Y. Bykhovskaya et al., EVIDENCE FOR COMPLEX NUCLEAR INHERITANCE IN A PEDIGREE WITH NONSYNDROMIC DEAFNESS DUE TO A HOMOPLASMIC MITOCHONDRIAL MUTATION, American journal of medical genetics, 77(5), 1998, pp. 421-426
The relationship between mitochondrial genotype and clinical phenotype
is complicated in most instances by the heteroplasmic nature of patho
genic mitochondrial mutations. We have previously shown that maternall
y inherited hearing loss in a large Arab-Israeli kindred is due to the
homoplasmic A1555G mutation in the mitochondrial 12S ribosomal RNA ge
ne [Prezant et al., 1993: Nat Genet 4:289-294]. Family members with th
is mutation have phenotypes ranging from profound hearing loss to comp
letely normal hearing, and we have shown that there is genetic and bio
chemical evidence for nuclear gene involvement in this family [Bu et a
l., 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 e
xcluded through linkage analysis and sequencing, and a genome-wide lin
kage search in family members who all have the identical homoplasmic m
itochondrial mutation, but differ in their hearing status, was perform
ed. In two stages a total of 560 polymorphic genetic markers was genot
yped, and the data were analyzed under model-dependent and model-free
assumptions. No chromosomal region was identified as a major contribut
or to the phenotypic expression of the mitochondrial mutation. Thus, i
n this simplified paradigm of a homoplasmic mitochondrial mutation in
a single kindred who all live in the similar environment of a small vi
llage, the penetrance of the mitochondrial mutation appears to depend
on the interaction of multiple nuclear genes. (C) 1998 Wiley-Liss, Inc
.