Molecular Genetics and Metabolism 83 (2004) 199–206 www.elsevier.com/locate/ymgme 1096-7192/$ - see front matter  2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2004.07.009 Phenotype of non-syndromic deafness associated with the mitochondrial A1555G mutation is modulated by mitochondrial RNA modifying enzymes MTO1 and GTPBP3 Yelena Bykhovskaya a , Emebet Mengesha a , Dai Wang a , Huiying Yang a , Xavier Estivill b , Mordechai Shohat c , Nathan Fischel-Ghodsian a,¤ a Medical Genetics Institute, Ahmanson Department of Pediatrics, Steven Spielberg Pediatric Research Center, Cedars-Sinai Medical Center and David GeVen School of Medicine at UCLA, Los Angeles, CA 90048, USA b Genes and Disease Program, Center for Genomics Regulation, Barcelona Biomedical Research Park, Barcelona, Spain c Department of Pediatrics and Medical Genetics, Basil and Gerald Felsenstein Medical Resxaearch Center, Tel Aviv University Medical School, Petah Tikva, Israel Received 2 June 2004; received in revised form 10 July 2004; accepted 13 July 2004 Available online 25 August 2004 Abstract Phenotypic expression of the deafness-associated mitochondrial A1555G mutation in the 12S rRNA gene is inXuenced by amino- glycosides and complex inheritance of nuclear-encoded modiWer genes. The position of a major nuclear modiWer gene has been local- ized to chromosome 8p23.1, but the identiWcation of this gene has remained elusive. Recently, we identiWed a second modiWer gene, mitochondrial transcription factor B1 (TFB1M), involved in mitochondrial rRNA modiWcation. In the present study, we tested three genes involved in mitochondrial tRNA or rRNA modiWcation, 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 signiWcant LD results. Since both genes, as well as TFB1M, are involved in the pro- cess of mitochondrial RNA modiWcation, it appears that the modiWcation of mitochondrial RNA is an important regulatory path- way 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 modiWcation.  2004 Elsevier Inc. All rights reserved. Keywords: Maternal inherited deafness; Complex disease; Linkage; Linkage disequilibrium; Candidate gene; Mitochondrial RNA modiWcation; ModiWer gene; Simulation analysis Introduction Mitochondrial DNA mutations have been associ- ated with a wide range of human diseases (MITOMAP, http://www.mitomap.org), but the pathophysiological pathways leading from a speciWc mutation to a speciWc phenotype remain elusive. The homoplasmic A1555G mutation in the mitochondrial 12S rRNA gene has been associated with maternally inherited deafness and ami- noglycoside-induced ototoxicity [1]. In pedigrees with the A1555G mutation, phenotypic expression can range from profound congenital hearing loss to normal hear- ing, and genetic segregation analysis indicated that phenotypic expression is inXuenced by a complex * Corresponding author. Fax: +1 310 423 1676. E-mail address: nathan.Wschel@cshs.org (N. Fischel-Ghodsian).