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Hum Genet. 2016 May;135(5):513-24. doi: 10.1007/s00439-016-1657-7. Epub 2016 Mar 29.

A mutation in SLC22A4 encoding an organic cation transporter expressed in the cochlea strial endothelium causes human recessive non-syndromic hearing loss DFNB60.

Author information

1
Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Route sidimansour Km 6, BP '1177', 3018, Sfax, Tunisia.
2
Department of Otolaryngology (D-48), University of Miami Miller School of Medicine, 1666 NW 12th Avenue, Miami, FL, 33136, USA.
3
Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, 920-1192, Japan.
4
Department of Biology, University of Miami, Miami, FL, 33146, USA.
5
Service Otorhinolaryngologie, Hôpital Universitaire Habib Bourguiba, Sfax, Tunisia.
6
Oregon Hearing Research Center, Department of Otolaryngology/Head and Neck Surgery, Oregon Health and Science University, Portland, OR, USA.
7
Dr. John T. Macdonald Foundation Department of Human Genetics, and John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, 33136, USA.
8
Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Route sidimansour Km 6, BP '1177', 3018, Sfax, Tunisia. saber.masmoudi@cbs.rnrt.tn.
9
Department of Otolaryngology (D-48), University of Miami Miller School of Medicine, 1666 NW 12th Avenue, Miami, FL, 33136, USA. xliu@med.miami.edu.
10
Dr. John T. Macdonald Foundation Department of Human Genetics, and John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, 33136, USA. xliu@med.miami.edu.
11
Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, Hunan, China. xliu@med.miami.edu.

Abstract

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.

PMID:
27023905
PMCID:
PMC4836961
DOI:
10.1007/s00439-016-1657-7
[Indexed for MEDLINE]
Free PMC Article

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