Four novel fbn1 mutations: Significance for mutant transcript level and egf-like domain calcium binding in the pathogenesis of marfan syndrome

Harry C. Dietz, Iain McIntosh, Lynn Sakai, Glen M. Corson, Stephen C. Chalberg, Reed E. Pyeritz, Clair A. Francomano

Research output: Contribution to journalArticle

230 Citations (Scopus)

Abstract

Defects of fibrillin (FBN1), a glycoprotein component of the extracellular microfibril, cause Marfan syndrome. This disorder is characterized by marked inter- and intrafamilial variation in phenotypic severity. To understand the molecular basis for this clinical observation, we have screened the fibrillin gene (FBN1) on chromosome 15, including the newly cloned 5′ coding sequence, for disease-producing alterations in a panel of patients with a wide range of manifestations and clinical severity. All the missense mutations identified to date, including two novel mutations discussed here, are associated with classic and moderate to severe disease and occur at residues with putative significance for calcium binding to epidermal growth factor (EGF)-like domains. In contrast, two new mutations that create premature signals for termination of translation of mRNA and are associated with reduction in the amount of mutant allele transcript produce a range of phenotypic severity. The patient with the lowest amount of mutant transcript has the mildest disease. These data support a role for altered calcium binding to EGF-like domains in the pathogenesis of Marfan syndrome and suggest a dominant negative mechanism for the pathogenesis of this disorder.

Original languageEnglish (US)
Pages (from-to)468-475
Number of pages8
JournalGenomics
Volume17
Issue number2
DOIs
StatePublished - Jan 1 1993

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Marfan Syndrome
Calcium
Epidermal Growth Factor
Mutation
Microfibrils
Chromosomes, Human, Pair 15
Protein Biosynthesis
Missense Mutation
Glycoproteins
Alleles
Observation
Genes
Fibrillins

ASJC Scopus subject areas

  • Genetics

Cite this

Four novel fbn1 mutations : Significance for mutant transcript level and egf-like domain calcium binding in the pathogenesis of marfan syndrome. / Dietz, Harry C.; McIntosh, Iain; Sakai, Lynn; Corson, Glen M.; Chalberg, Stephen C.; Pyeritz, Reed E.; Francomano, Clair A.

In: Genomics, Vol. 17, No. 2, 01.01.1993, p. 468-475.

Research output: Contribution to journalArticle

Dietz, Harry C. ; McIntosh, Iain ; Sakai, Lynn ; Corson, Glen M. ; Chalberg, Stephen C. ; Pyeritz, Reed E. ; Francomano, Clair A. / Four novel fbn1 mutations : Significance for mutant transcript level and egf-like domain calcium binding in the pathogenesis of marfan syndrome. In: Genomics. 1993 ; Vol. 17, No. 2. pp. 468-475.
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