Revertant Mutation Releases Confined Lethal Mutation, Opening Pandora's Box: A Novel Genetic Pathogenesis

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Loss of gene functions due to nonsense mutations is a typical pathogenic mechanism of hereditary diseases. They may, however, in certain genetic contexts, confine the effects of other dominant pathogenic mutations and suppress disease manifestations. We report the first instance in the literature where the reversion of a “confining” nonsense mutation in GJB2 gene released the dominant pathogenic effect of a coexsisting gain-of-function mutation, eliciting the lethal form of keratitis-ichthyosis-deafness syndrome (KID). We describe this form of KID syndrome caused by the reversion of the GJB2 nonsense mutation p.Tyr136X that would otherwise have confined the effect of another dominant lethal mutation, p.Gly45Glu, in the same allele. The patient's mother had the identical misssense mutation which was confined by the nonsense mutation. An epidemiologic estimation demonstrates that approximately 11,000 individuals in the Japanese population may have the same lethal GJB2 mutation, nonetheless protected from the manifestation of the syndrome because they also inherit the common “confining” nonsense mutation. The reversion-triggered onset of the disease shown in this study is a previously unreported genetic pathogenesis based on Mendelian inheritance.

Vyšlo v časopise: Revertant Mutation Releases Confined Lethal Mutation, Opening Pandora's Box: A Novel Genetic Pathogenesis. PLoS Genet 10(5): e32767. doi:10.1371/journal.pgen.1004276
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004276

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