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, Xue Z Liu

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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

Fingerprint

Cochlea
Hearing Loss
Endothelium
Cations
Mutation
Stria Vascularis
Ergothioneine
Endothelial Cells
Exome
Deafness
Amino Acid Substitution
Microsatellite Repeats
Haplotypes
Hearing
Genes
Libraries
Fluorescent Antibody Technique
Rodentia
Parents
Cell Membrane

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

A mutation in SLC22A4 encoding an organic cation transporter expressed in the cochlea strial endothelium causes human recessive non-syndromic hearing loss DFNB60. / Ben Said, Mariem; Grati, M’hamed; Ishimoto, Takahiro; Zou, Bing; Chakchouk, Imen; Ma, Qi; Yao, Qi; Hammami, Bouthaina; Yan, Denise; Mittal, Rahul; Nakamichi, Noritaka; Ghorbel, Abdelmonem; Neng, Lingling; Tekin, Mustafa; Shi, Xiao Rui; Kato, Yukio; Masmoudi, Saber; Lu, Zhongmin; Hmani, Mounira; Liu, Xue Z.

In: Human Genetics, Vol. 135, No. 5, 01.05.2016, p. 513-524.

Research output: Contribution to journalArticle

Ben Said, M, Grati, M, 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, XR, Kato, Y, Masmoudi, S, Lu, Z, Hmani, M & Liu, XZ 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, vol. 135, no. 5, pp. 513-524. https://doi.org/10.1007/s00439-016-1657-7
Ben Said, Mariem ; Grati, M’hamed ; Ishimoto, Takahiro ; Zou, Bing ; Chakchouk, Imen ; Ma, Qi ; Yao, Qi ; Hammami, Bouthaina ; Yan, Denise ; Mittal, Rahul ; Nakamichi, Noritaka ; Ghorbel, Abdelmonem ; Neng, Lingling ; Tekin, Mustafa ; Shi, Xiao Rui ; Kato, Yukio ; Masmoudi, Saber ; Lu, Zhongmin ; Hmani, Mounira ; Liu, Xue Z. / A mutation in SLC22A4 encoding an organic cation transporter expressed in the cochlea strial endothelium causes human recessive non-syndromic hearing loss DFNB60. In: Human Genetics. 2016 ; Vol. 135, No. 5. pp. 513-524.
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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.",
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AU - Ben Said, Mariem

AU - Grati, M’hamed

AU - Ishimoto, Takahiro

AU - Zou, Bing

AU - Chakchouk, Imen

AU - Ma, Qi

AU - Yao, Qi

AU - Hammami, Bouthaina

AU - Yan, Denise

AU - Mittal, Rahul

AU - Nakamichi, Noritaka

AU - Ghorbel, Abdelmonem

AU - Neng, Lingling

AU - Tekin, Mustafa

AU - Shi, Xiao Rui

AU - Kato, Yukio

AU - Masmoudi, Saber

AU - Lu, Zhongmin

AU - Hmani, Mounira

AU - Liu, Xue Z

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