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

Mariem Ben Said, M*Hamed Grati, Takahiro Ishimoto, Bing Zou, Imen Chakchouk, Qi Ma, Qi Yao, Bouthaina Hammami, Denise Yan, Rahul Mittal, Noritaka Nakamichi, Abdelmonem Ghorbel, Lingling Neng, Mustafa Tekin, Xiao Rui Shi, Yukio Kato, Saber Masmoudi, Zhongmin Lu, Mounira Hmani, Xuezhong Liu

Research output: Contribution to journalArticle

12 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)513-524
Number of pages12
JournalHuman genetics
Volume135
Issue number5
DOIs
StatePublished - May 1 2016

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Ben Said, M., Grati, MH., Ishimoto, T., Zou, B., Chakchouk, I., Ma, Q., Yao, Q., Hammami, B., Yan, D., Mittal, R., Nakamichi, N., Ghorbel, A., Neng, L., Tekin, M., Shi, X. R., Kato, Y., Masmoudi, S., Lu, Z., Hmani, M., & Liu, X. (2016). A mutation in SLC22A4 encoding an organic cation transporter expressed in the cochlea strial endothelium causes human recessive non-syndromic hearing loss DFNB60. Human genetics, 135(5), 513-524. https://doi.org/10.1007/s00439-016-1657-7