Candidate locus for a nuclear modifier gene for maternally inherited deafness

Maternally inherited deafness associated with the A1555G mutation in the mi tochondrial 12S ribosomal RNA (rRNA) gene appears to require additional env ironmental or genetic changes for phenotypic expression. Aminoglycosides ha ve been identified as one such environmental factor. In one large Arab-Isra eli pedigree with congenital hearing loss in some of the family members wit h the A1555G mutation and with no exposure to aminoglycosides, biochemical evidence has suggested the role of nuclear modifier gene(s), but a genomewi de search has indicated the absence of a single major locus having such an effect. Thus it has been concluded that the penetrance of the mitochondrial mutation appears to depend on additive effects of several nuclear genes. W e have now investigated 10 multiplex Spanish and Italian families with 35 m embers with the A1555G mutation and sensorineural deafness. Parametric anal ysis of a genomewide screen again failed to identify significant evidence f or linkage to a single autosomal locus, However, nonparametric analysis sup ported the role of the chromosomal region around marker D8S277, The combine d maximized allele-sharing LOD score of 3.1 in Arab-Israeli/Spanish/Italian families represents a highly suggestive linkage result, We suggest that th is region should be considered a candidate for containing the first human n uclear modifier gene for a mitochondrial DNA disorder, The locus operates i n Arab-Israeli, Spanish, and Italian families, resulting in the deafness ph enotype on a background of the mitochondrial A1555G mutation. No obvious ca ndidate genes are located in this region.