TY - JOUR
T1 - Mutations in KARS, encoding Lysyl-tRNA synthetase, cause autosomal-recessive nonsyndromic hearing impairment DFNB89
AU - Santos-Cortez, Regie Lyn P.
AU - Lee, Kwanghyuk
AU - Azeem, Zahid
AU - Antonellis, Patrick J.
AU - Pollock, Lana M.
AU - Khan, Saadullah
AU - Irfanullah,
AU - Andrade-Elizondo, Paula B.
AU - Chiu, Ilene
AU - Adams, Mark D.
AU - Basit, Sulman
AU - Smith, Joshua D.
AU - Nickerson, Deborah A.
AU - McDermott, Brian M.
AU - Ahmad, Wasim
AU - Leal, Suzanne M.
N1 - Funding Information:
We are very thankful to the families who participated in the study. This study was funded by grants DC003594, DC011651, and DC009437 from the National Institute on Deafness and Other Communication Disorders of the National Institutes of Health (NIH), grant HG006493 from the National Human Genome Research Institute of the NIH, and the Higher Education Commission of Pakistan. Genotyping of the families was performed at the Center for Inherited Disease Research, which is funded through the NIH to The Johns Hopkins University under contract number N01-HG-065403.
PY - 2013/7/11
Y1 - 2013/7/11
N2 - Previously, DFNB89, a locus associated with autosomal-recessive nonsyndromic hearing impairment (ARNSHI), was mapped to chromosomal region 16q21-q23.2 in three unrelated, consanguineous Pakistani families. Through whole-exome sequencing of a hearing-impaired individual from each family, missense mutations were identified at highly conserved residues of lysyl-tRNA synthetase (KARS): the c.1129G>A (p.Asp377Asn) variant was found in one family, and the c.517T>C (p.Tyr173His) variant was found in the other two families. 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 homozygous for KARS mutations had symmetric, severe hearing impairment across all frequencies but did not show evidence of auditory or limb neuropathy. It has been demonstrated that KARS is expressed in hair cells of zebrafish, chickens, and mice. Moreover, KARS has strong localization to the spiral ligament region of the cochlea, as well as to Deiters' cells, the sulcus epithelium, the 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-affected families defines a gene that is associated with ARNSHI.
AB - Previously, DFNB89, a locus associated with autosomal-recessive nonsyndromic hearing impairment (ARNSHI), was mapped to chromosomal region 16q21-q23.2 in three unrelated, consanguineous Pakistani families. Through whole-exome sequencing of a hearing-impaired individual from each family, missense mutations were identified at highly conserved residues of lysyl-tRNA synthetase (KARS): the c.1129G>A (p.Asp377Asn) variant was found in one family, and the c.517T>C (p.Tyr173His) variant was found in the other two families. 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 homozygous for KARS mutations had symmetric, severe hearing impairment across all frequencies but did not show evidence of auditory or limb neuropathy. It has been demonstrated that KARS is expressed in hair cells of zebrafish, chickens, and mice. Moreover, KARS has strong localization to the spiral ligament region of the cochlea, as well as to Deiters' cells, the sulcus epithelium, the 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-affected families defines a gene that is associated with ARNSHI.
UR - http://www.scopus.com/inward/record.url?scp=84880292975&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84880292975&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2013.05.018
DO - 10.1016/j.ajhg.2013.05.018
M3 - Article
C2 - 23768514
AN - SCOPUS:84880292975
SN - 0002-9297
VL - 93
SP - 132
EP - 140
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 1
ER -