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

Maria Eriksson, W. Ted Brown, Leslie B. Gordon, Michael W. Glynn, Joel Singer, Laura Scott, Michael R. Erdos, Christiane M. Robbins, Tracy Y. Moses, Peter Berglund, Amalia Dutra, Evgenia Pak, Sandra Durkin, Antonei B. Csoka, Michael Boehnke, Thomas W. Glover and Francis S. Collins ()
Additional contact information
Maria Eriksson: National Institutes of Health
W. Ted Brown: New York State Institute for Basic Research in Developmental Disabilities
Leslie B. Gordon: Tufts University School of Medicine
Michael W. Glynn: National Institutes of Health
Joel Singer: University of Michigan
Laura Scott: University of Michigan
Michael R. Erdos: National Institutes of Health
Christiane M. Robbins: National Institutes of Health
Tracy Y. Moses: National Institutes of Health
Peter Berglund: National Institutes of Health
Amalia Dutra: National Institutes of Health
Evgenia Pak: National Institutes of Health
Sandra Durkin: National Institutes of Health
Antonei B. Csoka: Brown University
Michael Boehnke: University of Michigan
Thomas W. Glover: National Institutes of Health
Francis S. Collins: National Institutes of Health

Nature, 2003, vol. 423, issue 6937, 293-298

Abstract: Abstract 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.

Date: 2003
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DOI: 10.1038/nature01629

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