title: Phenotype of non-syndromic deafness associated with the mitochondrial A1555G mutation is modulated by mitochondrial RNA modifying enzymes MTO1 and GTPBP3.
abstract: Phenotypic expression of the deafness-associated mitochondrial A1555G mutation in the 12S rRNA gene is influenced by aminoglycosides and complex inheritance of nuclear-encoded modifier genes. The position of a major nuclear modifier gene has been localized to chromosome 8p23.1, but the identification of this gene has remained elusive. Recently, we identified a second modifier gene, mitochondrial transcription factor B1 (TFB1M), involved in mitochondrial rRNA modification. In the present study, we tested three genes involved in mitochondrial tRNA or rRNA modification, and two genes associated with non-syndromic deafness, for linkage and linkage disequilibrium (LD) in 214 DNA samples from Spanish, Italian, and Arab-Israeli families with maternally inherited non-syndromic hearing loss. The multipoint non-parametric linkage analysis and transmission disequilibrium test testing were done using all families combined as well as divided based on linkage to the chromosome 8 locus and ethnicity. Two genes, MTO1 and GTPBP3, showed strongly suggestive linkage and significant LD results. Since both genes, as well as TFB1M, are involved in the process of mitochondrial RNA modification, it appears that the modification of mitochondrial RNA is an important regulatory pathway in the phenotypic expression of the deafness-associated mitochondrial A1555G mutation. This conclusion was supported by comparing linkage results of simulated genotypes with actual results for the four genes involved in mitochondrial RNA modification.
authors.affiliation: Medical Genetics Institute, Ahmanson Department of Pediatrics, Steven Spielberg Pediatric Research Center, Cedars-Sinai Medical Center and David Geffen School of Medicine at UCLA, Los Angeles, CA 90048, USA.
authors.forename: Yelena
authors.initials: Y
authors.lastname: Bykhovskaya
authors.forename: Emebet
authors.initials: E
authors.lastname: Mengesha
authors.forename: Dai
authors.initials: D
authors.lastname: Wang
authors.forename: Huiying
authors.initials: H
authors.lastname: Yang
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
authors.forename: Mordechai
authors.initials: M
authors.lastname: Shohat
authors.forename: Nathan
authors.initials: N
authors.lastname: Fischel-Ghodsian
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D003198:Computer Simulation; D004268:DNA-Binding Proteins / Q000378:metabolism; D003638:Deafness / Q000235:genetics*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D040461:Gene Components; D006801:Humans; D007557:Israel; D007558:Italy; D015810:Linkage Disequilibrium; D018895:Microsatellite Repeats / Q000235:genetics; D008928:Mitochondria / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism*; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics*; D012335:RNA, Ribosomal / Q000235:genetics*; D016601:RNA-Binding Proteins; D017422:Sequence Analysis, DNA; D013030:Spain; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C492006:MTO1 protein, human; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; D012335:RNA, Ribosomal; C075526:RNA, ribosomal, 12S; D016601:RNA-Binding Proteins; C499632:TFB1M protein, human; D014157:Transcription Factors; C422562:mitochondrial transcription factor A; D019204:GTP-Binding Proteins; C498989:GTPBP3 protein, human