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Nature 423, 293-298 (15 May 2003) | doi:10.1038/nature01629; Received 24 January 2003; Accepted 1 April 2003; Published online 25 April 2003

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Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome

Maria Eriksson1, W. Ted Brown2, Leslie B. Gordon3, Michael W. Glynn4, Joel Singer5, Laura Scott5, Michael R. Erdos1, Christiane M. Robbins1, Tracy Y. Moses1, Peter Berglund6, Amalia Dutra1, Evgenia Pak1, Sandra Durkin4, Antonei B. Csoka7, Michael Boehnke5, Thomas W. Glover4 & Francis S. Collins1

  1. 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
  2. Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, USA
  3. 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
  4. Department of Human Genetics, and Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA
  5. Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island 02912, USA

Correspondence to: Francis S. Collins1 Correspondence and requests for materials should be addressed to F.S.C. (Email: fc23a@nih.gov).

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Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by features reminiscent of marked premature ageing1, 2. 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 disorders3, 4, 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.