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Research Article Free access | 10.1172/JCI117930

A mutation in FBN1 disrupts profibrillin processing and results in isolated skeletal features of the Marfan syndrome.

D M Milewicz, J Grossfield, S N Cao, C Kielty, W Covitz, and T Jewett

Department of Internal Medicine, University of Texas-Houston Medical School 77030, USA.

Find articles by Milewicz, D. in: PubMed | Google Scholar

Department of Internal Medicine, University of Texas-Houston Medical School 77030, USA.

Find articles by Grossfield, J. in: PubMed | Google Scholar

Department of Internal Medicine, University of Texas-Houston Medical School 77030, USA.

Find articles by Cao, S. in: PubMed | Google Scholar

Department of Internal Medicine, University of Texas-Houston Medical School 77030, USA.

Find articles by Kielty, C. in: PubMed | Google Scholar

Department of Internal Medicine, University of Texas-Houston Medical School 77030, USA.

Find articles by Covitz, W. in: PubMed | Google Scholar

Department of Internal Medicine, University of Texas-Houston Medical School 77030, USA.

Find articles by Jewett, T. in: PubMed | Google Scholar

Published May 1, 1995 - More info

Published in Volume 95, Issue 5 on May 1, 1995
J Clin Invest. 1995;95(5):2373–2378. https://doi.org/10.1172/JCI117930.
© 1995 The American Society for Clinical Investigation
Published May 1, 1995 - Version history
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Abstract

Dermal fibroblasts from a 13-yr-old boy with isolated skeletal features of the Marfan syndrome were used to study fibrillin synthesis and processing. Only one half of the secreted profibrillin was proteolytically processed to fibrillin outside the cell and deposited into the extracellular matrix. Electron microscopic examination of rotary shadowed microfibrils made by the proband's fibroblasts were indistinguishable from control cells. Sequencing of the FBN1 gene revealed a heterozygous C to T transition at nucleotide 8176 resulting in the substitution of a tryptophan for an arginine (R2726W), at a site immediately adjacent to a consensus sequence recognized by a cellular protease. Six other individuals in the proband's family had the FBN1 mutation that segregated with tall stature. None of the affected individuals have cardiac or ocular manifestations of the Marfan syndrome. This mutation identifies a putative site for profibrillin to fibrillin processing, and is associated with isolated skeletal features of the Marfan syndrome, indicating that the FBN1 gene is one of the genes that determines height in the general population. The cellular effect of the mutation may be equivalent to a "null" FBN1 allele and may define the phenotype associated with FBN1 "null" alleles.

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