A single mutation that results in an Asp to His substitution and partial exon skipping in a family with congenital contractural arachnodactyly

Darcie Babcock, Cheryll Gasner, Uta Francke, Cheryl Maslen

    Research output: Contribution to journalArticle

    26 Scopus citations

    Abstract

    Congenital contractural arachnodactyly (CCA) is an autosomal dominant disorder of connective tissue and is characterized by multiple congenital contractures, arachnodactyly, and external ear malformations. Recent investigations indicate that mutations in the fibrillin-2 gene (FBN2) cause CCA. Here, we report a G→C transversion at nucleotide 3340 (G3340C) of FBN2 in a family with phenotypic characteristics of CCA. The G3340C mutation predicts the substitution of histidine for aspartic acid at amino acid residue 1114 (Asp1114His) and also alters the 5' donor splice site consensus sequence of exon 25. Reverse transcription/polymerase chain reaction and DNA sequence analyses demonstrate that this missense mutation also causes low level in-frame mis-splicing of exon 25 (del exon 25). Consequently, this single point mutation produces a heterogeneous population of mutant fibrillin-2 molecules in a single individual. Despite the complex manifestation of the mutation, it is associated with a relatively mild phenotype. Analysis of FBN2 allele expression in cultured dermal fibroblasts derived from the proband has shown that the mutant allele is preferentially expressed, contributing about 84% of the total transcript. This indicates that an overabundance of mutant transcript does not necessarily correlate with a more severe CCA phenotype.

    Original languageEnglish (US)
    Pages (from-to)22-28
    Number of pages7
    JournalHuman genetics
    Volume103
    Issue number1
    DOIs
    StatePublished - Sep 8 1998

    ASJC Scopus subject areas

    • Genetics
    • Genetics(clinical)

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