Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene

Harry C. Dietz, Carry R. Cutting, Reed E. Pyeritz, Cheryl L. Maslen, Lynn Y. Sakai, Glen M. Corson, Erik G. Puffenberger, Ada Hamosh, Elizabeth J. Nanthakumar, Sheila M. Curristin, Gail Stetten, Deborah A. Meyers, Clair A. Francomano

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Abstract

MARFAN syndrome is an inherited disorder of connective tissue manifested in the ocular, skeletal and cardiovascular systems. It is inherited as an autosomal dominant with high penetrance, but has great clinical variability1. Linkage studies have mapped the Marfan locus to chromosome 15q 15-21.3 (refs 2, 3). There have been no reports of genetic heterogeneity in the syndrome. Following the identification of fibrillin (a glycoprotein component of the extracellular microfibril4), immunohistopathological quantification of the protein in skin and fibroblast culture5, and examination of fibrillin synthesis, extracellular transport, and incorporation into the extracellular matrix (D. M. Milewicz, R.E.P., E. S. Crawford and P. H. Byers, manuscript in preparation) have demonstrated abnormalities of fibrillin metabolism in most patients. A portion of the complementary DNA encoding fibrillin has been cloned6 and mapped by in situ hybridization to chromosome 15 (ref. 7). Here we report that the fibrillin gene is linked to the Marfan phenotype (θ=0.00; logarithm of the odds (lod) = 3.9) and describe a de novo missense mutation in the fibrillin gene in two patients with sporadic disease. We thus implicate fibrillin as the protein defective in patients with the Marfan syndrome.

Original languageEnglish (US)
Pages (from-to)337-339
Number of pages3
JournalNature
Volume352
Issue number6333
DOIs
StatePublished - 1991

ASJC Scopus subject areas

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    Dietz, H. C., Cutting, C. R., Pyeritz, R. E., Maslen, C. L., Sakai, L. Y., Corson, G. M., Puffenberger, E. G., Hamosh, A., Nanthakumar, E. J., Curristin, S. M., Stetten, G., Meyers, D. A., & Francomano, C. A. (1991). Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature, 352(6333), 337-339. https://doi.org/10.1038/352337a0