Evidence for complex nuclear inheritance in a pedigree with nonsyndromic deafness due to a homoplasmic mitochondrial mutation

Yelena Bykhovskaya, Mordechai Shohat, Karen Ehrenman, David Johnson, Melanie Hamon, Rita M. Cantor, Bradley Aouizerat, Xiangdong Bu, Jerome I. Rotter, Lutfi Jaber, Nathan Fischel-Ghodsian

Research output: Contribution to journalArticle

Abstract

The relationship between mitochondrial genotype and clinical phenotype is complicated in most instances by the heteroplasmic nature of pathogenic mitochondrial mutations. We have previously shown that maternally inherited hearing loss in a large Arab-Israeli kindred is due to the homoplasmic A1555G mutation in the mitochondrial 12S ribosomal RNA gene [Prezant et al., 1993: Nat Genet 4:289-294]. Family members with this mutation have phenotypes ranging from profound hearing loss to completely normal hearing, and we have shown that there is genetic and biochemical evidence for nuclear gene involvement in this family [Bu et al., 1993: Genet Epidemiol 9:27-44; Guan et al., 1996: Hum Mol Genet 5:963-971]. To identify such a nuclear locus, two candidate genes were excluded through linkage analysis and sequencing, and a genome-wide linkage search in family members who all have the identical homoplasmic mitochondrial mutation, but differ in their hearing status, was performed. In two stages a total of 560 polymorphic genetic markers was genotyped, and the data were analyzed under model-dependent and model-free assumptions. No chromosomal region was identified as a major contributor to the phenotypic expression of the mitochondrial mutation. Thus, in this simplified paradigm of a homoplasmic mitochondrial mutation in a single kindred who all live in the similar environment of a small village, the penetrance of the mitochondrial mutation appears to depend on the interaction of multiple nuclear genes.

Original languageEnglish (US)
Pages (from-to)421-426
Number of pages6
JournalAmerican Journal of Medical Genetics
Volume77
Issue number5
DOIs
StatePublished - Jun 5 1998

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Keywords

  • Hereditary hearing loss
  • Linkage analysis
  • Maternal inheritance
  • Mitochondria

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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