Revertant Mutation Releases Confined Lethal Mutation, Opening Pandora's Box

A Novel Genetic Pathogenesis

Yasushi Ogawa, Takuya Takeichi, Michihiro Kono, Nobuyuki Hamajima, Toshimichi Yamamoto, Kazumitsu Sugiura, Masashi Akiyama

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

When two mutations, one dominant pathogenic and the other "confining" nonsense, coexist in the same allele, theoretically, reversion of the latter may elicit a disease, like the opening of Pandora's box. However, cases of this hypothetical pathogenic mechanism have never been reported. We describe a lethal form of keratitis-ichthyosis-deafness (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. The biological relationship between the parents and the child was confirmed by genotyping of 15 short tandem repeat loci. Haplotype analysis using 40 SNPs spanning the >39 kbp region surrounding the GJB2 gene and an extended SNP microarray analysis spanning 83,483 SNPs throughout chromosome 13 in the family showed that an allelic recombination event involving the maternal allele carrying the mutations generated the pathogenic allele unique to the patient, although the possibility of coincidental accumulation of spontaneous point mutations cannot be completely excluded. Previous reports and our mutation screening support that p.Gly45Glu is in complete linkage disequilibrium with p.Tyr136X in the Japanese population. Estimated from statisitics in the literature, there may be approximately 11,000 p.Gly45Glu carriers in the Japanese population who have this second-site confining mutation, which acts as natural genetic protection from the lethal disease. The reversion-triggered onset of the disesase shown in this study is a previously unreported genetic pathogenesis based on Mendelian inheritance.

Original languageEnglish
Article numbere1004276
JournalPLoS Genetics
Volume10
Issue number5
DOIs
Publication statusPublished - 01-01-2014
Externally publishedYes

Fingerprint

lethal genes
mutation
pathogenesis
Mutation
Alleles
nonsense mutation
alleles
Single Nucleotide Polymorphism
Nonsense Codon
allele
Mothers
deafness
Parent-Child Relations
Mendelian inheritance
Chromosomes, Human, Pair 13
keratitis
Linkage Disequilibrium
point mutation
Microarray Analysis
linkage disequilibrium

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Ogawa, Yasushi ; Takeichi, Takuya ; Kono, Michihiro ; Hamajima, Nobuyuki ; Yamamoto, Toshimichi ; Sugiura, Kazumitsu ; Akiyama, Masashi. / Revertant Mutation Releases Confined Lethal Mutation, Opening Pandora's Box : A Novel Genetic Pathogenesis. In: PLoS Genetics. 2014 ; Vol. 10, No. 5.
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Revertant Mutation Releases Confined Lethal Mutation, Opening Pandora's Box : A Novel Genetic Pathogenesis. / Ogawa, Yasushi; Takeichi, Takuya; Kono, Michihiro; Hamajima, Nobuyuki; Yamamoto, Toshimichi; Sugiura, Kazumitsu; Akiyama, Masashi.

In: PLoS Genetics, Vol. 10, No. 5, e1004276, 01.01.2014.

Research output: Contribution to journalArticle

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