Lysyl-tRNA Synthetase (KARS) Mutations Cause Autosomal Recessive Nonsyndromic Hearing Impairment DFNB89. R. Santos-Cortez1, K. Lee1, Z. Azeem2,3, P. J. Antonellis4,5, L. M. Pollock4,6, S. Khan2, . Irfanullah2, P. B. Andrade-Elizondo1, I. Chiu1, M. D. Adams6, S. Basit2, J. D. Smith7, D. A. Nickerson7, B. M.Jr. McDermott4,5,6, W. Ahmad2, S. M. Leal1, University of Washington Center for Mendelian Genomics 1) Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA; 2) Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan; 3) Department of Biochemistry, AJK Medical College, Muzaffarabad, Azad Jammu & Kashmir, Pakistan; 4) Department of Otolaryngology - Head and Neck Surgery, Case Western Reserve University, Cleveland, Ohio 44106, USA; 5) Department of Biology, Case Western Reserve University, Cleveland, Ohio 44106, USA; 6) Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio 44106, USA; 7) Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
Previously a novel autosomal recessive nonsyndromic hearing impairment (ARNSHI) locus DFNB89 was mapped to chromosome 16q21-q23.2 in three unrelated, consanguineous Pakistani families. Through whole-exome sequencing of a hearing-impaired individual from each family, novel missense mutations were identified at highly conserved residues of lysyl tRNA-synthetase (KARS), namely one family with the c.1129G>A (p.Asp377Asn) variant and two families with the c.517T>C (p.Tyr173His) variant. Both variants were predicted to be damaging by multiple bioinformatics tools. The two variants both segregated with the nonsyndromic hearing impairment phenotype within the three families and neither mutation was identified in ethnically matched controls or within variant databases. Individuals who were homozygous for KARS mutations had symmetric, severe hearing impairment across all frequencies, but did not show evidence of auditory or limb neuropathy. It is demonstrated that KARS is expressed in hair cells of zebrafish, chicken, and mouse. Moreover, KARS has strong localization to the spiral ligament region of the cochlea, and also to the sulcus epithelium, Deiters cells, basilar membrane, and the surface of the spiral limbus. It is hypothesized that KARS variants affect aminoacylation in inner ear cells by interfering with binding activity to tRNA or p38 and with tetramer formation. The identification of rare KARS variants in ARNSHI families defines a novel gene for ARNSHI.
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