title: Candidate locus for a nuclear modifier gene for maternally inherited deafness.
abstract: Maternally inherited deafness associated with the A1555G mutation in the mitochondrial 12S ribosomal RNA (rRNA) gene appears to require additional environmental or genetic changes for phenotypic expression. Aminoglycosides have been identified as one such environmental factor. In one large Arab-Israeli pedigree with congenital hearing loss in some of the family members with the A1555G mutation and with no exposure to aminoglycosides, biochemical evidence has suggested the role of nuclear modifier gene(s), but a genomewide 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. We have now investigated 10 multiplex Spanish and Italian families with 35 members with the A1555G mutation and sensorineural deafness. Parametric analysis of a genomewide screen again failed to identify significant evidence for linkage to a single autosomal locus. However, nonparametric analysis supported the role of the chromosomal region around marker D8S277. The combined maximized allele-sharing LOD score of 3.1 in Arab-Israeli/Spanish/Italian families represents a highly suggestive linkage result. We suggest that this region should be considered a candidate for containing the first human nuclear modifier gene for a mitochondrial DNA disorder. The locus operates in Arab-Israeli, Spanish, and Italian families, resulting in the deafness phenotype on a background of the mitochondrial A1555G mutation. No obvious candidate genes are located in this region.
authors.affiliation: Ahmanson Department of Pediatrics, Steven Spielberg Pediatric Research Center, Medical Genetics Birth Defects Center, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Bykhovskaya
authors.forename: X
authors.initials: X
authors.lastname: Estivill
authors.forename: K
authors.initials: K
authors.lastname: Taylor
authors.forename: T
authors.initials: T
authors.lastname: Hang
authors.forename: M
authors.initials: M
authors.lastname: Hamon
authors.forename: R A
authors.initials: RA
authors.lastname: Casano
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.forename: J I
authors.initials: JI
authors.lastname: Rotter
authors.forename: M
authors.initials: M
authors.lastname: Shohat
authors.forename: N
authors.initials: N
authors.lastname: Fischel-Ghodsian
mesh_terms: D018912:Arabs / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics*; D002874:Chromosome Mapping; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D005808:Genes, Recessive; D018740:Genetic Heterogeneity; D008040:Genetic Linkage / Q000235:genetics*; D005819:Genetic Markers / Q000235:genetics; D006319:Hearing Loss, Sensorineural / Q000151:congenital / Q000235:genetics*; D006801:Humans; D007557:Israel; D007558:Italy; D008126:Lod Score; D008297:Male; D016555:Matched-Pair Analysis; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance; D012335:RNA, Ribosomal / Q000235:genetics*; D013030:Spain; D018709:Statistics, Nonparametric
chemical_list: D004272:DNA, Mitochondrial; D005819:Genetic Markers; D012335:RNA, Ribosomal; C075526:RNA, ribosomal, 12S