Nature 352, 337 - 339 (25 July 1991); doi:10.1038/352337a0

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^†‡

^*Division of Pediatric Cardiology, Department of Pediatrics The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
^† Center for Medical Genetics, Departments of Pediatrics The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
^‡ Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
^¶ Gynecology and Obstetrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
^§ Shriners Hospital for Crippled Children, Health Sciences University, Portland, Oregon 97201, USA
Department of Biochemistry and Molecular Biology, Oregon Health Sciences University, Portland, Oregon 97201, USA

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 ( =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.

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