A mutation in SLC22A4 encoding an organic cation transporter expressed in the cochlea strial endothelium causes human recessive non-syndromic hearing loss DFNB60
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The high prevalence/incidence of hearing loss (HL) in humans makes it the most common sensory defect. The majority of the cases are of genetic origin. Non-syndromic hereditary HL is extremely heterogeneous. Genetic approaches have been instrumental in deciphering genes that are crucial for auditory function. In this study, we first used NADf chip to exclude the implication of known North-African mutations in HL in a large consanguineous Tunisian family (FT13) affected by autosomal recessive non-syndromic HL (ARNSHL). We then performed genome-wide linkage analysis and assigned the deafness gene locus to ch:5q23.2-31.1, corresponding to the DFNB60 ARNSHL locus. Moreover, we performed whole exome sequencing on FT13 patient DNA and uncovered amino acid substitution p.Cys113Tyr in SLC22A4, a transporter of organic cations, cosegregating with HL in FT13 and therefore the cause of ARNSHL DFNB60. We also screened a cohort of small Tunisian HL families and uncovered an additional deaf proband of consanguineous parents that is homozygous for p.Cys113Tyr carried by the same microsatellite marker haplotype as in FT13, indicating that this mutation is ancestral. Using immunofluorescence, we found that Slc22a4 is expressed in stria vascularis (SV) endothelial cells of rodent cochlea and targets their apical plasma membrane. We also found Slc22a4 transcripts in our RNA-seq library from purified primary culture of mouse SV endothelial cells. Interestingly, p.Cys113Tyr mutation affects the trafficking of the transporter and severely alters ergothioneine uptake. We conclude that SLC22A4 is an organic cation transporter of the SV endothelium that is essential for hearing, and its mutation causes DFNB60 form of HL.
KeywordsHearing Loss Hair Cell Carnitine Organic Cation Transporter Apical Plasma Membrane
We gratefully thank all the subjects in this study for their collaboration. This study was supported by the National Institutes of Health [Grant Numbers R01DC005575, 2P50DC000422-Sub-Project 6432 and R01DC012115] to X.Z.L., the National Institutes of Health [Grant Number R21DC009879], the University of Miami Provost Research Award, and the College of Arts and Sciences Gabelli Fellowship to Z.L., the National Institutes of Health [Grant Numbers R21DC012398 and R01DC010844] to X.R.S., and the National Institutes of Health [Grant Number R01DC009645] to M.T. This work was also supported by funds from the International Centre for Genetic Engineering and Biotechnology (ICGEB) and the Ministry of Higher Education and Research of Tunisia to S.M., and by a Grant-in-Aid of Scientific Research (B) from the Japanese Ministry of Education, Science and Culture [Grant Number 15H04664] and a Grant from Hoansha Foundation (3-1-8 Dosho-machi, Chuo-ku, Osaka 541-0045, Japan) to Y.K.
Compliance with ethical standards
Conflict of interest
The authors have declared that no competing financial interests exist.
This study was approved by the institutional review boards (IRB) of the University of Miami and the ethical committee of the University Hospital of Sfax, Tunisia.
Parental consents obtained.
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