PARENTAL SOMATIC AND GERM-LINE MOSAICISM FOR A FBN2 MUTATION AND ANALYSIS OF FBN2 TRANSCRIPT LEVELS IN DERMAL FIBROBLASTS

Congenital contractural arachnodactyly (CCA) is an autosomal dominant disorder that is phenotypically related to the Marfan syndrome. CCA ha s recently been shown to result from mutations in the FBN2 gene, which encodes an elastin-associated microfibrillar protein called fibrillin -2. Two siblings are reported here with classic manifestations of CCA with unaffected parents. Analysis of the FBN2 cDNA from dermal fibrobl asts from one of the affected siblings revealed a heterozygous exon sp licing error deleting nt 3722-3844 of the FBN2 mRNA. This cDNA deletio n resulted in selective removal of one of the 43 calcium-binding EGF-l ike domains of the fibrillin-2 protein. Analysis of the FBN2 gene in t he affected siblings' DNA indicated that the splicing error resulted f rom an A-to-G transition 15 nt upstream from the 3' splice site of the intron. The genomic mutation resulting in the splicing error alters a putative branch point sequence important for lariat formation, an int ermediate structure of normal splicing. The mutation was detectable in DNA from the father's hair bulbs and buccal cells but not his white b lood cell DNA, indicating that the father was a somatic mosaic. Analys is of transcript levels by use of dermal fibroblasts from the proband demonstrated that the FBN2 allele containing the exon deletion was exp ressed at a higher level than the allele inherited from the mother. Th ese results indicate that FBN2 exon splicing errors are a cause of CCA , furthering the understanding of the molecular basis of this disorder . In addition, the demonstration of gonadal mosaicism in the FBN2 gene is important for accurate genetic counseling of families with sporadi c cases of CCA. Finally, the preferential expression of the mutated FB N2 allele in dermal fibroblasts may have implications for understandin g the pathogenesis and rarity of CCA.