Intrafamilial variable expressivity of osteogenesis imperfecta due to mosaicism for a lethal G382R substitution in theCOL1A1gene

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• 作者：Cohen-Solal ; Lola ; Zolezzi ; Francesca ; Pignatti ; Pier Franco ; Mottes ; Monica
• 刊名：Molecular and Cellular Probes
• 出版年：1996
• 出版时间：June, 1996
• 年：1996
• 卷：10
• 期：3
• 页码：219-225
• 全文大小：317 K

文摘

Fibroblasts from a 23 week old fetus affected with lethal (type II) osteogenesis imperfecta (OI) produced normal and abnormal type I procollagen molecules. The abnormal molecules were shown to contain proα1(I) chains in which the glycine at position 382 of the triple helical domain was substituted by arginine, as the result of a G-to-C transversion at nucleotide 1797 of the proα(I) coding sequence. Also fibroblasts from the apparently normal father produced abnormal type I collagen but the overmodified α1(I) chains tended to disappear with increasing passage number. We determined that the mutant allele accounted for approximately 36 % of theCOL1A1alleles in the father's skin fibroblasts. Upon careful clinical reexamination, the man appeared to be very mildly affected with OI. The most plausible explanation for such a phenotypic variation is that the father is a mosaic for a mutation that is lethal in the heterozygous son. This finding confirms previous observations that somatic mosaicism for new dominant mutations is responsible for extreme intrafamilial variability and poses some caveats in genetic counselling.