Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome
Maria Eriksson,W. Ted Brown,Leslie B. Gordon,Leslie B. Gordon,Michael W. Glynn,Joel Singer,Laura J. Scott,Michael R. Erdos,Christiane M. Robbins,Tracy Moses,Peter Berglund,Amalia Dutra,Evgenia Pak,Sandra G. Durkin,Antonei B. Csoka,Michael Boehnke,Thomas W. Glover,Francis S. Collins +17 more
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TLDR
Evidence of mutations in lamin A (LMNA) as the cause of Hutchinson–Gilford progeria syndrome is presented, and the discovery of the molecular basis of this disease may shed light on the general phenomenon of human ageing.Abstract:
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by features reminiscent of marked premature ageing. Here, we present evidence of mutations in lamin A (LMNA) as the cause of this disorder. The HGPS gene was initially localized to chromosome 1q by observing two cases of uniparental isodisomy of 1q-the inheritance of both copies of this material from one parent-and one case with a 6-megabase paternal interstitial deletion. Sequencing of LMNA, located in this interval and previously implicated in several other heritable disorders, revealed that 18 out of 20 classical cases of HGPS harboured an identical de novo (that is, newly arisen and not inherited) single-base substitution, G608G(GGC > GGT), within exon 11. One additional case was identified with a different substitution within the same codon. Both of these mutations result in activation of a cryptic splice site within exon 11, resulting in production of a protein product that deletes 50 amino acids near the carboxy terminus. Immunofluorescence of HGPS fibroblasts with antibodies directed against lamin A revealed that many cells show visible abnormalities of the nuclear membrane. The discovery of the molecular basis of this disease may shed light on the general phenomenon of human ageing.read more
Citations
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The Hallmarks of Aging
TL;DR: Nine tentative hallmarks that represent common denominators of aging in different organisms are enumerated, with special emphasis on mammalian aging, to identify pharmaceutical targets to improve human health during aging, with minimal side effects.
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Lamin A-Dependent Nuclear Defects in Human Aging
Paola Scaffidi,Tom Misteli +1 more
TL;DR: It is shown that the same molecular mechanism responsible for HGPS is active in healthy cells, and inhibition of this splice site reverses the nuclear defects associated with aging.
Journal ArticleDOI
Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome.
Robert D. Goldman,Dale K. Shumaker,Michael R. Erdos,Maria Eriksson,Anne E. Goldman,Leslie B. Gordon,Leslie B. Gordon,Yosef Gruenbaum,Satya Khuon,Melissa G. Mendez,Renee Varga,Francis S. Collins +11 more
TL;DR: It is shown by light and electron microscopy that HGPS is associated with significant changes in nuclear shape, including lobulation of the nuclear envelope, thickening of thenuclear lamina, loss of peripheral heterochromatin, and clustering of nuclear pores.
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Telomeres and Aging
TL;DR: The crucial role of telomeres in cell turnover and aging is highlighted by patients with 50% of normal telomere levels resulting from a mutation in one of the telomerase genes, implicated in a variety of disorders including dyskeratosis congenita, aplastic anemia, pulmonary fibrosis, and cancer.
Journal ArticleDOI
Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction
Jan Lammerding,P. Christian Schulze,Tomosaburo Takahashi,Serguei Kozlov,Teresa Sullivan,Roger D. Kamm,Colin L. Stewart,Richard T. Lee +7 more
TL;DR: The 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.
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