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Title:
Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome
Authors:
Eriksson, Maria; Brown, W. Ted; Gordon, Leslie B.; Glynn, Michael W.; Singer, Joel; Scott, Laura; Erdos, Michael R.; Robbins, Christiane M.; Moses, Tracy Y.; Berglund, Peter; Dutra, Amalia; Pak, Evgenia; Durkin, Sandra; Csoka, Antonei B.; Boehnke, Michael; Glover, Thomas W.; Collins, Francis S.
Affiliation:
AA(National Human Genome Research Institute, and Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA), AB(Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, USA), AC(Department of Anatomy and Cellular Biology, Tufts University School of Medicine, Boston, Massachusetts 02111, and Department of Pediatrics, Rhode Island Hospital, Providence, Rhode Island 02903, USA), AD(Department of Human Genetics, and Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA), AG(National Human Genome Research Institute, and Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA), AH(National Human Genome Research Institute, and Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA), AI(National Human Genome Research Institute, and Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA), AK(National Human Genome Research Institute, and Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA), AL(National Human Genome Research Institute, and Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA), AM(Department of Human Genetics, and Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA), AN(Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island 02912, USA), AP(Department of Human Genetics, and Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA), AQ(National Human Genome Research Institute, and Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA)
Publication:
Nature, Volume 423, Issue 6937, pp. 293-298 (2003). (Nature Homepage)
Publication Date:
05/2003
Origin:
NATURE
Abstract Copyright:
(c) 2003: Nature
DOI:
10.1038/nature01629
Bibliographic Code:
2003Natur.423..293E

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.
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