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

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.

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Figure 1: Localization of the HGPS gene to a 4.82-Mb interval on chromosome 1q.
Figure 2: Point mutations in exon 11 of LMNA cause HGPS.
Figure 3: Immunofluorescence on primary dermal fibroblasts from an unaffected mother and a child with classical HGPS, using antibody JOL2 against lamin A/C.

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Acknowledgements

We are grateful to all of the families with HGPS who donated blood and skin samples, without which this study would not have been possible. We would also like to express our gratitude to the entire Progeria Research Consortium, especially B. Toole, for their encouragement during the course of this work. We also thank E. Gillanders for providing the linkage marker set; P. Hollstein for assistance with genotyping; P. Chines for the identification of additional microsatellite markers on chromosome 1q; and M. Kirby for assistance with the flow cytometry. Support from the Progeria Research Foundation (L.B.G., M.W.G. and T.W.G.) and the Bedminster Foundation (W.T.B.) is gratefully acknowledged.

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Correspondence to Francis S. Collins.

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Eriksson, M., Brown, W., Gordon, L. et al. Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome. Nature 423, 293–298 (2003). https://doi.org/10.1038/nature01629

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