patients exhibit cellular phenotypes associated with accelerated aging. We examined a series of isogenic skin fibroblast lines transfected with LMNA constructs bearing known pathogenic point mutations or deletion mutations found in progeroid syndromes. Fibroblasts overexpressing mutant lamin A exhibited accelerated rates of loss of telomeres and shortened replicative lifespans, in addition to abnormal nuclear morphology. To our surprise, these abnormalities were also observed in lines overexpressing wild-type lamin A. Copy number variants are common in human populations; those involving LMNA, whether arising meiotically or mitotically, might lead to progeroid phenotypes. In an initial pilot study of 23 progeroid cases without detectible WRN or LMNA mutations, however, no cases of altered LMNA copy number were detected. Nevertheless, our findings raise a hypothesis that changes in lamina organization may cause accelerated telomere attrition, with different kinetics for overexpession of wild-type and mutant lamin A, which leads to rapid replicative senescence and progroid phenotypes. PMID:17870066

  14. Transformation Resistance in a Premature Aging Disorder Identifies a Tumor-Protective Function of BRD4

    Directory of Open Access Journals (Sweden)

    Patricia Fernandez

    2014-10-01

    Full Text Available Advanced age and DNA damage accumulation are prominent risk factors for cancer. The premature aging disorder Hutchinson-Gilford progeria syndrome (HGPS provides a unique opportunity for studying the interplay between DNA damage and aging-associated tumor mechanisms, given that HGPS patients do not develop tumors despite elevated levels of DNA damage. Here, we have used HGPS patient cells to identify a protective mechanism to oncogenesis. We find that HGPS cells are resistant to neoplastic transformation. Resistance is mediated by the bromodomain protein BRD4, which exhibits altered genome-wide binding patterns in transformation-resistant cells, leading to inhibition of oncogenic dedifferentiation. BRD4 also inhibits, albeit to a lower extent, the tumorigenic potential of transformed cells from healthy individuals. BRD4-mediated tumor protection is clinically relevant given that a BRD4 gene signature predicts positive clinical outcome in breast and lung cancer. Our results demonstrate a protective function for BRD4 and suggest tissue-specific roles for BRD4 in tumorigenesis.

  15. Lifespan extension by dietary intervention in a mouse model of Cockayne syndrome uncouples early postnatal development from segmental progeria.

    Science.gov (United States)

    Brace, Lear E; Vose, Sarah C; Vargas, Dorathy F; Zhao, Shuangyun; Wang, Xiu-Ping; Mitchell, James R

    2013-12-01

    Cockayne syndrome (CS) is a rare autosomal recessive segmental progeria characterized by growth failure, lipodystrophy, neurological abnormalities, and photosensitivity, but without skin cancer predisposition. Cockayne syndrome life expectancy ranges from 5 to 16 years for the two most severe forms (types II and I, respectively). Mouse models of CS have thus far been of limited value due to either very mild phenotypes, or premature death during postnatal development prior to weaning. The cause of death in severe CS models is unknown, but has been attributed to extremely rapid aging. Here, we found that providing mutant pups with soft food from as late as postnatal day 14 allowed survival past weaning with high penetrance independent of dietary macronutrient balance in a novel CS model (Csa(-/-) | Xpa(-/-)). Survival past weaning revealed a number of CS-like symptoms including small size, progressive loss of adiposity, and neurological symptoms, with a maximum lifespan of 19 weeks. Our results caution against interpretation of death before weaning as premature aging, and at the same time provide a valuable new tool for understanding mechanisms of progressive CS-related progeroid symptoms including lipodystrophy and neurodysfunction.

  16. Cardiac electrical defects in progeroid mice and Hutchinson–Gilford progeria syndrome patients with nuclear lamina alterations

    Science.gov (United States)

    Rivera-Torres, José; Calvo, Conrado J.; Llach, Anna; Guzmán-Martínez, Gabriela; Caballero, Ricardo; González-Gómez, Cristina; Jiménez-Borreguero, Luis J.; Guadix, Juan A.; Osorio, Fernando G.; López-Otín, Carlos; Herraiz-Martínez, Adela; Cabello, Nuria; Vallmitjana, Alex; Benítez, Raul; Gordon, Leslie B.; Pérez-Pomares, José M.; Tamargo, Juan; Delpón, Eva; Hove-Madsen, Leif; Filgueiras-Rama, David; Andrés, Vicente

    2016-01-01

    Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disease caused by defective prelamin A processing, leading to nuclear lamina alterations, severe cardiovascular pathology, and premature death. Prelamin A alterations also occur in physiological aging. It remains unknown how defective prelamin A processing affects the cardiac rhythm. We show age-dependent cardiac repolarization abnormalities in HGPS patients that are also present in the Zmpste24−/− mouse model of HGPS. Challenge of Zmpste24−/− mice with the β-adrenergic agonist isoproterenol did not trigger ventricular arrhythmia but caused bradycardia-related premature ventricular complexes and slow-rate polymorphic ventricular rhythms during recovery. Patch-clamping in Zmpste24−/− cardiomyocytes revealed prolonged calcium-transient duration and reduced sarcoplasmic reticulum calcium loading and release, consistent with the absence of isoproterenol-induced ventricular arrhythmia. Zmpste24−/− progeroid mice also developed severe fibrosis-unrelated bradycardia and PQ interval and QRS complex prolongation. These conduction defects were accompanied by overt mislocalization of the gap junction protein connexin43 (Cx43). Remarkably, Cx43 mislocalization was also evident in autopsied left ventricle tissue from HGPS patients, suggesting intercellular connectivity alterations at late stages of the disease. The similarities between HGPS patients and progeroid mice reported here strongly suggest that defective cardiac repolarization and cardiomyocyte connectivity are important abnormalities in the HGPS pathogenesis that increase the risk of arrhythmia and premature death. PMID:27799555

  17. CDKN2A/p16INK4a expression is associated with vascular progeria in chronic kidney disease

    Science.gov (United States)

    Stenvinkel, Peter; Luttropp, Karin; McGuinness, Dagmara; Witasp, Anna; Rashid Qureshi, Abdul; Wernerson, Annika; Nordfors, Louise; Schalling, Martin; Ripsweden, Jonaz; Wennberg, Lars; Söderberg, Magnus; Bárány, Peter; Olauson, Hannes; Shiels, Paul G

    2017-01-01

    Patients with chronic kidney disease (CKD) display a progeric vascular phenotype linked to apoptosis, cellular senescence and osteogenic transformation. This has proven intractable to modelling appropriately in model organisms. We have therefore investigated this directly in man, using for the first time validated cellular biomarkers of ageing (CDKN2A/p16INK4a, SA-β-Gal) in arterial biopsies from 61 CKD patients undergoing living donor renal transplantation. We demonstrate that in the uremic milieu, increased arterial expression of CDKN2A/p16INK4a associated with vascular progeria in CKD, independently of chronological age. The arterial expression of CDKN2A/p16INK4a was significantly higher in patients with coronary calcification (p=0.01) and associated cardiovascular disease (CVD) (p=0.004). The correlation between CDKN2A/p16INK4a and media calcification was statistically significant (p=0.0003) after correction for chronological age. We further employed correlate expression of matrix Gla protein (MGP) and runt-related transcription factor 2 (RUNX2) as additional pathognomonic markers. Higher expression of CDKN2A/p16INK4a, RUNX2 and MGP were observed in arteries with severe media calcification. The number of p16INK4a and SA-β-Gal positive cells was higher in biopsies with severe media calcification. A strong inverse correlation was observed between CDKN2A/p16INK4a expression and carboxylated osteocalcin levels. Thus, impaired vitamin K mediated carboxylation may contribute to premature vascular senescence. PMID:28192277

  18. Mitotic defects lead to pervasive aneuploidy and accompany loss of RB1 activity in mouse LmnaDhe dermal fibroblasts.

    Directory of Open Access Journals (Sweden)

    C Herbert Pratt

    Full Text Available BACKGROUND: Lamin A (LMNA is a component of the nuclear lamina and is mutated in several human diseases, including Emery-Dreifuss muscular dystrophy (EDMD; OMIM ID# 181350 and the premature aging syndrome Hutchinson-Gilford progeria syndrome (HGPS; OMIM ID# 176670. Cells from progeria patients exhibit cell cycle defects in both interphase and mitosis. Mouse models with loss of LMNA function have reduced Retinoblastoma protein (RB1 activity, leading to aberrant cell cycle control in interphase, but how mitosis is affected by LMNA is not well understood. RESULTS: We examined the cell cycle and structural phenotypes of cells from mice with the Lmna allele, Disheveled hair and ears (Lmna(Dhe. We found that dermal fibroblasts from heterozygous Lmna(Dhe (Lmna(Dhe/+ mice exhibit many phenotypes of human laminopathy cells. These include severe perturbations to the nuclear shape and lamina, increased DNA damage, and slow growth rates due to mitotic delay. Interestingly, Lmna(Dhe/+ fibroblasts also had reduced levels of hypophosphorylated RB1 and the non-SMC condensin II-subunit D3 (NCAP-D3, a mitosis specific centromere condensin subunit that depends on RB1 activity. Mitotic check point control by mitotic arrest deficient-like 1 (MAD2L1 also was perturbed in Lmna(Dhe/+ cells. Lmna(Dhe/+ fibroblasts were consistently aneuploid and had higher levels of micronuclei and anaphase bridges than normal fibroblasts, consistent with chromosome segregation defects. CONCLUSIONS: These data indicate that RB1 may be a key regulator of cellular phenotype in laminopathy-related cells, and suggest that the effects of LMNA on RB1 include both interphase and mitotic cell cycle control.

  19. A Novel Lamin A Mutant Responsible for Congenital Muscular Dystrophy Causes Distinct Abnormalities of the Cell Nucleus

    Science.gov (United States)

    Barateau, Alice; Vadrot, Nathalie; Vicart, Patrick; Ferreiro, Ana; Mayer, Michèle; Héron, Delphine; Vigouroux, Corinne

    2017-01-01

    A-type lamins, the intermediate filament proteins participating in nuclear structure and function, are encoded by LMNA. LMNA mutations can lead to laminopathies such as lipodystrophies, premature aging syndromes (progeria) and muscular dystrophies. Here, we identified a novel heterozygous LMNA p.R388P de novo mutation in a patient with a non-previously described severe phenotype comprising congenital muscular dystrophy (L-CMD) and lipodystrophy. In culture, the patient’s skin fibroblasts entered prematurely into senescence, and some nuclei showed a lamina honeycomb pattern. C2C12 myoblasts were transfected with a construct carrying the patient’s mutation; R388P-lamin A (LA) predominantly accumulated within the nucleoplasm and was depleted at the nuclear periphery, altering the anchorage of the inner nuclear membrane protein emerin and the nucleoplasmic protein LAP2-alpha. The mutant LA triggered a frequent and severe nuclear dysmorphy that occurred independently of prelamin A processing, as well as increased histone H3K9 acetylation. Nuclear dysmorphy was not significantly improved when transfected cells were treated with drugs disrupting microtubules or actin filaments or modifying the global histone acetylation pattern. Therefore, releasing any force exerted at the nuclear envelope by the cytoskeleton or chromatin did not rescue nuclear shape, in contrast to what was previously shown in Hutchinson-Gilford progeria due to other LMNA mutations. Our results point to the specific cytotoxic effect of the R388P-lamin A mutant, which is clinically related to a rare and severe multisystemic laminopathy phenotype. PMID:28125586

  20. Increased progerin expression associated with unusual LMNA mutations causes severe progeroid syndromes.

    Science.gov (United States)

    Moulson, Casey L; Fong, Loren G; Gardner, Jennifer M; Farber, Emily A; Go, Gloriosa; Passariello, Annalisa; Grange, Dorothy K; Young, Stephen G; Miner, Jeffrey H

    2007-09-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare precocious aging syndrome caused by mutations in LMNA that lead to synthesis of a mutant form of prelamin A, generally called progerin, that cannot be processed to mature lamin A. Most HGPS patients have a recurrent heterozygous de novo mutation in exon 11 of LMNA, c.1824C>T/p.G608G; this synonymous mutation activates a nearby cryptic splice donor site, resulting in synthesis of the mutant prelamin A, progerin, which lacks 50 amino acids within the carboxyl-terminal domain. Abnormal splicing is incomplete, so the mutant allele produces some normally-spliced transcripts. Nevertheless, the synthesis of progerin is sufficient to cause misshapen nuclei in cultured cells and severe disease phenotypes in affected patients. Here we present two patients with extraordinarily severe forms of progeria caused by unusual mutations in LMNA. One had a splice site mutation (c.1968+1G>A; or IVS11+1G>A), and the other had a novel synonymous coding region mutation (c.1821G>A/p.V607V). Both mutations caused very frequent use of the same exon 11 splice donor site that is activated in typical HGPS patients. As a consequence, the ratios of progerin mRNA and protein to wild-type were higher than in typical HGPS patients. Fibroblasts from both patients exhibited nuclear shape abnormalities typical of HGPS, and cells treated with a protein farnesyltransferase inhibitor exhibited fewer misshapen nuclei. Thus, farnesyltransferase inhibitors may prove to be useful even when progerin expression levels are higher than those in typical HGPS patients.

  1. Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy associated with a novel frameshift mutation at the 3' terminus of the FBN1-gene.

    Science.gov (United States)

    Graul-Neumann, Luitgard M; Kienitz, Tina; Robinson, Peter N; Baasanjav, Sevjidmaa; Karow, Benjamin; Gillessen-Kaesbach, Gabriele; Fahsold, Raimund; Schmidt, Hartmut; Hoffmann, Katrin; Passarge, Eberhard

    2010-11-01

    We report on a 25-year-old woman with pronounced generalized lipodystrophy and a progeroid aspect since birth, who also had Marfan syndrome (MFS; fulfilling the Ghent criteria) with mild skeletal features, dilated aortic bulb, dural ectasia, bilateral subluxation of the lens, and severe myopia in addition to the severe generalized lipodystrophy. She lacked insulin resistance, hypertriglyceridemia, hepatic steatosis, and diabetes. Mutation analysis in the gene encoding fibrillin 1 (FBN1) revealed a novel de novo heterozygous deletion, c.8155_8156del2 in exon 64. The severe generalized lipodystrophy in this patient with progeroid features has not previously been described in other patients with MFS and FBN1 mutations. We did not find a mutation in genes known to be associated with congenital lipodystrophy (APGAT2, BSCL2, CAV1, PTRF-CAVIN, PPARG, LMNB2) or with Hutchinson-Gilford progeria (ZMPSTE24, LMNA/C). Other progeria syndromes were considered unlikely because premature greying, hypogonadism, and scleroderma-like skin disease were not present. Our patient shows striking similarity to two patients who have been published in this journal by O'Neill et al. [O'Neill et al. (2007); Am J Med Genet Part A 143A:1421-1430] with the diagnosis of neonatal progeroid syndrome (NPS). This condition also known as Wiedemann-Rautenstrauch syndrome is a rare disorder characterized by accelerated aging and lipodystrophy from birth, poor postnatal weight gain, and characteristic facial features. The course is usually progressive with early lethality. However this entity seems heterogeneous. We suggest that our patient and the two similar cases described before represent a new entity, a subgroup of MFS with overlapping features to NPS syndrome.

  2. Relationship between Farnesylation of prelamin A and aging%核层蛋白A前体的法尼基化与衰老

    Institute of Scientific and Technical Information of China (English)

    袁源; 陈维春; 刘新光; 周中军

    2011-01-01

    Specific mutation in LMNA gives rise to a truncated prelamin A called progerin leading to Hutchinson-Gilford progeria syndrome (HGPS). A more severe progeroid disorder, restrictive dermopathy (RD), is caused by the loss of the prelamin A-processing enzyme, ZMPSTE24. The absence of ZMPSTE24 prevents the endoproteolytic processing of famesyl-prelamin A to mature lamin A and leads to the accumulation of farnesyl-prelamin A. In both HGPS and RD, the farnesyl-prelamin A is targeted to the nuclear envelope, where it interferes with the integrity of the nuclear envelope and causes misshapen cell nuclei, resulting in cellular senescence. Recent studies have shown that the frequency of misshapen nuclei can be reduced by treating cells with a famesyltransferase inhibitor (FTI). Also, administering an FTI to mouse models of HGPS and RD ameliorates the phenotypes of progeria. This paper summarizes the advance in study on the contribution of prelamin A farnesylation to premature aging.%编码核层蛋白A(lamin A)的LMNA基因突变导致法尼基化的核层蛋白A前体(prelamin A)不能被进一步加工成成熟的核层蛋白A,从而导致一种Hutchinson-Gilford早老症综合征(Hutchinson-Gilford progeria syndrome,HGPS).一种更严重的早老症——限制性皮肤病(restrictive dermopathy,RD),是由于缺失核层蛋白A前体加工过程中的剪切酶ZMPSTE24引起的.ZMPSTE24的缺失阻止了法尼基化的核层蛋白A前体不能正常加工成为成熟的核层蛋白A,同时导致法尼基化的核层蛋白A前体的堆积.在HGPS和RD病人的成纤维细胞中,发现法尼基化的核层蛋白A前体都定位在核膜,从而影响细胞核膜的完整性,并导致细胞核形的异常,进而导致衰老.最近研究表明经过法尼基酰转移酶抑制剂(famesyltransferase inhibitor,FTI)处理后的细胞的核形异常减少.同时,FTI能够改善HGPS和RD小鼠的早老症状.本文就核层蛋白A前体的法尼基化对衰老的影响有关研究进展作一综述.

  3. Schizophrenia as segmental progeria

    OpenAIRE

    Papanastasiou, Evangelos; Gaughran, Fiona; Smith, Shubulade

    2011-01-01

    Schizophrenia is associated with a variety of physical manifestations (i.e. metabolic, neurological) and despite psychotropic medication being blamed for some of these (in particular obesity and diabetes), there is evidence that schizophrenia itself confers an increased risk of physical disease and early death. The observation that schizophrenia and progeroid syndromes share common clinical features and molecular profiles gives rise to the hypothesis that schizophrenia could be conceptualized...

  4. Learning about Progeria

    Science.gov (United States)

    ... Specific Genetic Disorders Specific Genetic Disorders Learning About Prostate Cancer See Also: Talking Glossary of Genetic Terms Definitions ... from symptoms typically seen in much older people: stiffness of joints, hip dislocations and severe, progressive cardiovascular ...

  5. Differential temporal and spatial progerin expression during closure of the ductus arteriosus in neonates.

    Directory of Open Access Journals (Sweden)

    Regina Bökenkamp

    Full Text Available Closure of the ductus arteriosus (DA at birth is essential for the transition from fetal to postnatal life. Before birth the DA bypasses the uninflated lungs by shunting blood from the pulmonary trunk into the systemic circulation. The molecular mechanism underlying DA closure and degeneration has not been fully elucidated, but is associated with apoptosis and cytolytic necrosis in the inner media and intima. We detected features of histology during DA degeneration that are comparable to Hutchinson Gilford Progeria syndrome and ageing. Immunohistochemistry on human fetal and neonatal DA, and aorta showed that lamin A/C was expressed in all layers of the vessel wall. As a novel finding we report that progerin, a splicing variant of lamin A/C was expressed almost selectively in the normal closing neonatal DA, from which we hypothesized that progerin is involved in DA closure. Progerin was detected in 16.2%±7.2 cells of the DA. Progerin-expressing cells were predominantly located in intima and inner media where cytolytic necrosis accompanied by apoptosis will develop. Concomitantly we found loss of α-smooth muscle actin as well as reduced lamin A/C expression compared to the fetal and non-closing DA. In cells of the adjacent aorta, that remains patent, progerin expression was only sporadically detected in 2.5%±1.5 of the cells. Data were substantiated by the detection of mRNA of progerin in the neonatal DA but not in the aorta, by PCR and sequencing analysis. The fetal DA and the non-closing persistent DA did not present with progerin expressing cells. Our analysis revealed that the spatiotemporal expression of lamin A/C and progerin in the neonatal DA was mutually exclusive. We suggest that activation of LMNA alternative splicing is involved in vascular remodeling in the circulatory system during normal neonatal DA closure.

  6. Antisense-Based Progerin Downregulation in HGPS-Like Patients’ Cells

    Directory of Open Access Journals (Sweden)

    Karim Harhouri

    2016-07-01

    Full Text Available Progeroid laminopathies, including Hutchinson-Gilford Progeria Syndrome (HGPS, OMIM #176670, are premature and accelerated aging diseases caused by defects in nuclear A-type Lamins. Most HGPS patients carry a de novo point mutation within exon 11 of the LMNA gene encoding A-type Lamins. This mutation activates a cryptic splice site leading to the deletion of 50 amino acids at its carboxy-terminal domain, resulting in a truncated and permanently farnesylated Prelamin A called Prelamin A Δ50 or Progerin. Some patients carry other LMNA mutations affecting exon 11 splicing and are named “HGPS-like” patients. They also produce Progerin and/or other truncated Prelamin A isoforms (Δ35 and Δ90 at the transcriptional and/or protein level. The results we present show that morpholino antisense oligonucleotides (AON prevent pathogenic LMNA splicing, markedly reducing the accumulation of Progerin and/or other truncated Prelamin A isoforms (Prelamin A Δ35, Prelamin A Δ90 in HGPS-like patients’ cells. Finally, a patient affected with Mandibuloacral Dysplasia type B (MAD-B, carrying a homozygous mutation in ZMPSTE24, encoding an enzyme involved in Prelamin A maturation, leading to accumulation of wild type farnesylated Prelamin A, was also included in this study. These results provide preclinical proof of principle for the use of a personalized antisense approach in HGPS-like and MAD-B patients, who may therefore be eligible for inclusion in a therapeutic trial based on this approach, together with classical HGPS patients.

  7. Research Progress in Function of FAM96B%96序列相似的家庭成员B功能的研究进展

    Institute of Scientific and Technical Information of China (English)

    马丹丹(综述); 张智勇; 蔡逊(审校)

    2015-01-01

    FAM96B,family with sequence similarity 96,member B,is a small molecular protein encoded by 163 amino acids.At present,there is just a few research about FAM96B gene.Recent studies have found that,FAM96B functions through interaction its interacting protein .FAM96B is correlated with the prolifera-tion,migration,and tube formation of endothelial cells.And it may play an important role in the cell mitosis and Apoptin-induced specific tumor cell apoptisis.Moreover FAM96B may be associated with the occurrence of xeroderma pigmentosum and Hutchinson-Gilford progeria syndrome.%96序列相似的家庭成员B(FAM96B)是由163个氨基酸组成的小分子蛋白。目前国内外关于FAM96B基因的研究甚少。最近研究发现,FAM96B基因通过与其相互作用蛋白相互作用发挥功能,可能与血管内皮细胞增殖、迁移及微管形成密切相关,可能在细胞有丝分裂及 Apoptin 特异性诱导肿瘤细胞凋亡中发挥作用,并可能与着色性干皮病及早老症等疾病的发生有关。但其具体功能尚不明确。

  8. Antisense oligonucleotide induction of progerin in human myogenic cells.

    Directory of Open Access Journals (Sweden)

    Yue-Bei Luo

    Full Text Available We sought to use splice-switching antisense oligonucleotides to produce a model of accelerated ageing by enhancing expression of progerin, translated from a mis-spliced lamin A gene (LMNA transcript in human myogenic cells. The progerin transcript (LMNA Δ150 lacks the last 150 bases of exon 11, and is translated into a truncated protein associated with the severe premature ageing disease, Hutchinson-Gilford progeria syndrome (HGPS. HGPS arises from de novo mutations that activate a cryptic splice site in exon 11 of LMNA and result in progerin accumulation in tissues of mesodermal origin. Progerin has also been proposed to play a role in the 'natural' ageing process in tissues. We sought to test this hypothesis by producing a model of accelerated muscle ageing in human myogenic cells. A panel of splice-switching antisense oligonucleotides were designed to anneal across exon 11 of the LMNA pre-mRNA, and these compounds were transfected into primary human myogenic cells. RT-PCR showed that the majority of oligonucleotides were able to modify LMNA transcript processing. Oligonucleotides that annealed within the 150 base region of exon 11 that is missing in the progerin transcript, as well as those that targeted the normal exon 11 donor site induced the LMNA Δ150 transcript, but most oligonucleotides also generated variable levels of LMNA transcript missing the entire exon 11. Upon evaluation of different oligomer chemistries, the morpholino phosphorodiamidate oligonucleotides were found to be more efficient than the equivalent sequences prepared as oligonucleotides with 2'-O-methyl modified bases on a phosphorothioate backbone. The morpholino oligonucleotides induced nuclear localised progerin, demonstrated by immunostaining, and morphological nuclear changes typical of HGPS cells. We show that it is possible to induce progerin expression in myogenic cells using splice-switching oligonucleotides to redirect splicing of LMNA. This may offer a model

  9. Requirements for efficient proteolytic cleavage of prelamin A by ZMPSTE24.

    Science.gov (United States)

    Barrowman, Jemima; Hamblet, Corinne; Kane, Megan S; Michaelis, Susan

    2012-01-01

    The proteolytic maturation of the nuclear protein lamin A by the zinc metalloprotease ZMPSTE24 is critical for human health. The lamin A precursor, prelamin A, undergoes a multi-step maturation process that includes CAAX processing (farnesylation, proteolysis and carboxylmethylation of the C-terminal CAAX motif), followed by ZMPSTE24-mediated cleavage of the last 15 amino acids, including the modified C-terminus. Failure to cleave the prelamin A "tail", due to mutations in either prelamin A or ZMPSTE24, results in a permanently prenylated form of prelamin A that underlies the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS) and related progeroid disorders. Here we have investigated the features of the prelamin A substrate that are required for efficient cleavage by ZMPSTE24. We find that the C-terminal 41 amino acids of prelamin A contain sufficient context to allow cleavage of the tail by ZMPSTE24. We have identified several mutations in amino acids immediately surrounding the cleavage site (between Y646 and L647) that interfere with efficient cleavage of the prelamin A tail; these mutations include R644C, L648A and N650A, in addition to the previously reported L647R. Our data suggests that 9 of the 15 residues within the cleaved tail that lie immediately upstream of the CAAX motif are not critical for ZMPSTE24-mediated cleavage, as they can be replaced by the 9 amino acid HA epitope. However, duplication of the same 9 amino acids (to increase the distance between the prenyl group and the cleavage site) impairs the ability of ZMPSTE24 to cleave prelamin A. Our data reveals amino acid preferences flanking the ZMPSTE24 cleavage site of prelamin A and suggests that spacing from the farnesyl-cysteine to the cleavage site is important for optimal ZMPSTE24 cleavage. These studies begin to elucidate the substrate requirements of an enzyme activity critical to human health and longevity.

  10. Nesprin-2G, a Component of the Nuclear LINC Complex, Is Subject to Myosin-Dependent Tension.

    Science.gov (United States)

    Arsenovic, Paul T; Ramachandran, Iswarya; Bathula, Kranthidhar; Zhu, Ruijun; Narang, Jiten D; Noll, Natalie A; Lemmon, Christopher A; Gundersen, Gregg G; Conway, Daniel E

    2016-01-01

    The nucleus of a cell has long been considered to be subject to mechanical force. Despite the observation that mechanical forces affect nuclear geometry and movement, how forces are applied onto the nucleus is not well understood. The nuclear LINC (linker of nucleoskeleton and cytoskeleton) complex has been hypothesized to be the critical structure that mediates the transfer of mechanical forces from the cytoskeleton onto the nucleus. Previously used techniques for studying nuclear forces have been unable to resolve forces across individual proteins, making it difficult to clearly establish if the LINC complex experiences mechanical load. To directly measure forces across the LINC complex, we generated a fluorescence resonance energy transfer-based tension biosensor for nesprin-2G, a key structural protein in the LINC complex, which physically links this complex to the actin cytoskeleton. Using this sensor we show that nesprin-2G is subject to mechanical tension in adherent fibroblasts, with highest levels of force on the apical and equatorial planes of the nucleus. We also show that the forces across nesprin-2G are dependent on actomyosin contractility and cell elongation. Additionally, nesprin-2G tension is reduced in fibroblasts from Hutchinson-Gilford progeria syndrome patients. This report provides the first, to our knowledge, direct evidence that nesprin-2G, and by extension the LINC complex, is subject to mechanical force. We also present evidence that nesprin-2G localization to the nuclear membrane is altered under high-force conditions. Because forces across the LINC complex are altered by a variety of different conditions, mechanical forces across the LINC complex, as well as the nucleus in general, may represent an important mechanism for mediating mechanotransduction.

  11. Coronary Artery Disease in a Werner Syndrome-Like Form of Progeria Characterized by Low Levels of Progerin, a Splice Variant of Lamin A

    Science.gov (United States)

    Hisama, Fuki M.; Lessel, Davor; Leistritz, Dru; Friedrich, Katrin; McBride, Kim L.; Pastore, Matthew T.; Gottesman, Gary S.; Saha, Bidisha; Martin, George M.; Kubisch, Christian; Oshima, Junko

    2015-01-01

    Classical Hutchinson–Gilford progeria syndrome (HGPS) is caused by LMNA mutations that generate an alternatively spliced form of lamin A, termed progerin. HGPS patients present in early childhood with atherosclerosis and striking features of accelerated aging. We report on two pedigrees of adult-onset coronary artery disease with progeroid features, who were referred to our International Registry of Werner Syndrome (WS) because of clinical features consistent with the diagnosis. No mutations were identified in the WRN gene that is responsible for WS, among these patients. Instead, we found two novel heterozygous mutations at the junction of exon 10 and intron 11 of the LMNA gene. These mutations resulted in the production of progerin at a level substantially lower than that of HGPS. Our findings indicate that LMNA mutations may result in coronary artery disease presenting in the fourth to sixth decades along with short stature and a progeroid appearance resembling WS. The absence of early-onset cataracts in this setting should suggest the diagnosis of progeroid laminopathy. This study illustrates the evolving genotype–phenotype relationship between the amount of progerin produced and the age of onset among the spectrum of restrictive dermopathy, HGPS, and atypical forms of WS. PMID:22065502

  12. New Lmna knock-in mice provide a molecular mechanism for the ‘segmental aging’ in Hutchinson–Gilford progeria syndrome†

    Science.gov (United States)

    Jung, Hea-Jin; Tu, Yiping; Yang, Shao H.; Tatar, Angelica; Nobumori, Chika; Wu, Daniel; Young, Stephen G.; Fong, Loren G.

    2014-01-01

    Lamins A and C (products of the LMNA gene) are found in roughly equal amounts in peripheral tissues, but the brain produces mainly lamin C and little lamin A. In HeLa cells and fibroblasts, the expression of prelamin A (the precursor to lamin A) can be reduced by miR-9, but the relevance of those cell culture studies to lamin A regulation in the brain was unclear. To address this issue, we created two new Lmna knock-in alleles, one (LmnaPLAO-5NT) with a 5-bp mutation in a predicted miR-9 binding site in prelamin A's 3′ UTR, and a second (LmnaPLAO-UTR) in which prelamin A's 3′ UTR was replaced with lamin C's 3′ UTR. Neither allele had significant effects on lamin A levels in peripheral tissues; however, both substantially increased prelamin A transcript levels and lamin A protein levels in the cerebral cortex and the cerebellum. The increase in lamin A expression in the brain was more pronounced with the LmnaPLAO-UTR allele than with the LmnaPLAO-5NT allele. With both alleles, the increased expression of prelamin A transcripts and lamin A protein was greater in the cerebral cortex than in the cerebellum. Our studies demonstrate the in vivo importance of prelamin A's 3′ UTR and its miR-9 binding site in regulating lamin A expression in the brain. The reduced expression of prelamin A in the brain likely explains why children with Hutchinson–Gilford progeria syndrome (a progeroid syndrome caused by a mutant form of prelamin A) are spared from neurodegenerative disease. PMID:24203701

  13. Science and Science Fiction

    Science.gov (United States)

    Oravetz, David

    2005-01-01

    This article is for teachers looking for new ways to motivate students, increase science comprehension, and understanding without using the old standard expository science textbook. This author suggests reading a science fiction novel in the science classroom as a way to engage students in learning. Using science fiction literature and language…

  14. Embryonic senescence and laminopathies in a progeroid zebrafish model.

    Directory of Open Access Journals (Sweden)

    Eriko Koshimizu

    Full Text Available BACKGROUND: Mutations that disrupt the conversion of prelamin A to mature lamin A cause the rare genetic disorder Hutchinson-Gilford progeria syndrome and a group of laminopathies. Our understanding of how A-type lamins function in vivo during early vertebrate development through aging remains limited, and would benefit from a suitable experimental model. The zebrafish has proven to be a tractable model organism for studying both development and aging at the molecular genetic level. Zebrafish show an array of senescence symptoms resembling those in humans, which can be targeted to specific aging pathways conserved in vertebrates. However, no zebrafish models bearing human premature senescence currently exist. PRINCIPAL FINDINGS: We describe the induction of embryonic senescence and laminopathies in zebrafish harboring disturbed expressions of the lamin A gene (LMNA. Impairments in these fish arise in the skin, muscle and adipose tissue, and sometimes in the cartilage. Reduced function of lamin A/C by translational blocking of the LMNA gene induced apoptosis, cell-cycle arrest, and craniofacial abnormalities/cartilage defects. By contrast, induced cryptic splicing of LMNA, which generates the deletion of 8 amino acid residues lamin A (zlamin A-Δ8, showed embryonic senescence and S-phase accumulation/arrest. Interestingly, the abnormal muscle and lipodystrophic phenotypes were common in both cases. Hence, both decrease-of-function of lamin A/C and gain-of-function of aberrant lamin A protein induced laminopathies that are associated with mesenchymal cell lineages during zebrafish early development. Visualization of individual cells expressing zebrafish progerin (zProgerin/zlamin A-Δ37 fused to green fluorescent protein further revealed misshapen nuclear membrane. A farnesyltransferase inhibitor reduced these nuclear abnormalities and significantly prevented embryonic senescence and muscle fiber damage induced by zProgerin. Importantly, the adult

  15. Science in Science Fiction.

    Science.gov (United States)

    Allday, Jonathan

    2003-01-01

    Offers some suggestions as to how science fiction, especially television science fiction programs such as "Star Trek" and "Star Wars", can be drawn into physics lessons to illuminate some interesting issues. (Author/KHR)

  16. Science in Computational Sciences

    Directory of Open Access Journals (Sweden)

    Jameson Cerrosen

    2012-12-01

    Full Text Available The existing theory in relation to science presents the physics as an ideal, although many sciences not approach the same, so that the current philosophy of science-Theory of Science- is not much help when it comes to analyze the computer science, an emerging field of knowledge that aims investigation of computers, which are included in the materialization of the ideas that try to structure the knowledge and information about the world. Computer Science is based on logic and mathematics, but both theoretical research methods and experimental follow patterns of classical scientific fields. Modeling and computer simulation, as a method, are specific to the discipline and will be further developed in the near future, not only applied to computers but also to other scientific fields. In this article it is analyze the aspects of science in computer science, is presenting an approach to the definition of science and the scientific method in general and describes the relationships between science, research, development and technology.

  17. Science or Science Fiction?

    DEFF Research Database (Denmark)

    Lefsrud, Lianne M.; Meyer, Renate

    2012-01-01

    This paper examines the framings and identity work associated with professionals’ discursive construction of climate change science, their legitimation of themselves as experts on ‘the truth’, and their attitudes towards regulatory measures. Drawing from survey responses of 1077 professional......, legitimation strategies, and use of emotionality and metaphor. By linking notions of the science or science fiction of climate change to the assessment of the adequacy of global and local policies and of potential organizational responses, we contribute to the understanding of ‘defensive institutional work...

  18. Requirements for efficient proteolytic cleavage of prelamin A by ZMPSTE24.

    Directory of Open Access Journals (Sweden)

    Jemima Barrowman

    Full Text Available BACKGROUND: The proteolytic maturation of the nuclear protein lamin A by the zinc metalloprotease ZMPSTE24 is critical for human health. The lamin A precursor, prelamin A, undergoes a multi-step maturation process that includes CAAX processing (farnesylation, proteolysis and carboxylmethylation of the C-terminal CAAX motif, followed by ZMPSTE24-mediated cleavage of the last 15 amino acids, including the modified C-terminus. Failure to cleave the prelamin A "tail", due to mutations in either prelamin A or ZMPSTE24, results in a permanently prenylated form of prelamin A that underlies the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS and related progeroid disorders. METHODOLOGY/PRINCIPAL FINDINGS: Here we have investigated the features of the prelamin A substrate that are required for efficient cleavage by ZMPSTE24. We find that the C-terminal 41 amino acids of prelamin A contain sufficient context to allow cleavage of the tail by ZMPSTE24. We have identified several mutations in amino acids immediately surrounding the cleavage site (between Y646 and L647 that interfere with efficient cleavage of the prelamin A tail; these mutations include R644C, L648A and N650A, in addition to the previously reported L647R. Our data suggests that 9 of the 15 residues within the cleaved tail that lie immediately upstream of the CAAX motif are not critical for ZMPSTE24-mediated cleavage, as they can be replaced by the 9 amino acid HA epitope. However, duplication of the same 9 amino acids (to increase the distance between the prenyl group and the cleavage site impairs the ability of ZMPSTE24 to cleave prelamin A. CONCLUSIONS/SIGNIFICANCE: Our data reveals amino acid preferences flanking the ZMPSTE24 cleavage site of prelamin A and suggests that spacing from the farnesyl-cysteine to the cleavage site is important for optimal ZMPSTE24 cleavage. These studies begin to elucidate the substrate requirements of an enzyme activity critical to human

  19. The Nuclear Envelope Dynamics and the Nuclear Envelopathies%核膜结构动态变化及核膜相关病征

    Institute of Scientific and Technical Information of China (English)

    古欣; 祁燃; 张传茂

    2013-01-01

    真核生物的细胞核膜主要由外层核膜、核孔复合体、内层核膜及其下面的核纤层组成.越来越多的证据表明,细胞核膜结构的变化与核膜相关疾病的发生发展有着极为密切的关系.已鉴定出的核膜病征多与核膜蛋白突变或缺失有关,目前导致疾病种类最多且突变研究相对最全面的是核纤层蛋白lamin A,即核纤层的骨架组分之一.核膜相关疾病的几种主要类型是:以多器官加速衰老为症状的人类早老综合征(Hutchinson-Gilford progeria syndrome,HGPS),导致全身性严重早老的限制性皮肤病(restrictive dermopathy,RD),具有肌肉组织特异性的肌肉营养不良症(Emery-Dreifuss muscular dystrophy,EDMD)、扩张性心肌病(dilated cardiomyopathy,DCM),具有脂肪组织特异性的家族性脂营养不良症(dunnigan familial partial lipodystrophy,FPLD),同时具有骨组织与脂肪组织特异性的下颌骨端发育不良脂肪代谢异常症(mandibuloacral dysplasia,MAD).这些疾病已逐渐引起人们的广泛关注.该文主要总结核膜结构变化并简述核膜相关病征的症状与分子机制.

  20. Structural and Mechanical Properties of Intermediate Filaments under Extreme Conditions and Disease

    Science.gov (United States)

    Qin, Zhao

    Intermediate filaments are one of the three major components of the cytoskeleton in eukaryotic cells. It was discovered during the recent decades that intermediate filament proteins play key roles to reinforce cells subjected to large-deformation as well as participate in signal transduction. However, it is still poorly understood how the nanoscopic structure, as well as the biochemical properties of these protein molecules contribute to their biomechanical functions. In this research we investigate the material function of intermediate filaments under various extreme mechanical conditions as well as disease states. We use a full atomistic model and study its response to mechanical stresses. Learning from the mechanical response obtained from atomistic simulations, we build mesoscopic models following the finer-trains-coarser principles. By using this multiple-scale model, we present a detailed analysis of the mechanical properties and associated deformation mechanisms of intermediate filament network. We reveal the mechanism of a transition from alpha-helices to beta-sheets with subsequent intermolecular sliding under mechanical force, which has been inferred previously from experimental results. This nanoscale mechanism results in a characteristic nonlinear force-extension curve, which leads to a delocalization of mechanical energy and prevents catastrophic fracture. This explains how intermediate filament can withstand extreme mechanical deformation of > 1 00% strain despite the presence of structural defects. We combine computational and experimental techniques to investigate the molecular mechanism of Hutchinson-Gilford progeria syndrome, a premature aging disease. We find that the mutated lamin tail .domain is more compact and stable than the normal one. This altered structure and stability may enhance the association of intermediate filaments with the nuclear membrane, providing a molecular mechanism of the disease. We study the nuclear membrane association

  1. Accumulation of distinct prelamin A variants in human diploid fibroblasts differentially affects cell homeostasis

    Energy Technology Data Exchange (ETDEWEB)

    Candelario, Jose; Borrego, Stacey [Department of Molecular Microbiology and Immunology, Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 (United States); Reddy, Sita, E-mail: sitaredd@usc.edu [Department of Biochemistry and Molecular Biology, Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 (United States); Comai, Lucio, E-mail: comai@usc.edu [Department of Molecular Microbiology and Immunology, Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 (United States)

    2011-02-01

    Lamin A is a component of the nuclear lamina that plays a major role in the structural organization and function of the nucleus. Lamin A is synthesized as a prelamin A precursor which undergoes four sequential post-translational modifications to generate mature lamin A. Significantly, a large number of point mutations in the LMNA gene cause a range of distinct human disorders collectively known as laminopathies. The mechanisms by which mutations in lamin A affect cell function and cause disease are unclear. Interestingly, recent studies have suggested that alterations in the normal lamin A pathway can contribute to cellular dysfunction. Specifically, we and others have shown, at the cellular level, that in the absence of mutations or altered splicing events, increased expression of wild-type prelamin A results in a growth defective phenotype that resembles that of cells expressing the mutant form of lamin A, termed progerin, associated with Hutchinson-Gilford Progeria syndrome (HGPS). Remarkably, the phenotypes of cells expressing elevated levels of wild-type prelamin A can be reversed by either treatment with farnesyltransferase inhibitors or overexpression of ZMPSTE24, a critical prelamin A processing enzyme, suggesting that minor increases in the steady-state levels of one or more prelamin A intermediates is sufficient to induce cellular toxicity. Here, to investigate the molecular basis of the lamin A pathway toxicity, we characterized the phenotypic changes occurring in cells expressing distinct prelamin A variants mimicking specific prelamin A processing intermediates. This analysis demonstrates that distinct prelamin A variants differentially affect cell growth, nuclear membrane morphology, nuclear distribution of lamin A and the fundamental process of transcription. Expression of prelamin A variants that are constitutively farnesylated induced the formation of lamin A aggregates and dramatic changes in nuclear membrane morphology, which led to reduced

  2. 核纤层蛋白病--一个基因,多种疾病%Laminopathies -one gene, multiple diseases

    Institute of Scientific and Technical Information of China (English)

    宋书娟; 章远志; Nanbert ZHONG

    2005-01-01

    @@ 核纤层蛋白病(laminopathies)是指由LMNA基因及其编码蛋白lamin A/C异常引起的一组人类遗传病[1].根据临床特征不同,至今被认识的核纤层蛋白病已有10种,除一种由影响成熟lamin A形成的FACE-1基因突变引起外[2],其余9种均由LMNA基因突变引起,其中包括2种既可以常染色体显性又可以常染色体隐性遗传的遗传病:Emery-Dreifuss 肌营养不良(Emery-Dreifuss muscular dystrophy, EDMD,常显EDMD2,常隐EDMD3)[3,4] 和腓骨肌萎缩症2型(Charcot-Marie-Tooth2,常显AD-CMT2,常隐AR-CMT2)[5,6];6种常染色体显性遗传病:肢带型肌营养不良1B(limb girdle muscular dystrophy1B,LGMD1B)[7],扩张性心肌病伴心脏传导阻滞1A(dilated cardiomyopathy and cardiac conduction defects1A, CMD1A)[8],家族部分性脂肪营养不良(familial partial lipodystrophy, FPLD)[9],脂肪营养不良、胰岛素抵抗型糖尿病、弥漫性白黑皮病样丘疹、肝脂肪变性和心肌病综合征(lipoatrophy & insulin-resistant diabetes & disseminated leukomelanodermic papules & liver steatosis and cardiomyopathy,LDHPC)[10],Werner综合征(Werner syndrome, WRN)[11]和早老症(Hutchinson-Gilford progeria syndrome,HGPS)[12];1种常染色体隐性遗传病: Mandibuloacral dysplasia(MAD)[13].

  3. Communicating Science

    Science.gov (United States)

    Russell, Nicholas

    2009-10-01

    Introduction: what this book is about and why you might want to read it; Prologue: three orphans share a common paternity: professional science communication, popular journalism, and literary fiction are not as separate as they seem; Part I. Professional Science Communication: 1. Spreading the word: the endless struggle to publish professional science; 2. Walk like an Egyptian: the alien feeling of professional science writing; 3. The future's bright? Professional science communication in the age of the internet; 4. Counting the horse's teeth: professional standards in science's barter economy; 5. Separating the wheat from the chaff: peer review on trial; Part II. Science for the Public: What Science Do People Need and How Might They Get It?: 6. The Public Understanding of Science (PUS) movement and its problems; 7. Public engagement with science and technology (PEST): fine principle, difficult practice; 8. Citizen scientists? Democratic input into science policy; 9. Teaching and learning science in schools: implications for popular science communication; Part III. Popular Science Communication: The Press and Broadcasting: 10. What every scientist should know about mass media; 11. What every scientist should know about journalists; 12. The influence of new media; 13. How the media represents science; 14. How should science journalists behave?; Part IV. The Origins of Science in Cultural Context: Five Historic Dramas: 15. A terrible storm in Wittenberg: natural knowledge through sorcery and evil; 16. A terrible storm in the Mediterranean: controlling nature with white magic and religion; 17. Thieving magpies: the subtle art of false projecting; 18. Foolish virtuosi: natural philosophy emerges as a distinct discipline but many cannot take it seriously; 19. Is scientific knowledge 'true' or should it just be 'truthfully' deployed?; Part V. Science in Literature: 20. Science and the Gothic: the three big nineteenth-century monster stories; 21. Science fiction: serious

  4. Science Fiction and Science Education.

    Science.gov (United States)

    Cavanaugh, Terence

    2002-01-01

    Uses science fiction films such as "Jurassic Park" or "Anaconda" to teach science concepts while fostering student interest. Advocates science fiction as a teaching tool to improve learning and motivation. Describes how to use science fiction in the classroom with the sample activity Twister. (YDS)

  5. Science Fiction and Science Education.

    Science.gov (United States)

    Cavanaugh, Terence

    2002-01-01

    Uses science fiction films such as "Jurassic Park" or "Anaconda" to teach science concepts while fostering student interest. Advocates science fiction as a teaching tool to improve learning and motivation. Describes how to use science fiction in the classroom with the sample activity Twister. (YDS)

  6. Marine Science

    African Journals Online (AJOL)

    Aims and scope: The Western Indian Ocean Journal of Marine Science ... sustainable coastal development in the region, as well as contributing to the global base of marine science. ..... Gössling S (2003) The political ecology of tourism in Zan-.

  7. Sound Science

    Science.gov (United States)

    Sickel, Aaron J.; Lee, Michele H.; Pareja, Enrique M.

    2010-01-01

    How can a teacher simultaneously teach science concepts through inquiry while helping students learn about the nature of science? After pondering this question in their own teaching, the authors developed a 5E learning cycle lesson (Bybee et al. 2006) that concurrently embeds opportunities for fourth-grade students to (a) learn a science concept,…

  8. Sound Science

    Science.gov (United States)

    Sickel, Aaron J.; Lee, Michele H.; Pareja, Enrique M.

    2010-01-01

    How can a teacher simultaneously teach science concepts through inquiry while helping students learn about the nature of science? After pondering this question in their own teaching, the authors developed a 5E learning cycle lesson (Bybee et al. 2006) that concurrently embeds opportunities for fourth-grade students to (a) learn a science concept,…

  9. Science Teaching in Science Education

    Science.gov (United States)

    Callahan, Brendan E.; Dopico, Eduardo

    2016-01-01

    Reading the interesting article "Discerning selective traditions in science education" by Per Sund, which is published in this issue of "CSSE," allows us to open the discussion on procedures for teaching science today. Clearly there is overlap between the teaching of science and other areas of knowledge. However, we must…

  10. Science Bubbles

    DEFF Research Database (Denmark)

    Hendricks, Vincent Fella; Pedersen, David Budtz

    2013-01-01

    Much like the trade and trait sof bubbles in financial markets,similar bubbles appear on the science market. When economic bubbles burst, the drop in prices causes the crash of unsustainable investments leading to an investor confidence crisis possibly followed by a financial panic. But when...... bubbles appear in science, truth and reliability are the first victims. This paper explores how fashions in research funding and research management may turn science into something like a bubble economy....

  11. An Upregulation in the Expression of Vanilloid Transient Potential Channels 2 Enhances Hypotonicity-Induced Cytosolic Ca2+ Rise in Human Induced Pluripotent Stem Cell Model of Hutchinson Gillford Progeria

    Science.gov (United States)

    Ho, Jenny Chung-Yee; Siu, Chung-Wah; Cheung, Sin-Ying; Tang, Nelson L.; Yu, Shan; Tse, Hung-Fat; Yao, Xiaoqiang

    2014-01-01

    Hutchinson-Gillford Progeria Syndrome (HGPS) is a fatal genetic disorder characterized by premature aging in multiple organs including the skin, musculoskeletal and cardiovascular systems. It is believed that an increased mechanosensitivity of HGPS cells is a causative factor for vascular cell death and vascular diseases in HGPS patients. However, the exact mechanism is unknown. Transient receptor potential (TRP) channels are cationic channels that can act as cellular sensors for mechanical stimuli. The aim of this present study was to examine the expression and functional role of TRP channels in human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) from the patients with HGPS. The mRNA and protein expression of TRP channels in HGPS and control (IMR90) iPSC-ECs were examined by semi-quantitative RT-PCRs and immunoblots, respectively. Hypotonicity-induced cytosolic Ca2+ ([Ca2+]i) rise in iPSC-ECs was measured by confocal microscopy. RT-PCRs and immunoblots showed higher expressional levels of TRPV2 in iPSC-ECs from HGPS patients than those from normal individuals. In functional studies, hypotonicity induced a transient [Ca2+]i rise in iPSC-ECs from normal individuals but a sustained [Ca2+]i elevation in iPSC-ECs from HGPS patients. A nonselective TRPV inhibitor, ruthenium red (RuR, 20 µM), and a specific TRPV2 channel inhibitor, tranilast (100 µM), abolished the sustained phase of hypotonicity-induced [Ca2+]i rise in iPSC-ECs from HGPS patients, and also markedly attenuated the transient phase of the [Ca2+]i rise in these cells. Importantly, a short 10 min hypotonicity treatment caused a substantial increase in caspase 8 activity in iPSC-ECs from HGPS patients but not in cells from normal individuals. Tranilast could also inhibit the hypotonicity-induced increase in caspase 8 activity. Taken together, our data suggest that an up-regulation in TRPV2 expression causes a sustained [Ca2+]i elevation in HGPS-iPSC-ECs under hypotonicity, consequently

  12. An upregulation in the expression of vanilloid transient potential channels 2 enhances hypotonicity-induced cytosolic Ca²⁺ rise in human induced pluripotent stem cell model of Hutchinson-Gillford Progeria.

    Directory of Open Access Journals (Sweden)

    Chun-Yin Lo

    Full Text Available Hutchinson-Gillford Progeria Syndrome (HGPS is a fatal genetic disorder characterized by premature aging in multiple organs including the skin, musculoskeletal and cardiovascular systems. It is believed that an increased mechanosensitivity of HGPS cells is a causative factor for vascular cell death and vascular diseases in HGPS patients. However, the exact mechanism is unknown. Transient receptor potential (TRP channels are cationic channels that can act as cellular sensors for mechanical stimuli. The aim of this present study was to examine the expression and functional role of TRP channels in human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs from the patients with HGPS. The mRNA and protein expression of TRP channels in HGPS and control (IMR90 iPSC-ECs were examined by semi-quantitative RT-PCRs and immunoblots, respectively. Hypotonicity-induced cytosolic Ca²⁺ ([Ca²⁺](i rise in iPSC-ECs was measured by confocal microscopy. RT-PCRs and immunoblots showed higher expressional levels of TRPV2 in iPSC-ECs from HGPS patients than those from normal individuals. In functional studies, hypotonicity induced a transient [Ca²⁺](i rise in iPSC-ECs from normal individuals but a sustained [Ca²⁺](i elevation in iPSC-ECs from HGPS patients. A nonselective TRPV inhibitor, ruthenium red (RuR, 20 µM, and a specific TRPV2 channel inhibitor, tranilast (100 µM, abolished the sustained phase of hypotonicity-induced [Ca²⁺](i rise in iPSC-ECs from HGPS patients, and also markedly attenuated the transient phase of the [Ca²⁺](i rise in these cells. Importantly, a short 10 min hypotonicity treatment caused a substantial increase in caspase 8 activity in iPSC-ECs from HGPS patients but not in cells from normal individuals. Tranilast could also inhibit the hypotonicity-induced increase in caspase 8 activity. Taken together, our data suggest that an up-regulation in TRPV2 expression causes a sustained [Ca²⁺](i elevation in HGPS

  13. An upregulation in the expression of vanilloid transient potential channels 2 enhances hypotonicity-induced cytosolic Ca²⁺ rise in human induced pluripotent stem cell model of Hutchinson-Gillford Progeria.

    Science.gov (United States)

    Lo, Chun-Yin; Tjong, Yung-Wui; Ho, Jenny Chung-Yee; Siu, Chung-Wah; Cheung, Sin-Ying; Tang, Nelson L; Yu, Shan; Tse, Hung-Fat; Yao, Xiaoqiang

    2014-01-01

    Hutchinson-Gillford Progeria Syndrome (HGPS) is a fatal genetic disorder characterized by premature aging in multiple organs including the skin, musculoskeletal and cardiovascular systems. It is believed that an increased mechanosensitivity of HGPS cells is a causative factor for vascular cell death and vascular diseases in HGPS patients. However, the exact mechanism is unknown. Transient receptor potential (TRP) channels are cationic channels that can act as cellular sensors for mechanical stimuli. The aim of this present study was to examine the expression and functional role of TRP channels in human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) from the patients with HGPS. The mRNA and protein expression of TRP channels in HGPS and control (IMR90) iPSC-ECs were examined by semi-quantitative RT-PCRs and immunoblots, respectively. Hypotonicity-induced cytosolic Ca²⁺ ([Ca²⁺](i)) rise in iPSC-ECs was measured by confocal microscopy. RT-PCRs and immunoblots showed higher expressional levels of TRPV2 in iPSC-ECs from HGPS patients than those from normal individuals. In functional studies, hypotonicity induced a transient [Ca²⁺](i) rise in iPSC-ECs from normal individuals but a sustained [Ca²⁺](i) elevation in iPSC-ECs from HGPS patients. A nonselective TRPV inhibitor, ruthenium red (RuR, 20 µM), and a specific TRPV2 channel inhibitor, tranilast (100 µM), abolished the sustained phase of hypotonicity-induced [Ca²⁺](i) rise in iPSC-ECs from HGPS patients, and also markedly attenuated the transient phase of the [Ca²⁺](i) rise in these cells. Importantly, a short 10 min hypotonicity treatment caused a substantial increase in caspase 8 activity in iPSC-ECs from HGPS patients but not in cells from normal individuals. Tranilast could also inhibit the hypotonicity-induced increase in caspase 8 activity. Taken together, our data suggest that an up-regulation in TRPV2 expression causes a sustained [Ca²⁺](i) elevation in HGPS

  14. Science Shops

    DEFF Research Database (Denmark)

    Jørgensen, Michael Søgaard

    1999-01-01

    The paper prsents the overall concept of science shops as practised in most of the European science shops and present the concept practised and some experience obtained at the Technical University of Denmark. An outline for the planning of new sceince shops is presented.......The paper prsents the overall concept of science shops as practised in most of the European science shops and present the concept practised and some experience obtained at the Technical University of Denmark. An outline for the planning of new sceince shops is presented....

  15. Computer science

    CERN Document Server

    Blum, Edward K

    2011-01-01

    Computer Science: The Hardware, Software and Heart of It focuses on the deeper aspects of the two recognized subdivisions of Computer Science, Software and Hardware. These subdivisions are shown to be closely interrelated as a result of the stored-program concept. Computer Science: The Hardware, Software and Heart of It includes certain classical theoretical computer science topics such as Unsolvability (e.g. the halting problem) and Undecidability (e.g. Godel's incompleteness theorem) that treat problems that exist under the Church-Turing thesis of computation. These problem topics explain in

  16. Science Shops

    DEFF Research Database (Denmark)

    Jørgensen, Michael Søgaard

    1999-01-01

    The paper prsents the overall concept of science shops as practised in most of the European science shops and present the concept practised and some experience obtained at the Technical University of Denmark. An outline for the planning of new sceince shops is presented.......The paper prsents the overall concept of science shops as practised in most of the European science shops and present the concept practised and some experience obtained at the Technical University of Denmark. An outline for the planning of new sceince shops is presented....

  17. Soundsational Science

    Science.gov (United States)

    Carrier, Sarah J.; Scott, Catherine Marie; Hall, Debra T.

    2012-01-01

    The science of sound helps students learn that sound is energy traveling in waves as vibrations transfer the energy through various media: solids, liquids, and gases. In addition to learning about the physical science of sound, students can learn about the sounds of different animal species: how sounds contribute to animals' survival, and how…

  18. Life sciences

    Energy Technology Data Exchange (ETDEWEB)

    Day, L. (ed.)

    1991-04-01

    This document is the 1989--1990 Annual Report for the Life Sciences Divisions of the University of California/Lawrence Berkeley Laboratory. Specific progress reports are included for the Cell and Molecular Biology Division, the Research Medicine and Radiation Biophysics Division (including the Advanced Light Source Life Sciences Center), and the Chemical Biodynamics Division. 450 refs., 46 figs. (MHB)

  19. Deconstructing Science

    Science.gov (United States)

    Trifonas, Peter Pericles

    2012-01-01

    In this paper I expand on the premises of Jesse Bazzul's thesis in his paper, "Neoliberal ideology, global capitalism, and science education: engaging the question of subjectivity," exploring the implications of the ideologies within the culturally emerging logic of science exposes the incommensurability of intents and purposes in its methods and…

  20. Dramatic Science

    Science.gov (United States)

    McGregor, Debbie; Precious, Wendy

    2010-01-01

    The setting: the science classroom. The characters: you and your students. The scene: Your students acting out scientific discoveries, modeling a frog's life cycle, mimicking the transition from liquid to solid. This is "dramatic science", a teaching approach that uses acting techniques to explore and develop young children's ideas about…

  1. Marine Science

    African Journals Online (AJOL)

    Chief Editor José Paula | Faculty of Sciences of University of Lisbon, ... Aims and scope: The Western Indian Ocean Journal of Marine Science provides an avenue for the wide dissem- .... in the region are some of the poorest in the world,.

  2. [Basic science and applied science].

    Science.gov (United States)

    Pérez-Tamayo, R

    2001-01-01

    A lecture was presented by the author at the Democratic Opinion Forum on Health Teaching and Research, organized by Mexico's National Health Institutes Coordinating Office, at National Cardiology Institute "Ignacio Chavez", where he presented a critical review of the conventional classification of basic and applied science, as well as his personal view on health science teaching and research. According to the author, "well-conducted science" is that "generating reality-checked knowledge" and "mis-conducted science" is that "unproductive or producing 'just lies' and 'non-fundable'. To support his views, the author reviews utilitarian and pejorative definitions of science, as well as those of committed and pure science, useful and useless science, and practical and esoterical science, as synonyms of applied and basic science. He also asserts that, in Mexico, "this classification has been used in the past to justify federal funding cutbacks to basic science, allegedly because it is not targeted at solving 'national problems' or because it was not relevant to priorities set in a given six-year political administration period". Regarding health education and research, the author asserts that the current academic programs are inefficient and ineffective; his proposal to tackle these problems is to carry out a solid scientific study, conducted by a multidisciplinary team of experts, "to design the scientific researcher curricula from recruitment of intelligent young people to retirement or death". Performance assessment of researchers would not be restricted to publication of papers, since "the quality of scientific work and contribution to the development of science is not reflected by the number of published papers". The English version of this paper is available at: http://www.insp.mx/salud/index.html

  3. Science teaching in science education

    Science.gov (United States)

    Callahan, Brendan E.; Dopico, Eduardo

    2016-06-01

    Reading the interesting article Discerning selective traditions in science education by Per Sund , which is published in this issue of CSSE, allows us to open the discussion on procedures for teaching science today. Clearly there is overlap between the teaching of science and other areas of knowledge. However, we must constantly develop new methods to teach and differentiate between science education and teaching science in response to the changing needs of our students, and we must analyze what role teachers and teacher educators play in both. We must continually examine the methods and concepts involved in developing pedagogical content knowledge in science teachers. Otherwise, the possibility that these routines, based on subjective traditions, prevent emerging processes of educational innovation. Modern science is an enormous field of knowledge in its own right, which is made more expansive when examined within the context of its place in society. We propose the need to design educative interactions around situations that involve science and society. Science education must provide students with all four dimensions of the cognitive process: factual knowledge, conceptual knowledge, procedural knowledge, and metacognitive knowledge. We can observe in classrooms at all levels of education that students understand the concepts better when they have the opportunity to apply the scientific knowledge in a personally relevant way. When students find value in practical exercises and they are provided opportunities to reinterpret their experiences, greater learning gains are achieved. In this sense, a key aspect of educational innovation is the change in teaching methodology. We need new tools to respond to new problems. A shift in teacher education is needed to realize the rewards of situating science questions in a societal context and opening classroom doors to active methodologies in science education to promote meaningful learning through meaningful teaching.

  4. Revolutionary Science

    Directory of Open Access Journals (Sweden)

    Arturo Casadevall

    2016-05-01

    Full Text Available On rare occasions in the history of science, remarkable discoveries transform human society and forever alter mankind’s view of the world. Examples of such discoveries include the heliocentric theory, Newtonian physics, the germ theory of disease, quantum theory, plate tectonics and the discovery that DNA carries genetic information. The science philosopher Thomas Kuhn famously described science as long periods of normality punctuated by times of crisis, when anomalous observations culminate in revolutionary changes that replace one paradigm with another. This essay examines several transformative discoveries in the light of Kuhn’s formulation. We find that each scientific revolution is unique, with disparate origins that may include puzzle solving, serendipity, inspiration, or a convergence of disparate observations. The causes of revolutionary science are varied and lack an obvious common structure. Moreover, it can be difficult to draw a clear distinction between so-called normal and revolutionary science. Revolutionary discoveries often emerge from basic science and are critically dependent on nonrevolutionary research. Revolutionary discoveries may be conceptual or technological in nature, lead to the creation of new fields, and have a lasting impact on many fields in addition to the field from which they emerge. In contrast to political revolutions, scientific revolutions do not necessarily require the destruction of the previous order. For humanity to continue to benefit from revolutionary discoveries, a broad palette of scientific inquiry with a particular emphasis on basic science should be supported.

  5. Revolutionary Science.

    Science.gov (United States)

    Casadevall, Arturo; Fang, Ferric C

    2016-03-01

    On rare occasions in the history of science, remarkable discoveries transform human society and forever alter mankind's view of the world. Examples of such discoveries include the heliocentric theory, Newtonian physics, the germ theory of disease, quantum theory, plate tectonics and the discovery that DNA carries genetic information. The science philosopher Thomas Kuhn famously described science as long periods of normality punctuated by times of crisis, when anomalous observations culminate in revolutionary changes that replace one paradigm with another. This essay examines several transformative discoveries in the light of Kuhn's formulation. We find that each scientific revolution is unique, with disparate origins that may include puzzle solving, serendipity, inspiration, or a convergence of disparate observations. The causes of revolutionary science are varied and lack an obvious common structure. Moreover, it can be difficult to draw a clear distinction between so-called normal and revolutionary science. Revolutionary discoveries often emerge from basic science and are critically dependent on nonrevolutionary research. Revolutionary discoveries may be conceptual or technological in nature, lead to the creation of new fields, and have a lasting impact on many fields in addition to the field from which they emerge. In contrast to political revolutions, scientific revolutions do not necessarily require the destruction of the previous order. For humanity to continue to benefit from revolutionary discoveries, a broad palette of scientific inquiry with a particular emphasis on basic science should be supported.

  6. Revolutionary Science

    Science.gov (United States)

    Fang, Ferric C.

    2016-01-01

    ABSTRACT On rare occasions in the history of science, remarkable discoveries transform human society and forever alter mankind’s view of the world. Examples of such discoveries include the heliocentric theory, Newtonian physics, the germ theory of disease, quantum theory, plate tectonics and the discovery that DNA carries genetic information. The science philosopher Thomas Kuhn famously described science as long periods of normality punctuated by times of crisis, when anomalous observations culminate in revolutionary changes that replace one paradigm with another. This essay examines several transformative discoveries in the light of Kuhn’s formulation. We find that each scientific revolution is unique, with disparate origins that may include puzzle solving, serendipity, inspiration, or a convergence of disparate observations. The causes of revolutionary science are varied and lack an obvious common structure. Moreover, it can be difficult to draw a clear distinction between so-called normal and revolutionary science. Revolutionary discoveries often emerge from basic science and are critically dependent on nonrevolutionary research. Revolutionary discoveries may be conceptual or technological in nature, lead to the creation of new fields, and have a lasting impact on many fields in addition to the field from which they emerge. In contrast to political revolutions, scientific revolutions do not necessarily require the destruction of the previous order. For humanity to continue to benefit from revolutionary discoveries, a broad palette of scientific inquiry with a particular emphasis on basic science should be supported. PMID:26933052

  7. Science Instructors' Views of Science and Nature of Science

    Science.gov (United States)

    Karakas, Mehmet

    2011-01-01

    This qualitative study examined how college science faculty who teach introductory level undergraduate science courses including the fields of chemistry, biology, physics, and earth science, understand and define science and nature of science (NOS). Participants were seventeen science instructors from five different institutions in the…

  8. Science Notes.

    Science.gov (United States)

    Thurman, Shirley; And Others

    1988-01-01

    Describes 36 science activities. Topics include: osmosis, fermentation, anhydrobiotic organisms, breathing monitors, trypsin, weeds, amyloplasts, electrolysis, polarimeters, ethene ripening of fruit, colorimetry, diffusion, redox reactions, equilibria, acid-base relationships, electricity, power, resonance, measurement, parallax, amplifiers,…

  9. Science Notes.

    Science.gov (United States)

    School Science Review, 1990

    1990-01-01

    Included are 30 science activities that include computer monitoring, fieldwork, enzyme activity, pH, drugs, calorimeters, Raoult's Law, food content, solubility, electrochemistry, titration, physical properties of materials, gel filtration, energy, concepts in physics, and electricity. (KR)

  10. Marine Science

    African Journals Online (AJOL)

    Science (WIOJMS), as a special issue entitled “Coral reefs of Mauritius in a changing global climate”. This issue is ... ing compounds from Mauritian coral reef and lagoonal seawater. ..... bleaching event at Koh Tao, Gulf of Thailand. Coral.

  11. Marine Science

    African Journals Online (AJOL)

    Science features state-of-the-art review articles and short communications. ... The last couple of years have been a time of change for the Western Indian Ocean Journal of Marine ...... planning under future sea level predictions, coastal sci-.

  12. Forensic Science.

    Science.gov (United States)

    Brettell, T. A.; Saferstein, R.

    1989-01-01

    Presents a review of articles appealing to forensic practitioners. Topics include: drugs and poisons, forensic biochemistry, and trace evidence. Lists noteworthy books published on forensic science topics since 1986. (MVL)

  13. Capitalist Science

    CERN Document Server

    Knuteson, Bruce

    2011-01-01

    The economic structure of basic science is currently socialist, funded by the public at large through taxes for the benefit of the public at large. This socialist system should be augmented by a capitalist system, in which basic science is also funded by private investors who reap financial benefit from the sale of subsequent technologies based on the knowledge obtained from the research funded by their investments. A capitalist system will provide benefits extending from the broad target audience of this paper -- which includes politicians, financiers, economists, and scientists in all fields -- to the average taxpayer and consumer. Capitalist science will better align the incentives of scientists with taxpayer interests, channel more money into basic science, lower your taxes, and generally improve the quality of your life.

  14. Environmental sciences

    NARCIS (Netherlands)

    Kwa, C.; Wright, J.D.

    2015-01-01

    The environmental sciences are engaged in a remarkable effort of interdisciplinary cooperation and integration. Some long-running international scientific programs, notably the World Climate Research Programme and the International Geosphere-Biosphere Programme, play an important role therein. The

  15. Big science

    CERN Multimedia

    Nadis, S

    2003-01-01

    " "Big science" is moving into astronomy, bringing large experimental teams, multi-year research projects, and big budgets. If this is the wave of the future, why are some astronomers bucking the trend?" (2 pages).

  16. Marine Science

    African Journals Online (AJOL)

    Aims and scope: The Western Indian Ocean Journal of Marine Science provides an avenue for the wide dissem- ination of high .... great barracuda (Sphyraena barracuda), and the giant ...... Smale MJ, Watson G, Hecht T (1995) Otolith atlas of.

  17. Marine Science

    African Journals Online (AJOL)

    sustainable coastal development in the region, as well as contributing to the global base of marine science. The journal .... 48% maize flour, 3% cassava flour, 3% vitamins (Premix for broilers) ..... resulting in inappropriate dietary energy utiliza-.

  18. Marine Science

    African Journals Online (AJOL)

    between humans and the coastal and marine environment. ... dissemination of knowledge generated through research activities at the ... Science (WIOJMS), as a special issue entitled “Coral reefs of Mauritius in a .... tion and damage.

  19. Forensic Science.

    Science.gov (United States)

    Brettell, T. A.; Saferstein, R.

    1989-01-01

    Presents a review of articles appealing to forensic practitioners. Topics include: drugs and poisons, forensic biochemistry, and trace evidence. Lists noteworthy books published on forensic science topics since 1986. (MVL)

  20. Citizen Science

    Science.gov (United States)

    Citizen Science is a fast-growing field in which scientific investigations are conducted by volunteers, which have been successful in expanding scientific knowledge, raising environmental awareness, and leveraging change.

  1. Marine Science

    African Journals Online (AJOL)

    Aims and scope: The Western Indian Ocean Journal of Marine Science provides an ... are not limited to: theoretical studies, oceanography, marine biology and ecology, ... consist of special issues on major events or important thematic issues.

  2. Science Notes.

    Science.gov (United States)

    School Science Review, 1985

    1985-01-01

    Presents 23 experiments, activities, field projects and computer programs in the biological and physical sciences. Instructional procedures, experimental designs, materials, and background information are suggested. Topics include fluid mechanics, electricity, crystals, arthropods, limpets, acid neutralization, and software evaluation. (ML)

  3. Science Topics

    Science.gov (United States)

    EPA is one of the world’s leading environmental and human health research organizations. Science provides the foundation for Agency policies, actions, and decisions made on behalf of the American people.

  4. Managing Science.

    OpenAIRE

    Bert Klandermans

    2011-01-01

    Quality Assessment. Rector manificus , ladies and gentlemen, the answer that is given increasingly within the science system reads, “Let us count.” Let us count how many Euros have been acquired, how many publications are realized, and how many citations are generated. The higher the score, the better the researcher. However, it is not that simple. I showed how different the opportunities are for the three science domains to acquire research funds. A report of the Rathenau Institute about ......

  5. Science Coalition

    Science.gov (United States)

    The National Coalition of Science and Technology (NCST) has elected S. Thomas Moser, of the international accounting firm Peat Marwick, to their board of advisors. Moser is the national director of Marwick's high-technology practice.NCST, based in Washington, D.C., is a broad-based science and technology advocacy organization that seeks to bridge the political interests of the scientific and academic research community with the business community.

  6. Science Fairs for Science Literacy

    Science.gov (United States)

    Mackey, Katherine; Culbertson, Timothy

    2014-03-01

    Scientific discovery, technological revolutions, and complex global challenges are commonplace in the modern era. People are bombarded with news about climate change, pandemics, and genetically modified organisms, and scientific literacy has never been more important than in the present day. Yet only 29% of American adults have sufficient understanding to be able to read science stories reported in the popular press [Miller, 2010], and American students consistently rank below other nations in math and science [National Center for Education Statistics, 2012].

  7. Effects of rapamycin induced cellular autophagy in aging-related diseases%雷帕霉素诱导细胞自噬在衰老相关疾病中的作用

    Institute of Scientific and Technical Information of China (English)

    吴伯艳; 刘新光; 陈维春

    2015-01-01

    哺乳动物雷帕霉素靶蛋白( mammalian target of rapamy-cin, mTOR)是衰老和衰老相关疾病的一个关键调节因子。雷帕霉素( rapamycin, RAPA)可通过抑制mTOR通路,诱导和促进细胞自噬的发生。细胞自噬是维持细胞内稳态的主要方式与途径,通过降解多余的、受损的及衰老的蛋白与细胞器,为细胞重建、再生和修复提供必需原料。早老症( hutchinson-gil-ford progeria syndrome, HGPS )患者细胞中伴随早老蛋白( progerin)的异常聚集;此外,诸如亨廷顿病、帕金森病、阿尔茨海默病等神经退行性疾病细胞内同样出现异常蛋白质的聚集,而这些异常蛋白的清除正依赖于细胞的自噬作用。由此可见,雷帕霉素是潜在的抗衰老、治疗早老症及衰老相关疾病的重要药物。该文主要阐述雷帕霉素促进细胞自噬方面的功能及在HGPS、神经退行性疾病方面的应用。%Mammalian target of rapamycin( mTOR) is a key reg-ulator of aging and aging-related diseases. Rapamycin ( RAPA) induces and promotes the process of cell autophagy through in-hibiting mTOR pathway. Autophagy exerts a crucial role in main-taining the cellular meostasis, which provides essential materials for cell reconstruction, regeneration and repair via degradating the redundant, damaged, or senescent proteins and organelles. Hutchinson Gilford progeria syndrome ( HGPS ) patients are al-ways accompanied with abnormally accumulated progerin in cells. Similar to HGPS, abnormal protein accumulation is the common pathological feature of neurodegenerative diseases, in-cluding Huntington′s disease, Parkinson′s disease, Alzheimer′s disease and so on. Degradation of these abnormal proteins pre-dominantly depends on cell autophagy. Thus, rapamycin is a po-tential anti-aging drug for HGPS and aging-related diseases thera-py. This view focuses on the effects of rapamycin on cell autoph-agy and clinical application in HGPS and neurodegenerative

  8. Is normal science good science?

    Directory of Open Access Journals (Sweden)

    Adrianna Kępińska

    2015-09-01

    Full Text Available “Normal science” is a concept introduced by Thomas Kuhn in The Structure of Scientific Revolutions (1962. In Kuhn’s view, normal science means “puzzle solving”, solving problems within the paradigm—framework most successful in solving current major scientific problems—rather than producing major novelties. This paper examines Kuhnian and Popperian accounts of normal science and their criticisms to assess if normal science is good. The advantage of normal science according to Kuhn was “psychological”: subjective satisfaction from successful “puzzle solving”. Popper argues for an “intellectual” science, one that consistently refutes conjectures (hypotheses and offers new ideas rather than focus on personal advantages. His account is criticized as too impersonal and idealistic. Feyerabend’s perspective seems more balanced; he argues for a community that would introduce new ideas, defend old ones, and enable scientists to develop in line with their subjective preferences. The paper concludes that normal science has no one clear-cut set of criteria encompassing its meaning and enabling clear assessment.

  9. Exploring science through science fiction

    CERN Document Server

    Luokkala, Barry B

    2014-01-01

    How does Einstein’s description of space and time compare with Dr. Who? Can James Bond really escape from an armor-plated railroad car by cutting through the floor with a laser concealed in a wristwatch? What would it take to create a fully-intelligent android, such as Star Trek’s Commander Data? How might we discover intelligent civilizations on other planets in the galaxy? Is human teleportation possible? Will our technological society ever reach the point at which it becomes lawful to discriminate on the basis of genetic information, as in the movie GATTACA? Exploring Science Through Science Fiction addresses these and other interesting questions, using science fiction as a springboard for discussing fundamental science concepts and cutting-edge science research. The book is designed as a primary text for a college-level course which should appeal to students in the fine arts and humanities as well as to science and engineering students. It includes references to original research papers, landmark scie...

  10. Network science

    CERN Document Server

    Barabasi, Albert-Laszlo

    2016-01-01

    Networks are everywhere, from the Internet, to social networks, and the genetic networks that determine our biological existence. Illustrated throughout in full colour, this pioneering textbook, spanning a wide range of topics from physics to computer science, engineering, economics and the social sciences, introduces network science to an interdisciplinary audience. From the origins of the six degrees of separation to explaining why networks are robust to random failures, the author explores how viruses like Ebola and H1N1 spread, and why it is that our friends have more friends than we do. Using numerous real-world examples, this innovatively designed text includes clear delineation between undergraduate and graduate level material. The mathematical formulas and derivations are included within Advanced Topics sections, enabling use at a range of levels. Extensive online resources, including films and software for network analysis, make this a multifaceted companion for anyone with an interest in network sci...

  11. Islam and Science

    Science.gov (United States)

    Salam, Abdus

    The following sections are included: * The Holy Quran and Science * Modem Science, A Greco- Islamic Legacy * The Decline of Sciences in Islam * The Limitations of Science * Faith and Science * The Present Picture of Sciences in the Islamic Countries * Renaissance of Sciences in Islam * Steps Needed for Building up Sciences in the Islamic Countries * Science Education * Science Foundations in Islam * Technology in Our Countries * Concluding Remarks * REFERENCES

  12. Literacy, science, and science education

    Science.gov (United States)

    McVittie, Janet Elizabeth

    In examining the connections between literacy, science and science education, I laid out a number of questions. For example, what sorts of literate tools might facilitate writing to learn, and do children who are just becoming literate use these tools? I then examined the writing of children in science class in an attempt to determine if their writing can indeed facilitate their learning. The results of this research could help teachers make decisions about the use of writing in the learning of science. The kinds of literate tools I identified as being potentially helpful were transitionals---those words or grammatical devices which demonstrate how ideas are connected. Also, I suggested that data tables, sentences and paragraphs were also useful for students to learn. I found that grade 5/6 students used a wide range of literate tools, but that they were much more competent with those tools which were both oral and literate than those which could only be used for writing (punctuation, sentences, paragraphs, and data tables). When I attempted to determine if the children used their writing to learn, I found very little evidence that this was certainly so. However, there was some evidence that paragraphs had the potential to create a "dialogue" between student writing and thinking, so the students could make more explicit connections between science ideas. Lastly, I noticed certain gender difference in the classroom. Because of this, I contrasted the writing of the girls with the writing of the boys. I learned the girls were generally much more capable writers than the boys. More interesting, however, was that the girls generally attempted to explain their science concepts in different ways than did the boys. The girls were more likely to rely on their own reasoning, whereas the boys were more likely to persist in using culturally created science explanations. The research findings have important implications for analyzing students' learning and for finding ways to

  13. Managing Science.

    Directory of Open Access Journals (Sweden)

    Bert Klandermans

    2011-01-01

    Full Text Available Quality Assessment. Rector manificus , ladies and gentlemen, the answer that is given increasingly within the science system reads, “Let us count.” Let us count how many Euros have been acquired, how many publications are realized, and how many citations are generated. The higher the score, the better the researcher. However, it is not that simple. I showed how different the opportunities are for the three science domains to acquire research funds. A report of the Rathenau Institute about ...

  14. Nonlinear Science

    CERN Document Server

    Yoshida, Zensho

    2010-01-01

    This book gives a general, basic understanding of the mathematical structure "nonlinearity" that lies in the depths of complex systems. Analyzing the heterogeneity that the prefix "non" represents with respect to notions such as the linear space, integrability and scale hierarchy, "nonlinear science" is explained as a challenge of deconstruction of the modern sciences. This book is not a technical guide to teach mathematical tools of nonlinear analysis, nor a zoology of so-called nonlinear phenomena. By critically analyzing the structure of linear theories, and cl

  15. Boundless Science

    Science.gov (United States)

    Spilhaus, F.

    2009-04-01

    Our science is critical to understanding the future prospects for life. The laboratory for natural sciences encompasses our planet and reaches into the solar system. The forces of nature respect no boundaries. But, we who try to understand these forces are handicapped by national, political, language, religious, and other concocted barriers. These barriers limit both our effectiveness as scientists and our ability to reach those outside our community who need to know what we have uncovered about our environment. An unencumbered worldwide scientific community has been an objective with limited successes for too long. Action began in earnest after the first world war with the formation of the various scientific Unions and ICSU. Fifty years later Keith Runcorn initiated another approach, when he proposed what quickly became EGS and which has grown and evolved with the merger with EUG. To be truly effective we need to communicate and share comfortably with colleagues worldwide. Personal relationships and trust are required. We count on a high level of ethical behavior within our community. We individually must also be constantly vigilant for the encroachment of the manmade barriers that have held back science through time immemorial. Our scientific organizations cannot achieve this alone. They will facilitate, however, the onus is on each of us to reach out and form interlocking informal communities, which will bring our whole planet-wide community together at many overlapping levels. When we achieve this community, our science will more bountiful and better address the needs of human society.

  16. Marine Science

    African Journals Online (AJOL)

    Science features state-of-the-art review articles and short communications. The journal will, from time to time, .... dinophytes and cyanophytes, can help in predicting and in quantifying the ...... tions over a three-year period. In the current study,.

  17. Cognitive Science.

    Science.gov (United States)

    Cocking, Rodney R.; Mestre, Jose P.

    The focus of this paper is on cognitive science as a model for understanding the application of human skills toward effective problem-solving. Sections include: (1) "Introduction" (discussing information processing framework, expert-novice distinctions, schema theory, and learning process); (2) "Application: The Expert-Novice…

  18. Science Journalism

    Science.gov (United States)

    Polman, Joseph; Newman, Alan; Farrar, Cathy; Saul, E. Wendy

    2012-01-01

    Much of the National Science Education Standards (NRC 1996), aside from the inquiry and teaching sections, focus on content. The authors' call is instead to build standards that focus on what students need to be scientifically literate in 10 or 15 years. Although a basic understanding of important scientific concepts and an understanding of how…

  19. Actuarial Science.

    Science.gov (United States)

    Warren, Bette

    1982-01-01

    Details are provided of a program on actuarial training developed at the State University of New York (SUNY) at Binghamton through the Department of Mathematical Sciences. An outline of its operation, including a few statistics on students in the program, is included. (MP)

  20. Organizational Science

    Science.gov (United States)

    Beriwal, Madhu; Clegg, Stewart; Collopy, Fred; McDaniel, Reuben, Jr.; Morgan, Gareth; Sutcliffe, Kathleen; Kaufman, Roger; Marker, Anthony; Selwyn, Neil

    2013-01-01

    Scholars representing the field of organizational science, broadly defined as including many fields--organizational behavior and development, management, workplace performance, and so on--were asked to identify what they considered to be the most exciting and imaginative work currently being done in their field, as well as how that work might…

  1. Marine Science

    African Journals Online (AJOL)

    Aims and scope: The Western Indian Ocean Journal of Marine Science provides an avenue for the wide dissem- ination of high .... tions at global (e.g. sea temperature, hurricanes) and ..... Jameson SC (1976) Early life history of the giant clams.

  2. Marine Science

    African Journals Online (AJOL)

    Sweden. Cover image: Relief model of the WIO surface that integrates land topography and ocean bathymetry. Amante and ... WIO Journal of Marine Science 14 (1 & 2) 2015 1-9 | L. J. Chauka et al. ... bar, from September 2008 to August 2010.

  3. Actuarial Science.

    Science.gov (United States)

    Warren, Bette

    1982-01-01

    Details are provided of a program on actuarial training developed at the State University of New York (SUNY) at Binghamton through the Department of Mathematical Sciences. An outline of its operation, including a few statistics on students in the program, is included. (MP)

  4. Environmental sciences

    NARCIS (Netherlands)

    Kwa, C.; Wright, J.D.

    2015-01-01

    The environmental sciences are engaged in a remarkable effort of interdisciplinary cooperation and integration. Some long-running international scientific programs, notably the World Climate Research Programme and the International Geosphere-Biosphere Programme, play an important role therein. The o

  5. Nuclear Science.

    Science.gov (United States)

    Pennsylvania State Dept. of Education, Harrisburg. Bureau of Curriculum Services.

    This document is a report on a course in nuclear science for the high school curriculum. The course is designed to provide a basic but comprehensive understanding of the atom in the light of modern knowledge, and to show how people attempt to harness the tremendous energy liberated through fission and fusion reactions. The course crosses what are…

  6. Science Notes.

    Science.gov (United States)

    School Science Review, 1986

    1986-01-01

    Describes activities, games, experiments, demonstrations, and computer-oriented exercises in all science areas. Topics include energy flow through a marine ecosystem, using 2,4-dichlorophenoxyethanoic acid to demonstrate translocation in plants, use of the dichotomous key, use of leaf yeasts to monitor atmospheric pollution, and others. (JN)

  7. Skeptical Science.

    Science.gov (United States)

    Scott, Alan J.; Barnhart, Carolyn M.; Parejko, Ken S.; Schultz, Forrest S.; Schultz, Steven E.

    2001-01-01

    Discusses the legitimacy of teaching about astrology, extrasensory perception, UFOs, touch therapy, cloning dinosaurs, or any other unusual claims in the classroom. Suggests that bringing unusual claims to the science classroom is an opportunity to motivate students in the principles of scientific thought. (SAH)

  8. Marine Science

    African Journals Online (AJOL)

    between humans and the coastal and marine environment. ... dissemination of knowledge generated through research activities at the ... Science (WIOJMS), as a special issue entitled “Coral reefs of Mauritius in a changing global climate”. .... C – growth anomaly; D – brown band; E - skeletal eroding band affecting A.

  9. Science Notes.

    Science.gov (United States)

    Shaw, G. W.; And Others

    1989-01-01

    Provides a reading list for A- and S-level biology. Contains several experiments and demonstrations with topics on: the intestine, bullock corneal cells, valences, the science of tea, automated hydrolysis, electronics characteristics, bromine diffusion, enthalpy of vaporization determination, thermometers, pendulums, hovercraft, Bernoulli fluid…

  10. Computational Science

    Institute of Scientific and Technical Information of China (English)

    K. Li

    2007-01-01

    @@ Computer science is the discipline that anchors the computer industry which has been improving processor performance, communication bandwidth and storage capacity on the so called "Moore's law" curve or at the rate of doubling every 18 to 24 months during the past decades.

  11. Environmental sciences

    NARCIS (Netherlands)

    Kwa, C.; Wright, J.D.

    2015-01-01

    The environmental sciences are engaged in a remarkable effort of interdisciplinary cooperation and integration. Some long-running international scientific programs, notably the World Climate Research Programme and the International Geosphere-Biosphere Programme, play an important role therein. The o

  12. Brewing Science

    Science.gov (United States)

    Pelter, Michael

    2006-01-01

    Following the brewing process from grain to glass, this course uses the biological and chemical principles of brewing to teach science to the nonscience major. Discussion of the scientific aspects of malting, mashing, fermentation, and the making of different beer styles is complemented by laboratory exercises that use scientific methods to…

  13. Science Notes.

    Science.gov (United States)

    School Science Review, 1990

    1990-01-01

    Presented are 25 science activities on colorations of prey, evolution, blood, physiology, nutrition, enzyme kinetics, leaf pigments, analytical chemistry, milk, proteins, fermentation, surface effects of liquids, magnetism, drug synthesis, solvents, wintergreen synthesis, chemical reactions, multicore cables, diffraction, air resistance,…

  14. Science and anti-science

    CERN Document Server

    Holton, Gerald

    1997-01-01

    What is good science? What goal--if any--is the proper end of scientific activity? Is there a legitimating authority that scientists mayclaim? Howserious athreat are the anti-science movements? These questions have long been debated but, as Gerald Holton points out, every era must offer its own responses. This book examines these questions not in the abstract but shows their historic roots and the answers emerging from the scientific and political controversies of this century. Employing the case-study method and the concept of scientific thematathat he has pioneered, Holton displays the broad scope of his insight into the workings of science: from the influence of Ernst Mach on twentiethcentury physicists, biologists, psychologists, and other thinkers to the rhetorical strategies used in the work of Albert Einstein, Niels Bohr, and others; from the bickering between Thomas Jefferson and the U.S. Congress over the proper form of federal sponsorship of scientific research to philosophical debates since Oswald...

  15. Science Literacy Circles: Big Ideas about Science

    Science.gov (United States)

    Devick-Fry, Jane; LeSage, Teresa

    2010-01-01

    Science literacy circles incorporate the organization of both science notebooks and literature circles to help K-8 students internalize big ideas about science. Using science literacy circles gives students opportunities to engage in critical thinking as they inductively develop understanding about science concepts. (Contains 1 table and 7…

  16. Mouse models and aging: longevity and progeria.

    Science.gov (United States)

    Liao, Chen-Yu; Kennedy, Brian K

    2014-01-01

    Aging is a complex, multifactorial process that is likely influenced by the activities of a range of biological pathways. Genetic approaches to identify genes modulating longevity have been highly successful and recent efforts have extended these studies to mammalian aging. A variety of genetic models have been reported to have enhanced lifespan and, similarly, many genetic interventions lead to progeroid phenotypes. Here, we detail and evaluate both sets of models, focusing on the insights they provide about the molecular processes modulating aging and the extent to which mutations conferring progeroid pathologies really phenocopy accelerated aging.

  17. Autophagy and aging: lessons from progeria models.

    Science.gov (United States)

    Mariño, Guillermo; Fernández, Alvaro F; López-Otín, Carlos

    2010-01-01

    Autophagy is an evolutionarily conserved process essential for cellular homeostasis and organismal viability. In fact, this pathway is one of the major protein degradation mechanisms in eukaryotic cells. It has been repeatedly reported that the autophagic activity of living cells decreases with age, probably contributing to the accumulation of damaged macromolecules and organelles during aging. Moreover, autophagy modulation in different model organisms has yielded very promising results suggesting that the maintenance of a proper autophagic activity contributes to extend longevity. On the other hand, recent findings have shown that distinct premature-aging murine models exhibit an extensive basal activation of autophagy instead of the characteristic decline in this process occurring during normal aging. This unexpected autophagic increase in progeroid models is usually associated with a series of metabolic alterations resembling those occurring under calorie restriction or in other situations reported to prolong life-span. In this chapter, we will discuss the current knowledge on the relationship between the autophagy pathway and aging with a special emphasis on the unexpected and novel link between premature aging and autophagy up-regulation.

  18. Physical Therapy and Occupational Therapy in Progeria

    Science.gov (United States)

    ... school setting is to maintain range of motion, strength, and functional status so a student can access the school building and playground and participate with peers in classroom activities, at recess, and in Physical Education class. Proactive PT and OT are important, since ...

  19. The Science in Science Fiction.

    Science.gov (United States)

    Nicholls, Peter, Ed.

    This 12-chapter book discusses the scientific facts behind the ideas included in the novels of Robert Heinlein, Isaac Asimov, Frederik Pohl, Arthur C. Clark and other science fiction writers. Areas explored in the first 11 chapters include: exploration of deep space; energy and exotic power sources; likelihood of extra-terrestrial life and the…

  20. Science Centres and Science Learning.

    Science.gov (United States)

    Rennie, Leonie J.; McClafferty, Terence P.

    1996-01-01

    Focuses on the interactive science center and its history over the last four decades. Traces the original idea to Francis Bacon. Recommends the use of cross-site studies to develop a model of learning in this setting. Contains 141 references. (DDR)

  1. The Science in Science Fiction.

    Science.gov (United States)

    Nicholls, Peter, Ed.

    This 12-chapter book discusses the scientific facts behind the ideas included in the novels of Robert Heinlein, Isaac Asimov, Frederik Pohl, Arthur C. Clark and other science fiction writers. Areas explored in the first 11 chapters include: exploration of deep space; energy and exotic power sources; likelihood of extra-terrestrial life and the…

  2. The Science of Filming Science

    Science.gov (United States)

    Harned, D.

    2016-12-01

    Filmmaking is a science. It is observation, data collection, analysis, experimentation, structure, and presentation. Filmmaking is a process that is familiar to scientists. Observation - what we know is gained from observation of the world around us. Film allows us to focus this observation, to pick out details, to understand nuance, to direct seeing. Filmmaking is a tool for learning about the world. Data collection - to study what we observe we must see what it is now, and how it is changing. This element of filmmaking is collecting images, video, documenting events, and gathering information. Analysis - to understand the film data we have collected we must understand connections, correlations, and cause and effect. We ask questions. We discover. Experimentation - film allows us to experiment with different scenarios, to test observations and make models. Structure - what we find or what we want to present must be sorted into a structured format using the tools of writing, filming, and editing. Presentation - the final film is the result of what we observe, what observations we collect, what we learn from those observations, how we test what we've learned, and how we organize and show what we find. Online video is transforming the way we see the world. We now have easy access to lectures by the famous and the obscure; we can observe lab experiments, documentaries of field expeditions, and actually see recent research results. Video is omnipresent in our culture and supplements or even replaces writing in many applications. We can easily present our own scientific results to new and important audiences. Video can do a lot for science and scientists: It can provide an expanded audience for scientific news and information, educate thousands, spread the word about scientific developments, help frame controversial science issues, show real scientists at work in the real world, promote interest in scientific publications, and report on science-agency programs. It can

  3. Computer sciences

    Science.gov (United States)

    Smith, Paul H.

    1988-01-01

    The Computer Science Program provides advanced concepts, techniques, system architectures, algorithms, and software for both space and aeronautics information sciences and computer systems. The overall goal is to provide the technical foundation within NASA for the advancement of computing technology in aerospace applications. The research program is improving the state of knowledge of fundamental aerospace computing principles and advancing computing technology in space applications such as software engineering and information extraction from data collected by scientific instruments in space. The program includes the development of special algorithms and techniques to exploit the computing power provided by high performance parallel processors and special purpose architectures. Research is being conducted in the fundamentals of data base logic and improvement techniques for producing reliable computing systems.

  4. Mechanical science

    CERN Document Server

    Bolton, W C

    2013-01-01

    This book gives comprehensive coverage of mechanical science for HNC/HND students taking mechanical engineering courses, including all topics likely to be covered in both years of such courses, as well as for first year undergraduate courses in mechanical engineering. It features 500 problems with answers and 200 worked examples. The third edition includes a new section on power transmission and an appendix on mathematics to help students with the basic notation of calculus and solution of differential equations.

  5. Network science.

    Science.gov (United States)

    Barabási, Albert-László

    2013-03-28

    Professor Barabási's talk described how the tools of network science can help understand the Web's structure, development and weaknesses. The Web is an information network, in which the nodes are documents (at the time of writing over one trillion of them), connected by links. Other well-known network structures include the Internet, a physical network where the nodes are routers and the links are physical connections, and organizations, where the nodes are people and the links represent communications.

  6. Fictitious Science

    Science.gov (United States)

    Foladori, Guillermo

    2016-01-01

    Science and Technology (S&T), like Research and Development (R&D), has become a case of capital investment like any other economic sector. This has distanced R&D from social needs, to the extent that part of R&D ends up actually being fictitious, in the sense that it acquires a price on the market but never becomes part of material…

  7. Preservice Science Teachers' Science Teaching Orientations and Beliefs about Science

    Science.gov (United States)

    Kind, Vanessa

    2016-01-01

    This paper offers clarification of science teacher orientations as a potential component of pedagogical content knowledge. Science teaching orientations and beliefs about science held by 237 preservice science teachers were gathered via content-specific vignettes and questionnaire, respectively, prior to participation in a UK-based teacher…

  8. Communicating Science

    Science.gov (United States)

    Holland, G. J.; McCaffrey, M. S.; Kiehl, J. T.; Schmidt, C.

    2010-12-01

    We are in an era of rapidly changing communication media, which is driving a major evolution in the modes of communicating science. In the past, a mainstay of scientific communication in popular media was through science “translators”; science journalists and presenters. These have now nearly disappeared and are being replaced by widespread dissemination through, e.g., the internet, blogs, YouTube and journalists who often have little scientific background and sharp deadlines. Thus, scientists are required to assume increasing responsibility for translating their scientific findings and calibrating their communications to non-technical audiences, a task for which they are often ill prepared, especially when it comes to controversial societal issues such as tobacco, evolution, and most recently climate change (Oreskes and Conway 2010). Such issues have been politicized and hi-jacked by ideological belief systems to such an extent that constructive dialogue is often impossible. Many scientists are excellent communicators, to their peers. But this requires careful attention to detail and logical explanation, open acknowledgement of uncertainties, and dispassionate delivery. These qualities become liabilities when communicating to a non-scientific audience where entertainment, attention grabbing, 15 second sound bites, and self assuredness reign (e.g. Olson 2009). Here we report on a program initiated by NCAR and UCAR to develop new approaches to science communication and to equip present and future scientists with the requisite skills. If we start from a sound scientific finding with general scientific consensus, such as the warming of the planet by greenhouse gases, then the primary emphasis moves from the “science” to the “art” of communication. The art cannot have free reign, however, as there remains a strong requirement for objectivity, honesty, consistency, and above all a resistance to advocating particular policy positions. Targeting audience

  9. Planning a Science Fair

    Science.gov (United States)

    Ebert, Jim

    1976-01-01

    Presented are views, on planning science fairs and science fair projects, of a fair coordinator, a science teacher, and students. Also included are 25 questions which might result in science fair projects. (SL)

  10. Life sciences and environmental sciences

    Energy Technology Data Exchange (ETDEWEB)

    1992-02-01

    The DOE laboratories play a unique role in bringing multidisciplinary talents -- in biology, physics, chemistry, computer sciences, and engineering -- to bear on major problems in the life and environmental sciences. Specifically, the laboratories utilize these talents to fulfill OHER`s mission of exploring and mitigating the health and environmental effects of energy use, and of developing health and medical applications of nuclear energy-related phenomena. At Lawrence Berkeley Laboratory (LBL) support of this mission is evident across the spectrum of OHER-sponsored research, especially in the broad areas of genomics, structural biology, basic cell and molecular biology, carcinogenesis, energy and environment, applications to biotechnology, and molecular, nuclear and radiation medicine. These research areas are briefly described.

  11. Life sciences and environmental sciences

    Energy Technology Data Exchange (ETDEWEB)

    1992-02-01

    The DOE laboratories play a unique role in bringing multidisciplinary talents -- in biology, physics, chemistry, computer sciences, and engineering -- to bear on major problems in the life and environmental sciences. Specifically, the laboratories utilize these talents to fulfill OHER's mission of exploring and mitigating the health and environmental effects of energy use, and of developing health and medical applications of nuclear energy-related phenomena. At Lawrence Berkeley Laboratory (LBL) support of this mission is evident across the spectrum of OHER-sponsored research, especially in the broad areas of genomics, structural biology, basic cell and molecular biology, carcinogenesis, energy and environment, applications to biotechnology, and molecular, nuclear and radiation medicine. These research areas are briefly described.

  12. Defining Data Science

    OpenAIRE

    Zhu, Yangyong; Xiong, Yun

    2015-01-01

    Data science is gaining more and more and widespread attention, but no consensus viewpoint on what data science is has emerged. As a new science, its objects of study and scientific issues should not be covered by established sciences. Data in cyberspace have formed what we call datanature. In the present paper, data science is defined as the science of exploring datanature.

  13. Do Gender-Science Stereotypes Predict Science Identification and Science Career Aspirations among Undergraduate Science Majors?

    Science.gov (United States)

    Cundiff, Jessica L.; Vescio, Theresa K.; Loken, Eric; Lo, Lawrence

    2013-01-01

    The present research examined whether gender-science stereotypes were associated with science identification and, in turn, science career aspirations among women and men undergraduate science majors. More than 1,700 students enrolled in introductory science courses completed measures of gender-science stereotypes (implicit associations and…

  14. Do Gender-Science Stereotypes Predict Science Identification and Science Career Aspirations among Undergraduate Science Majors?

    Science.gov (United States)

    Cundiff, Jessica L.; Vescio, Theresa K.; Loken, Eric; Lo, Lawrence

    2013-01-01

    The present research examined whether gender-science stereotypes were associated with science identification and, in turn, science career aspirations among women and men undergraduate science majors. More than 1,700 students enrolled in introductory science courses completed measures of gender-science stereotypes (implicit associations and…

  15. Science Night

    CERN Document Server

    2004-01-01

    Would it surprise you to know that you can measure the speed of light using chocolate and a microwave oven? If you're interested in this and in finding out much more, come along to the Museum of the History of Science on 3 and 4 July 2004, when dozens of companies, institutions, colleges and organizations will be running exhibits, shows, and displays on the theme of counting and measuring. CERN will be there with a display stand that includes two particle detectors. Full details are available from the Museum website at: http://www.lanuitdelascience.ch/

  16. Science blogging

    CERN Document Server

    Wilcox, Christie

    2016-01-01

    Here is the essential how-to guide for communicating scientific research and discoveries online, ideal for journalists, researchers, and public information officers looking to reach a wide lay audience. Drawing on the cumulative experience of twenty-seven of the greatest minds in scientific communication, this invaluable handbook targets the specific questions and concerns of the scientific community, offering help in a wide range of digital areas, including blogging, creating podcasts, tweeting, and more. With step-by-step guidance and one-stop expertise, this is the book every scientist, science writer, and practitioner needs to approach the Wild West of the Web with knowledge and confidence.

  17. Science commons

    CERN Document Server

    CERN. Geneva

    2007-01-01

    SCP: Creative Commons licensing for open access publishing, Open Access Law journal-author agreements for converting journals to open access, and the Scholar's Copyright Addendum Engine for retaining rights to self-archive in meaningful formats and locations for future re-use. More than 250 science and technology journals already publish under Creative Commons licensing while 35 law journals utilize the Open Access Law agreements. The Addendum Engine is a new tool created in partnership with SPARC and U.S. universities. View John Wilbanks's biography

  18. Science Circus

    Science.gov (United States)

    Thomas, Rhys D.

    2006-12-01

    As a Smithsonian artist in residence Rhys Thomas taught basic Newtonian Physics using circus tricks. As an Oregon Museum of Science and Industry outreach performer he has used his juggling and equilibristic skills to demonstrate gyroscopics, gravity, inertia and other topics in 10 states and three countries. Rhys will share his insights and tips on "performing" rather than just "presenting" physics. He will perform some demos ala Ed Sullivan. He will also discuss how a basic understanding of physics has influenced his artistic expression in non-educational theatrical performances that earned him an Oregon Arts Fellowship in 2005. Sponsored by Stanley Micklavzina of the University of Oregon.

  19. Nanomaterials science

    Directory of Open Access Journals (Sweden)

    Heinrich Rohrer

    2010-01-01

    Full Text Available The nanometer regime covers the transition from condensed matter behavior to atomic and molecular properties and thus is a very rich but also very demanding area in materials science. Close to the condensed matter side, properties and functions might still very well be scalable, whereas close to the atomic and molecular side, the scalability is mostly lost. Properties and functions change qualitatively or quantitatively by orders of magnitude when the dimensions become smaller than a critical size in the nanometer range. Examples are the ballistic regime for electron or spin transport at dimensions below the mean free path, near-field effects in scanning near-field optical microscopy and quantum wells when the dimensions are below an appropriate wavelength, novel electronic, mechanical, and chemical properties when the number of bulk atoms becomes smaller than that of surface atoms, quantum conduction, and Coulomb blockade. Thus, by going below a certain size, an abundance of novel properties and functions are at one's disposal, or, in other words, we can functionalize materials simply by reducing their size to the nanoscale.The key to the future lies in the functions that we give to materials, not just in finding 'novel functional materials'. This catch expression in many materials science programs and initiatives of the past two decades sounds great, but it is not what really counts. All materials are functional in one way or another and, therefore, all new materials are 'novel functional materials'. Certainly, finding new materials is always an important part of progress, but we should also focus on the much larger domain of novel functions that we can give to existing or modified materials. A good example is semiconductors: they are fifty or more years old and their properties are very well known, but they were not of widespread interest and use until the transistor changed their destiny into being the central material in the information

  20. Learning Science with Science Fiction Films.

    Science.gov (United States)

    Cavanaugh, Terence; Cavanaugh, Catherine

    This paper is an excerpt from a book on learning science using science fiction. The focus is on the use of science fiction films to engage students and encourage greater enthusiasm and interest in science. "Jurassic Park" is used as an example that can provide educators with countless lesson opportunities. This approach recommends the use of fun…

  1. Towards a Science of Science Teaching

    Science.gov (United States)

    Yates, Carolyn

    2009-01-01

    This article is a contribution to the search for evidence-based models of learning to improve science education. The author believes that modern teachers should look to the sciences of cognitive psychology and neuroscience to build a science of science teaching. Understanding the relationships between learning and the brain's structure and…

  2. Science Advising

    Science.gov (United States)

    Tannenbaum, Benn

    2004-05-01

    The need for competent physical scientists in public policy is often overlooked. Science and technology play an ever-growing role in our lives, but the people setting the policies governing their use too often lack the skills and knowledge needed to make well-informed decisions. Making the transition from academia to public policy is not as difficult as one might imagine and can lead to a challenging, rewarding career. Dr. Tannenbaum recently completed a 2002-2003 AAAS Science and Technology Fellowship sponsored by the American Physical Society during which he worked in the office of U.S. Representative Edward J. Markey (D-MA) on nuclear nonproliferation issues. His work in Congressman Markey's office focused on issues including US nuclear weapons policy, missile defense, the nuclear program in Iran, prevention of the transfer of U.S. nuclear technology to North Korea, and the security of nuclear sites in Iraq. Dr. Tannenbaum will discuss this experience and observations concerning "underinformed and uninformed" decision-making in Congress and the role of scientists in that process. He will also discuss his current position at the Federation of American Scientists.

  3. Science kitsch and pop science: A reconnaissance.

    Science.gov (United States)

    Kaeser, Eduard

    2013-07-01

    Science kitsch? The combination of these two words rings like an oxymoron. Science - as the common saying has it - exposes, discovers, tells the truth; kitsch conceals, covers, lies. I think, this "shadow" of science deserves a specific scrutiny, not only because it reflects the altered place and role of science in contemporary "knowledge" society but also because it pinpoints the task of relocating science in the "multicultural" context of postmodernism, with its different epistemic claims. The genre of science kitsch may help to regain credit by working as a probe to detect false pretensions, explanatory exuberance and exaggerations in science.

  4. Enacting science

    Science.gov (United States)

    MacDonald, Anthony Leo

    My study examines the development of forms of knowing that arise when students engage in open-ended explorations involving self-directed design and building involving simple materials. It is grounded in an enactivist theoretical perspective on cognition which holds that the creation of action-thought processes for engaging the world is interwoven with the meanings that are constructed for these experiences. A dynamic conception of persons-acting-in-a-setting is fundamental to an enactivist view of cognition. How is understanding enacted in building activity? How does the shape of a problem emerge? How do students enact meaning and understanding when they experience a high degree of physical engagement in building things? What are some characteristics of an enactive learning/teaching environment? My research settings comprise a range of individual, group and classroom engagements of varying lengths over a three and one-half year period. The first research episode involved two grade eight students in an investigation of Paper Towels. The second four month engagement was in a grade nine science class that culminated in the building of a Solar House. The third grade ten episode involved a one month project to build a Mousetrap Powered Car. A fourth Invent a Machine project was conducted in two grade eight science classes taught by the teacher who participated in the Solar House project. Two students were present in three of the four projects. I interviewed one of these students upon completion of his high school physics courses. I found that building is a form of thinking which develops competency in managing complex practical tasks. A triadic relationship of exploration, planning and acting is present. Practical and procedural understandings emerge as students enter and re-enter self-directed problem settings. Thinking patterns depend on the kinds of materials chosen, the ways they are used, and on how students contextualize the problem. Classroom assessment

  5. FOREWORD Nanomaterials science Nanomaterials science

    Science.gov (United States)

    Rohrer, Heinrich

    2010-10-01

    The nanometer regime covers the transition from condensed matter behavior to atomic and molecular properties and thus is a very rich but also very demanding area in materials science. Close to the condensed matter side, properties and functions might still very well be scalable, whereas close to the atomic and molecular side, the scalability is mostly lost. Properties and functions change qualitatively or quantitatively by orders of magnitude when the dimensions become smaller than a critical size in the nanometer range. Examples are the ballistic regime for electron or spin transport at dimensions below the mean free path, near-field effects in scanning near-field optical microscopy and quantum wells when the dimensions are below an appropriate wavelength, novel electronic, mechanical, and chemical properties when the number of bulk atoms becomes smaller than that of surface atoms, quantum conduction, and Coulomb blockade. Thus, by going below a certain size, an abundance of novel properties and functions are at one's disposal, or, in other words, we can functionalize materials simply by reducing their size to the nanoscale. The key to the future lies in the functions that we give to materials, not just in finding 'novel functional materials'. This catch expression in many materials science programs and initiatives of the past two decades sounds great, but it is not what really counts. All materials are functional in one way or another and, therefore, all new materials are 'novel functional materials'. Certainly, finding new materials is always an important part of progress, but we should also focus on the much larger domain of novel functions that we can give to existing or modified materials. A good example is semiconductors: they are fifty or more years old and their properties are very well known, but they were not of widespread interest and use until the transistor changed their destiny into being the central material in the information technology revolution

  6. Supercomputational science

    CERN Document Server

    Wilson, S

    1990-01-01

    In contemporary research, the supercomputer now ranks, along with radio telescopes, particle accelerators and the other apparatus of "big science", as an expensive resource, which is nevertheless essential for state of the art research. Supercomputers are usually provided as shar.ed central facilities. However, unlike, telescopes and accelerators, they are find a wide range of applications which extends across a broad spectrum of research activity. The difference in performance between a "good" and a "bad" computer program on a traditional serial computer may be a factor of two or three, but on a contemporary supercomputer it can easily be a factor of one hundred or even more! Furthermore, this factor is likely to increase with future generations of machines. In keeping with the large capital and recurrent costs of these machines, it is appropriate to devote effort to training and familiarization so that supercomputers are employed to best effect. This volume records the lectures delivered at a Summer School ...

  7. Salvaging Science Literacy

    Science.gov (United States)

    Feinstein, Noah

    2011-01-01

    There is little evidence that the prevailing strategies of science education have an impact on the use and interpretation of science in daily life. Most science educators and science education researchers nonetheless believe that science education is intrinsically useful for students who do not go on to scientific or technical careers. This essay…

  8. Salvaging Science Literacy

    Science.gov (United States)

    Feinstein, Noah

    2011-01-01

    There is little evidence that the prevailing strategies of science education have an impact on the use and interpretation of science in daily life. Most science educators and science education researchers nonetheless believe that science education is intrinsically useful for students who do not go on to scientific or technical careers. This essay…

  9. Voodoo Science

    Science.gov (United States)

    Park, Robert

    2011-03-01

    A remarkable scientific result that appears to violate natural law may portend a revolutionary advance in human knowledge. It is, however, more likely an experimental screw up. Error is normal; it can be reduced by repeating measurements and better design of controls, but the success and credibility of science is anchored in a culture of openness. Ideas and observations are freely exposed to independent testing and evaluation by others. What emerges is the book of nature. On its pages we find, if not a simple world, at least an orderly world, in which everything from the birth of stars to falling in love is governed by the same natural laws. These laws cannot be circumvented by any amount of piety or cleverness, they can be understood - with the possible exception of String Theory. For those who elect to work outside the scientific community, errors may go unrecognized. We will examine examples of this, including claims of perpetual motion and cancer caused by cell-phone radiation.

  10. Science Education Notes.

    Science.gov (United States)

    School Science Review, 1987

    1987-01-01

    Provides perspectives and background information on selected aspects of science instruction. Addresses concerns related to physics teaching, academic assessment, problem-solving, integrated science, readability, college science for pre-nursing students, and a graded assessment scheme. (ML)

  11. Science Education After Dainton

    Science.gov (United States)

    Keohane, Kevin

    1969-01-01

    The Dainton committee indicated that science must not be directed simply at the committed students. Curriculum changes, including those related to teaching science as a unity, could have a profound effect in making science more attractive and relevant. (JK)

  12. Science and Religion: Implications for Science Educators

    Science.gov (United States)

    Reiss, Michael J.

    2010-01-01

    A religious perspective on life shapes how and what those with such a perspective learn in science; for some students a religious perspective can hinder learning in science. For such reasons Staver's article is to be welcomed as it proposes a new way of resolving the widely perceived discord between science and religion. Staver notes that Western…

  13. Common Earth Science Misconceptions in Science Teaching

    Science.gov (United States)

    King, Chris

    2012-01-01

    A survey of the Earth science content of science textbooks found a wide range of misconceptions. These are discussed in this article with reference to the published literature on Earth science misconceptions. Most misconceptions occurred in the "sedimentary rocks and processes" and "Earth's structure and plate tectonics" categories; the most…

  14. Citizen Science: Getting More Involved with Science

    Science.gov (United States)

    Leeder, Poppy

    2014-01-01

    One of the things that this author enjoys most about working at the Natural Environment Research Council (NERC) is the science that she finds out about and the researchers she meets. Having loved science throughout school and then on into university, the author is always keen to learn more. The increase in citizen science projects over the last…

  15. Promoting science through science fiction and pseudoscience.

    Science.gov (United States)

    Roslund, C.

    1986-11-01

    A great deal of physics can be learned from reading good science fiction. Many writers of this genre have shown great talent in explaining the laws of physics in language that is both lucid and accessible. Their writings can readily be used by the science teacher to enhance and to stimulate student understanding of physics and science.

  16. How to Motivate Science Teachers to Use Science Experiments

    OpenAIRE

    Josef Trna

    2012-01-01

    A science experiment is the core tool in science education. This study describes the science teachers' professional competence to implement science experiments in teaching/learning science. The main objective is the motivation of science teachers to use science experiments. The presented research tries to answer questions aimed at the science teachers' skills to use science experiments in teaching/learning science. The research discovered the following facts: science teachers do not include s...

  17. MicroRNA transcriptome analysis identifies miR-365 as a novel negative regulator of cell proliferation in Zmpste24-deficient mouse embryonic fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Xiong, Xing-dong [Institute of Aging Research, Guangdong Medical College, Xin Cheng Avenue 1#, Songshan Lake, Dongguan, Guangdong 523808 (China); Institute of Biochemistry & Molecular Biology, Guangdong Medical College, Zhanjiang 524023 (China); Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Dongguan 523808 (China); Institute of Laboratory Medicine, Guangdong Medical College, Dongguan, Guangdong 523808 (China); Jung, Hwa Jin [Departments of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461 (United States); Gombar, Saurabh [Departments of Systems Biology, Albert Einstein College of Medicine, Bronx, NY 10461 (United States); Park, Jung Yoon [Departments of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461 (United States); Zhang, Chun-long; Zheng, Huiling [Institute of Aging Research, Guangdong Medical College, Xin Cheng Avenue 1#, Songshan Lake, Dongguan, Guangdong 523808 (China); Institute of Biochemistry & Molecular Biology, Guangdong Medical College, Zhanjiang 524023 (China); Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Dongguan 523808 (China); Ruan, Jie; Li, Jiang-bin [Institute of Aging Research, Guangdong Medical College, Xin Cheng Avenue 1#, Songshan Lake, Dongguan, Guangdong 523808 (China); Institute of Biochemistry & Molecular Biology, Guangdong Medical College, Zhanjiang 524023 (China); Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Dongguan 523808 (China); Institute of Laboratory Medicine, Guangdong Medical College, Dongguan, Guangdong 523808 (China); Kaeberlein, Matt [Institute of Aging Research, Guangdong Medical College, Xin Cheng Avenue 1#, Songshan Lake, Dongguan, Guangdong 523808 (China); Department of Pathology, University of Washington, Seattle, WA 98195 (United States); and others

    2015-07-15

    Highlights: • A comprehensive miRNA transcriptome of MEFs from Zmpste24{sup −/−} and control mice. • Identification of miR-365 as a down-regulated miRNA in Zmpste24{sup −/−} MEFs. • Characterization of miR-365 as a modulator of cellular growth in part by targeting Rasd1. - Abstract: Zmpste24 is a metalloproteinase responsible for the posttranslational processing and cleavage of prelamin A into mature laminA. Zmpste24{sup −/−} mice display a range of progeroid phenotypes overlapping with mice expressing progerin, an altered version of lamin A associated with Hutchinson-Gilford progeria syndrome (HGPS). Increasing evidence has demonstrated that miRNAs contribute to the regulation of normal aging process, but their roles in progeroid disorders remain poorly understood. Here we report the miRNA transcriptomes of mouse embryonic fibroblasts (MEFs) established from wild type (WT) and Zmpste24{sup −/−} progeroid mice using a massively parallel sequencing technology. With data from 19.5 × 10{sup 6} reads from WT MEFs and 16.5 × 10{sup 6} reads from Zmpste24{sup −/−} MEFs, we discovered a total of 306 known miRNAs expressed in MEFs with a wide dynamic range of read counts ranging from 10 to over 1 million. A total of 8 miRNAs were found to be significantly down-regulated, with only 2 miRNAs upregulated, in Zmpste24{sup −/−} MEFs as compared to WT MEFs. Functional studies revealed that miR-365, a significantly down-regulated miRNA in Zmpste24{sup −/−} MEFs, modulates cellular growth phenotypes in MEFs. Overexpression of miR-365 in Zmpste24{sup −/−} MEFs increased cellular proliferation and decreased the percentage of SA-β-gal-positive cells, while inhibition of miR-365 function led to an increase of SA-β-gal-positive cells in WT MEFs. Furthermore, we identified Rasd1, a member of the Ras superfamily of small GTPases, as a functional target of miR-365. While expression of miR-365 suppressed Rasd1 3′ UTR luciferase-reporter activity

  18. 过氧化氢诱导的人正常和早老细胞中DNA损伤及其修复研究%The Study of Hydrogen Peroxide Induced DNA Damage and Recovery in Normal Aging and Premature Aging Human Cells

    Institute of Scientific and Technical Information of China (English)

    所起凤; 杜文婷; 杨鸣鸣; 范雪娇; 刘戟

    2011-01-01

    目的 研究人早老细胞和正常衰老细胞在氧化应激条件下的DNA损伤和修复.方法 采用免疫荧光技术和彗星电泳技术,分别检测3组不同群体倍增数(PD)的人正常二倍体成纤维细胞BJ(青年组第14代,成年组第30代,衰老组第45代)和2组不同PD的人赫-吉二氏综合征(HGPS)细胞(青年组第8代,衰老组第17代)的DNA基础损伤程度.研究过氧化氢诱导造成以上细胞组DNA损伤及去除致损因素正常培养后的修复水平,采用免疫荧光和彗星电泳技术检测细胞在沉默DNA损伤修复蛋白着色性干皮病蛋白A(XPA)表达前后的修复能力.结果 BJ细胞衰老组DNA损伤程度较高,与成年组相比,对DNA损伤诱导因子更加敏感(P<0.05);成年组与青年组相比,对损伤诱导因子也更敏感(P<0.05).HGPS细胞青年组的DNA基础损伤程度即已达到衰老BJ细胞类似或更高水平,且与BJ细胞具有一致的DNA损伤年龄变化趋势.经siRNA沉默XPA表达后可部分恢复HGPS细胞的修复能力,对BJ细胞则没有影响.随年龄增长无论正常还是早老细胞,DNA损伤程度增加,修复效率降低.结论 XPA功能异常抑制了HGPS细胞的损伤修复.%Objective To study the DNA damage and recovery induced by hydrogen peroxide in normal aging and premature aging human cells. Methods The immunofluorescent assay and comet assay were used to estimate basal DNA damage in normal aging BJ cells and premature aging Hutchinson-Gilford progeria syndrome (HGPS) cells, which were divided into three and two distinct population doubling (PD) number groups (BJ 14· 30, 45 and HGPS 8, 17) respectively. The DNA damage induced by hydrogen peroxide of these cell populations, as well as their repair activity, was also studied. Finally, the recovery capability before and after the xeroderma pigmentosum group A (XPA ) knocked down in these groups was measured. Results Our results indicated that the normal BJ cells of older PD number

  19. What's science? Where's science? Science journalism in German print media.

    Science.gov (United States)

    Summ, Annika; Volpers, Anna-Maria

    2016-10-01

    This article examines the current state of science coverage in German print media. It deals with the following questions: (1) how the main characteristics of science journalism can be described, (2) whether there is a difference between various scientific fields, and (3) how different definitions of science journalism lead to differing findings. Two forms of science coverage were analyzed in a standardized, two-part content analysis of German newspapers (N = 1730 and N = 1640). The results show a significant difference between a narrow and a broad definition of science journalism. In the classic understanding, science journalism is prompted by scientific events and is rather noncritical. Science coverage in a broad sense is defined by a wider range of journalistic styles, driven by non-scientific events, and with a focus on the statements of scientific experts. Furthermore, the study describes the specific role of the humanities and social sciences in German science coverage. © The Author(s) 2015.

  20. Science, technology and society

    CERN Document Server

    Giacomelli, G

    2005-01-01

    We shall discuss some aspects of science and technology, their increasing role in the society, the fast advances in modern science, the apparent decrease of interest of the young generation in basic sciences, the importance of proper science popularization for better public education and awareness in scientific fields.

  1. Making Science Relevant

    Science.gov (United States)

    Eick, Charles; Deutsch, Bill; Fuller, Jennifer; Scott, Fletcher

    2008-01-01

    Science teachers are always looking for ways to demonstrate the relevance of science to students. By connecting science learning to important societal issues, teachers can motivate students to both enjoy and engage in relevant science (Bennet, Lubben, and Hogarth 2007). To develop that connection, teachers can help students take an active role in…

  2. Pragmaticism, Science and Theology

    DEFF Research Database (Denmark)

    Brier, Søren

    2016-01-01

    This review assesses Ashley and Deely’s claims regarding the relation of science and religion, taking Einstein’s famous statement that “science without religion is lame, religion without science is blind” as its starting point. It argues that Ashley and Deely’s book How Science Enriches Theology...

  3. Science and Scientificity

    Institute of Scientific and Technical Information of China (English)

    Zong-Liang Xu; Xin Zhang

    2005-01-01

    @@ A question about science We are now living in a scientific era, in which the theory and practice of science have penetrated into all aspects of society and science is often a hot topic.However, what on earth is science? This question is largely neglected by many people, even researchers focusing on scientific studies may not have a very clear understanding of it.

  4. Science to the People

    CERN Document Server

    Doswaldbeck, L; Brancati, D; Colombo, U; Coyaud, S; De Semir, V; Dupuy, G; Ellis, Jonathan Richard; Lecourt, D; Llewellyn Smith, Christopher Hubert; Mettan, G; Montagnier, L; Morrison, Douglas Robert Ogston; Rampini, F; Ting, Samuel C C; Ugo, R; Widman, A; CERN. Geneva

    1994-01-01

    Science & society : urgent topics Risk perception : Ringing the alarm bells Basic research : Understanding its relevance Science and Economics : Comparing puplic costs and puplic benefits Language(s) : Translating expert knowledge into common culture Science and ethics : Freedom of research and limits to its applications Science,Media & Society: A confrontation

  5. Science Fiction & Scientific Literacy

    Science.gov (United States)

    Czerneda, Julie E.

    2006-01-01

    The term "science fiction" has become synonymous, in the media at least, for any discovery in science too incredible or unexpected for the nonscientist to imagine. One of the most common classroom uses of science fiction is for students to pick out flaws in science fiction movies or television shows. Unfortunately, this approach can result in…

  6. Has Feminism Changed Science?

    Science.gov (United States)

    Schiebinger, Londa

    2000-01-01

    Discusses whether the presence of feminism in science has changed science, discounting the idea that simply encouraging more women to enter science will necessarily produce change and stressing the need for governmental funding and initiatives on women and gender in science. Argues for multiple arenas for change (research priorities, domestic…

  7. Science and Technology Facilities

    Science.gov (United States)

    Moonen, Jean-Marie; Buono, Nicolas; Handfield, Suzanne

    2004-01-01

    These four articles relate to science and technology infrastructure for secondary and tertiary institutions. The first article presents a view on approaches to teaching science in school and illustrates ideal science facilities for secondary education. The second piece reports on work underway to improve the Science Complex at the "Universite…

  8. A mirror for science.

    Science.gov (United States)

    Jasanoff, Sheila

    2014-01-01

    Early conceptions of the public understanding of science suffered from a narrow framing of what science means and a presumption that science is divided from its publics by walls of ignorance and indifference. Those assumptions amplified misunderstanding and led to faulty policies. It is time to reopen each element in the term "public understanding of science" to renewed reflection. This journal can advance that goal by encouraging research on actual rather than imagined public responses to science, on representations of science in the public sphere, and on interactions between science, technology and society.

  9. Science and Technology Metrics

    Science.gov (United States)

    2005-01-01

    Analysis (1974 1994)", PSICOLOGIA CONDUCTUAL 1996, Vol 4, Iss 1, pp 111 121 Irvine, J.; Martin, B., "The Isaac Newton Telescope", Social Studies of Science...analysing 1000 articles from the Science Citation Index(R) and Social Sciences Citation Index(R) [Ali, 1993]. These articles were selected in ten...occurrences of the same keywords among the shared references. However, there are some unique differences in the science and the social science

  10. The World of Science Fiction.

    Science.gov (United States)

    Schwartz, Sheila

    1971-01-01

    Science fiction is discussed from the following standpoints: What Is Science Fiction?; The History of Science Fiction; and The Themes of Science Fiction. A list of films, books, and records about science fiction is given. (DB)

  11. Science Film: An Aperture into Science Advocacy

    Science.gov (United States)

    2015-04-01

    The current funding environment for scientific research necessitates a change in how we foster support for the endeavor. Federal spending is not likely to grow unless constituents--APS members--help communicate the value of science to members of Congress and the public in a compelling and individual way. The event explores how popular film with science-based plots can help physicists communicate the value of science to members of Congress and an increasingly diverse electorate.

  12. Network science, nonlinear science and infrastructure systems

    CERN Document Server

    2007-01-01

    Network Science, Nonlinear Science and Infrastructure Systems has been written by leading scholars in these areas. Its express purpose is to develop common theoretical underpinnings to better solve modern infrastructural problems. It is felt by many who work in these fields that many modern communication problems, ranging from transportation networks to telecommunications, Internet, supply chains, etc., are fundamentally infrastructure problems. Moreover, these infrastructure problems would benefit greatly from a confluence of theoretical and methodological work done with the areas of Network Science, Dynamical Systems and Nonlinear Science. This book is dedicated to the formulation of infrastructural tools that will better solve these types of infrastructural problems. .

  13. A Science Cloud for Data Intensive Sciences

    Directory of Open Access Journals (Sweden)

    Ken T Murata

    2013-03-01

    Full Text Available It is often discussed that the fourth methodology for science research is "informatics". The first methodology is a theoretic approach, the second one is observation and/or experiment, and the third one is computer simulation. Informatics is a new methodology for data intensive science, which is a new concept based on the fact that most scientific data are digitalized and the amount of data is huge. The facilities to support informatics are cloud systems. Herein we propose a cloud system especially designed for science. The basic concepts, design, resources, implementation, and applications of the NICT science cloud are discussed.

  14. Different images of science

    DEFF Research Database (Denmark)

    Davidsson, Eva

      Within the science and technology centres (STC) movement there exists explicit aims and ambitions to enhance visitors' interest in and knowledge about science. Meanwhile, several researches question the choice of the scientific content in exhibitions when arguing that a too unproblematic view...... of science commonly is presented. But what images and aspects of science are visitors actually confronted with at STCs? How do staff members at STCs consider the scientific content and how do they choose what aspects of science to display in exhibitions? What ideas about visitors' learning do staff members...... images of science. Staff members at Nordic STC were therefore asked to consider to what extent they believe they display different aspects of science. The results suggest that it is possible to display different images of science depending on what aspects of science staff members choose to display...

  15. Different images of science

    DEFF Research Database (Denmark)

    Davidsson, Eva

      Within the science and technology centres (STC) movement there exists explicit aims and ambitions to enhance visitors' interest in and knowledge about science. Meanwhile, several researches question the choice of the scientific content in exhibitions when arguing that a too unproblematic view...... of science commonly is presented. But what images and aspects of science are visitors actually confronted with at STCs? How do staff members at STCs consider the scientific content and how do they choose what aspects of science to display in exhibitions? What ideas about visitors' learning do staff members...... images of science. Staff members at Nordic STC were therefore asked to consider to what extent they believe they display different aspects of science. The results suggest that it is possible to display different images of science depending on what aspects of science staff members choose to display...

  16. NX15 science workshop

    CERN Multimedia

    2015-01-01

    Science. For some of us, it's daunting or maybe even terrifying. How to tell a good science story? That's the question we will explore together in this workshop. Conceived and produced by journalist and Scientific News producer Claudio Rosmino of Euronews, and presented by Euronews' Jeremy Wilks, the workshop will look at actual case studies (from Euronews and beyond) where science news proved exciting, inspiring and accessible to audiences around the world. These might include the Rosetta mission and CERN's work on Science for Peace. Together, we'll share ideas and knowledge around how science journalism and science news can increase its visibility in the media and maybe save the planet...!

  17. Towards Data Science

    Directory of Open Access Journals (Sweden)

    Yangyong Zhu

    2015-05-01

    Full Text Available Currently, a huge amount of data is being rapidly generated in cyberspace. Datanature (all data in cyberspace is forming due to a data explosion. Exploring the patterns and rules in datanature is necessary but difficult. A new discipline called Data Science is coming. It provides a type of novel research method (a data-intensive method for natural and social sciences and goes beyond computer science in researching data. This paper presents the challenges presented by data and discusses what differentiates data science from the established sciences, data technologies, and big data. Our goal is to encourage data related researchers to transfer their focus towards this new science.

  18. Environmental Science Projects. LC Science Tracer Bullet.

    Science.gov (United States)

    Carter, Constance, Comp.

    This bibliography cites sources to assist middle, junior, and senior high school students and teachers in planning, preparing, and executing science fair projects in the environmental sciences. In addition, a few books with experiments suitable for elementary grade students are included. The listing includes: (1) 5 introductory texts; (2) 31…

  19. Discovery in Science and in Teaching Science

    Science.gov (United States)

    Kipnis, Nahum

    2007-01-01

    A proper presentation of scientific discoveries may allow science teachers to eliminate certain myths about the nature of science, which originate from an uncertainty among scholars about what constitutes a discovery. It is shown that a disagreement on this matter originates from a confusion of the act of discovery with response to it. It is…

  20. Giant Steps Through Science, Science I.

    Science.gov (United States)

    Bertke, Mary Christopher; Feistritzer, Emily

    This text is designed for use in a first year high school science course and is an attempt to put basic physical science concepts into a logical order. This organization involves an historical approach, beginning with four chapters on astronomy: Modern Astronomy, The Ancient Astronomers, Astronomy - Ptolemy to Kepler, and Galileo and Newton. The…

  1. Advancing the Science of Team Science

    Science.gov (United States)

    Falk‐Krzesinski, Holly J.; Börner, Katy; Contractor, Noshir; Fiore, Stephen M.; Hall, Kara L.; Keyton, Joann; Spring, Bonnie; Stokols, Daniel; Trochim, William; Uzzi, Brian

    2010-01-01

    Abstract The First Annual International Science of Team Science (SciTS) Conference was held in Chicago, IL April 22–24, 2010. This article presents a summary of the Conference proceedings. Clin Trans Sci 2010; Volume 3: 263–266. PMID:20973925

  2. Teaching Science Fact with Science Fiction

    Science.gov (United States)

    Raham, R. Gary

    2004-01-01

    The literature of science fiction packs up the facts and discoveries of science and runs off to futures filled with both wonders and warnings. Kids love to take the journeys it offers for the thrill of the ride, but they can learn as they travel, too. This book will provide the reader with: (1) an overview of the past 500 years of scientific…

  3. Science and religion: implications for science educators

    Science.gov (United States)

    Reiss, Michael J.

    2010-03-01

    A religious perspective on life shapes how and what those with such a perspective learn in science; for some students a religious perspective can hinder learning in science. For such reasons Staver's article is to be welcomed as it proposes a new way of resolving the widely perceived discord between science and religion. Staver notes that Western thinking has traditionally postulated the existence and comprehensibility of a world that is external to and independent of human consciousness. This has led to a conception of truth, truth as correspondence, in which our knowledge corresponds to the facts in this external world. Staver rejects such a conception, preferring the conception of truth as coherence in which the links are between and among independent knowledge claims themselves rather than between a knowledge claim and reality. Staver then proposes constructivism as a vehicle potentially capable of resolving the tension between religion and science. My contention is that the resolution between science and religion that Staver proposes comes at too great a cost—both to science and to religion. Instead I defend a different version of constructivism where humans are seen as capable of generating models of reality that do provide richer and more meaningful understandings of reality, over time and with respect both to science and to religion. I argue that scientific knowledge is a subset of religious knowledge and explore the implications of this for science education in general and when teaching about evolution in particular.

  4. Physical Sciences 2007 Science & Technology Highlights

    Energy Technology Data Exchange (ETDEWEB)

    Hazi, A U

    2008-04-07

    The Physical Sciences Directorate applies frontier physics and technology to grand challenges in national security. Our highly integrated and multidisciplinary research program involves collaborations throughout Lawrence Livermore National Laboratory, the National Nuclear Security Administration, the Department of Energy, and with academic and industrial partners. The Directorate has a budget of approximately $150 million, and a staff of approximately 350 employees. Our scientists provide expertise in condensed matter and high-pressure physics, plasma physics, high-energy-density science, fusion energy science and technology, nuclear and particle physics, accelerator physics, radiation detection, optical science, biotechnology, and astrophysics. This document highlights the outstanding research and development activities in the Physical Sciences Directorate that made news in 2007. It also summarizes the awards and recognition received by members of the Directorate in 2007.

  5. Science and Shakespeare.

    Science.gov (United States)

    Mah, Steven; Chinnery, Charlene

    2003-01-01

    Describes an assignment in which the preservice teacher must find a connection between science and Shakespeare. Connects the science of the witches in Shakespeare's "Macbeth" to the holistic approach of education. (SG)

  6. Integrating Forensic Science.

    Science.gov (United States)

    Funkhouser, John; Deslich, Barbara J.

    2000-01-01

    Explains the implementation of forensic science in an integrated curriculum and discusses the advantages of this approach. Lists the forensic science course syllabi studied in three high schools. Discusses the unit on polymers in detail. (YDS)

  7. ICASE Computer Science Program

    Science.gov (United States)

    1985-01-01

    The Institute for Computer Applications in Science and Engineering computer science program is discussed in outline form. Information is given on such topics as problem decomposition, algorithm development, programming languages, and parallel architectures.

  8. An Alternative Science Fair.

    Science.gov (United States)

    Romjue, Mary Kalen; Clementson, John J.

    1992-01-01

    Proposes the organization of noncompetitive science fairs to create a more positive learning experience for children in the elementary grades. Describes methods of organizing and judging the fair, and provides a list of suggested resources for science fair projects. (MDH)

  9. Integrating Forensic Science.

    Science.gov (United States)

    Funkhouser, John; Deslich, Barbara J.

    2000-01-01

    Explains the implementation of forensic science in an integrated curriculum and discusses the advantages of this approach. Lists the forensic science course syllabi studied in three high schools. Discusses the unit on polymers in detail. (YDS)

  10. Science Inventory | US EPA

    Science.gov (United States)

    The Science Inventory is a searchable database of research products primarily from EPA's Office of Research and Development. Science Inventory records provide descriptions of the product, contact information, and links to available printed material or websites.

  11. Science in General Education

    Science.gov (United States)

    Read, Andrew F.

    2013-01-01

    General education must develop in students an appreciation of the power of science, how it works, why it is an effective knowledge generation tool, and what it can deliver. Knowing what science has discovered is desirable but less important.

  12. Science and Shakespeare.

    Science.gov (United States)

    Mah, Steven; Chinnery, Charlene

    2003-01-01

    Describes an assignment in which the preservice teacher must find a connection between science and Shakespeare. Connects the science of the witches in Shakespeare's "Macbeth" to the holistic approach of education. (SG)

  13. JSTOR Plant Science

    OpenAIRE

    2010-01-01

    JSTOR Plant Science is an online environment that brings together content, tools, and people interested in plant science. It provides access to foundational content vital to plant science – plant type specimens, taxonomic structures, scientific literature, and related materials, making them widely accessible to the plant science community as well as to researchers in other fields and to the public. It also provides an easy to use interface with powerful functionality that su...

  14. CAREERS IN INFORMATION SCIENCE,

    Science.gov (United States)

    Information Science . Sets forth that Information Science is concerned with the properties, behavior, and flow of information...Describes how it is used, both by individuals and in large systems. Discusses the opportunities in Information Science and outlines three relatively...6or participation in these career areas. Concludes that Information Science is a new but rapidly growing field pushing the frontiers of human knowledge and, thus, 3ontributing to human wellbeing and progress.

  15. Science Fair Art

    Science.gov (United States)

    Sullivan, Kevin

    2004-01-01

    Sciences fair season is a time when seasoned non-science teachers typically give up all hope of cramming any more knowledge into the heads of their students. It's just too much. However, non-science types might be missing out on a pretty good deal. The science department has got these kids in a pretty tight grip as far as the process and the…

  16. Social science that matters

    DEFF Research Database (Denmark)

    Flyvbjerg, Bent

    2006-01-01

    Social science is headed down a dead end toward mere scientism, becoming a second-rate version of the hard sciences. We neeed to recognise and support a different kind of social science research - and so should those who demand accountability from researchers. This paper asks what kind of social...... science we - scholars, policy makers, administrators - should and should not promote in democratic societies, and how we may hold social scientists accountable to deliver what we ask them for....

  17. Inequalities in Science

    Science.gov (United States)

    Xie, Y.

    2014-01-01

    Inequalities in scientists’ contributions to science and their rewards have always been very high. There are good reasons to propose that inequalities in science across research institutions and across individual scientists have increased in recent years. In the meantime, however, globalization and internet technology have narrowed inequalities in science across nations and facilitated the expansion of science and rapid production of scientific discoveries through international collaborative networks. PMID:24855244

  18. Social science that matters

    DEFF Research Database (Denmark)

    Flyvbjerg, Bent

    2006-01-01

    Social science is headed down a dead end toward mere scientism, becoming a second-rate version of the hard sciences. We neeed to recognise and support a different kind of social science research - and so should those who demand accountability from researchers. This paper asks what kind of social...... science we - scholars, policy makers, administrators - should and should not promote in democratic societies, and how we may hold social scientists accountable to deliver what we ask them for....

  19. Artificiality in Social Sciences

    OpenAIRE

    Rennard, Jean-Philippe

    2007-01-01

    This text provides with an introduction to the modern approach of artificiality and simulation in social sciences. It presents the relationship between complexity and artificiality, before introducing the field of artificial societies which greatly benefited from the computer power fast increase, gifting social sciences with formalization and experimentation tools previously owned by "hard" sciences alone. It shows that as "a new way of doing social sciences", artificial societies should undo...

  20. 76 FR 38430 - Subcommittee on Forensic Science; Committee on Science; National Science and Technology Council

    Science.gov (United States)

    2011-06-30

    ... TECHNOLOGY POLICY Subcommittee on Forensic Science; Committee on Science; National Science and Technology... ). SUMMARY: The Subcommittee on Forensic Science (SoFS) of the National Science and Technology Council's... Science can be obtained through the Office of Science and Technology Policy's NSTC Web site at:......