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

Identifieur interne : 000321 ( Main/Exploration ); précédent : 000320; suivant : 000322

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

Auteurs : Mariem Ben Said [Tunisie] ; M Amed Grati [États-Unis] ; Takahiro Ishimoto [Japon] ; Bing Zou [États-Unis] ; Imen Chakchouk [Tunisie] ; Qi Ma [États-Unis] ; Qi Yao [États-Unis] ; Bouthaina Hammami [Tunisie] ; Denise Yan [États-Unis] ; Rahul Mittal [États-Unis] ; Noritaka Nakamichi [Japon] ; Abdelmonem Ghorbel [Tunisie] ; Lingling Neng [États-Unis] ; Mustafa Tekin [États-Unis] ; Xiao Rui Shi [États-Unis] ; Yukio Kato [Japon] ; Saber Masmoudi [Tunisie] ; Zhongmin Lu [États-Unis] ; Mounira Hmani [Tunisie] ; Xuezhong Liu [États-Unis, République populaire de Chine]

Source :

Human genetics [ 0340-6717 ] ; 2016.

RBID : PMC:4836961

Descripteurs français

English descriptors

KwdEn :
- Amino Acid Sequence (MeSH), Animals (MeSH), Cells, Cultured (MeSH), Cochlea (metabolism), Cochlea (pathology), Consanguinity (MeSH), Endothelium (metabolism), Endothelium (pathology), Exome (genetics), Female (MeSH), Genes, Recessive (genetics), HEK293 Cells (MeSH), Hearing Loss (genetics), Hearing Loss (pathology), High-Throughput Nucleotide Sequencing (MeSH), Humans (MeSH), Male (MeSH), Mice (MeSH), Mice, Inbred C57BL (MeSH), Molecular Sequence Data (MeSH), Mutation (genetics), Organic Cation Transport Proteins (genetics), Pedigree (MeSH), Polymerase Chain Reaction (MeSH), Polymorphism, Restriction Fragment Length (MeSH), Rats (MeSH), Rats, Sprague-Dawley (MeSH), Sequence Homology, Amino Acid (MeSH), Symporters (MeSH).
MESH :
- chemical , genetics : Organic Cation Transport Proteins.
- genetics : Exome, Genes, Recessive, Hearing Loss, Mutation.
- metabolism : Cochlea, Endothelium.
- pathology : Cochlea, Endothelium, Hearing Loss.
- Amino Acid Sequence, Animals, Cells, Cultured, Consanguinity, Female, HEK293 Cells, High-Throughput Nucleotide Sequencing, Humans, Male, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Pedigree, Polymerase Chain Reaction, Polymorphism, Restriction Fragment Length, Rats, Rats, Sprague-Dawley, Sequence Homology, Amino Acid, Symporters.

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 DFNB60 ARNSHL locus. Moreover, we performed whole-exome sequencing on FT13 patient DNA and uncovered aminoacid 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.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836961

DOI: 10.1007/s00439-016-1657-7
PubMed: 27023905
PubMed Central: 4836961

Affiliations:

Japon, République populaire de Chine, Tunisie, États-Unis

Le document en format XML

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 encoding an organic cation transporter expressed in the cochlea strial endothelium causes human recessive non-syndromic hearing loss DFNB60</title>
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<author><name sortKey="Hammami, Bouthaina" sort="Hammami, Bouthaina" uniqKey="Hammami B" first="Bouthaina" last="Hammami">Bouthaina Hammami</name>
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<author><name sortKey="Yan, Denise" sort="Yan, Denise" uniqKey="Yan D" first="Denise" last="Yan">Denise Yan</name>
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<author><name sortKey="Nakamichi, Noritaka" sort="Nakamichi, Noritaka" uniqKey="Nakamichi N" first="Noritaka" last="Nakamichi">Noritaka Nakamichi</name>
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<author><name sortKey="Ghorbel, Abdelmonem" sort="Ghorbel, Abdelmonem" uniqKey="Ghorbel A" first="Abdelmonem" last="Ghorbel">Abdelmonem Ghorbel</name>
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<author><name sortKey="Neng, Lingling" sort="Neng, Lingling" uniqKey="Neng L" first="Lingling" last="Neng">Lingling Neng</name>
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<country xml:lang="fr">États-Unis</country>
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<author><name sortKey="Tekin, Mustafa" sort="Tekin, Mustafa" uniqKey="Tekin M" first="Mustafa" last="Tekin">Mustafa Tekin</name>
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<author><name sortKey="Shi, Xiao Rui" sort="Shi, Xiao Rui" uniqKey="Shi X" first="Xiao Rui" last="Shi">Xiao Rui Shi</name>
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<author><name sortKey="Kato, Yukio" sort="Kato, Yukio" uniqKey="Kato Y" first="Yukio" last="Kato">Yukio Kato</name>
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<country xml:lang="fr">Japon</country>
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<author><name sortKey="Masmoudi, Saber" sort="Masmoudi, Saber" uniqKey="Masmoudi S" first="Saber" last="Masmoudi">Saber Masmoudi</name>
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<author><name sortKey="Lu, Zhongmin" sort="Lu, Zhongmin" uniqKey="Lu Z" first="Zhongmin" last="Lu">Zhongmin Lu</name>
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<author><name sortKey="Hmani, Mounira" sort="Hmani, Mounira" uniqKey="Hmani M" first="Mounira" last="Hmani">Mounira Hmani</name>
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<author><name sortKey="Liu, Xuezhong" sort="Liu, Xuezhong" uniqKey="Liu X" first="Xuezhong" last="Liu">Xuezhong Liu</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, United States of America</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136</wicri:regionArea>
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<country xml:lang="fr">États-Unis</country>
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<affiliation wicri:level="1"><nlm:aff id="A8">Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, Hunan, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, Hunan</wicri:regionArea>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A mutation in <italic>SLC22A4</italic>
 encoding an organic cation transporter expressed in the cochlea strial endothelium causes human recessive non-syndromic hearing loss DFNB60</title>
<author><name sortKey="Ben Said, Mariem" sort="Ben Said, Mariem" uniqKey="Ben Said M" first="Mariem" last="Ben Said">Mariem Ben Said</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Sfax, Tunisia</nlm:aff>
<country xml:lang="fr">Tunisie</country>
<wicri:regionArea>Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Sfax</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Grati, M Amed" sort="Grati, M Amed" uniqKey="Grati M" first="M Amed" last="Grati">M Amed Grati</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, United States of America</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Ishimoto, Takahiro" sort="Ishimoto, Takahiro" uniqKey="Ishimoto T" first="Takahiro" last="Ishimoto">Takahiro Ishimoto</name>
<affiliation wicri:level="1"><nlm:aff id="A3">Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa 920-1192</wicri:regionArea>
</affiliation>
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<author><name sortKey="Zou, Bing" sort="Zou, Bing" uniqKey="Zou B" first="Bing" last="Zou">Bing Zou</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, United States of America</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Chakchouk, Imen" sort="Chakchouk, Imen" uniqKey="Chakchouk I" first="Imen" last="Chakchouk">Imen Chakchouk</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Sfax, Tunisia</nlm:aff>
<country xml:lang="fr">Tunisie</country>
<wicri:regionArea>Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Sfax</wicri:regionArea>
</affiliation>
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<author><name sortKey="Ma, Qi" sort="Ma, Qi" uniqKey="Ma Q" first="Qi" last="Ma">Qi Ma</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, United States of America</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Yao, Qi" sort="Yao, Qi" uniqKey="Yao Q" first="Qi" last="Yao">Qi Yao</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, United States of America</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A4">Department of Biology, University of Miami, Miami, FL 33146, United States of America</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biology, University of Miami, Miami, FL 33146</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Hammami, Bouthaina" sort="Hammami, Bouthaina" uniqKey="Hammami B" first="Bouthaina" last="Hammami">Bouthaina Hammami</name>
<affiliation wicri:level="1"><nlm:aff id="A5">Service Otorhinolaryngologie, Hôpital Universitaire Habib Bourguiba, Sfax, Tunisia</nlm:aff>
<country xml:lang="fr">Tunisie</country>
<wicri:regionArea>Service Otorhinolaryngologie, Hôpital Universitaire Habib Bourguiba, Sfax</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Yan, Denise" sort="Yan, Denise" uniqKey="Yan D" first="Denise" last="Yan">Denise Yan</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, United States of America</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Mittal, Rahul" sort="Mittal, Rahul" uniqKey="Mittal R" first="Rahul" last="Mittal">Rahul Mittal</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, United States of America</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Nakamichi, Noritaka" sort="Nakamichi, Noritaka" uniqKey="Nakamichi N" first="Noritaka" last="Nakamichi">Noritaka Nakamichi</name>
<affiliation wicri:level="1"><nlm:aff id="A3">Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa 920-1192</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Ghorbel, Abdelmonem" sort="Ghorbel, Abdelmonem" uniqKey="Ghorbel A" first="Abdelmonem" last="Ghorbel">Abdelmonem Ghorbel</name>
<affiliation wicri:level="1"><nlm:aff id="A5">Service Otorhinolaryngologie, Hôpital Universitaire Habib Bourguiba, Sfax, Tunisia</nlm:aff>
<country xml:lang="fr">Tunisie</country>
<wicri:regionArea>Service Otorhinolaryngologie, Hôpital Universitaire Habib Bourguiba, Sfax</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Neng, Lingling" sort="Neng, Lingling" uniqKey="Neng L" first="Lingling" last="Neng">Lingling Neng</name>
<affiliation wicri:level="1"><nlm:aff id="A6">Oregon Hearing Research Center, Department of Otolaryngology/Head and Neck Surgery, Oregon Health & Science University, Portland, Oregon, United States of America</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Oregon Hearing Research Center, Department of Otolaryngology/Head and Neck Surgery, Oregon Health & Science University, Portland, Oregon</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Tekin, Mustafa" sort="Tekin, Mustafa" uniqKey="Tekin M" first="Mustafa" last="Tekin">Mustafa Tekin</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, United States of America</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A7">Dr. John T. Macdonald Foundation Department of Human Genetics, and John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL 33136, United States of America</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Dr. John T. Macdonald Foundation Department of Human Genetics, and John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL 33136</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Shi, Xiao Rui" sort="Shi, Xiao Rui" uniqKey="Shi X" first="Xiao Rui" last="Shi">Xiao Rui Shi</name>
<affiliation wicri:level="1"><nlm:aff id="A6">Oregon Hearing Research Center, Department of Otolaryngology/Head and Neck Surgery, Oregon Health & Science University, Portland, Oregon, United States of America</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Oregon Hearing Research Center, Department of Otolaryngology/Head and Neck Surgery, Oregon Health & Science University, Portland, Oregon</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Kato, Yukio" sort="Kato, Yukio" uniqKey="Kato Y" first="Yukio" last="Kato">Yukio Kato</name>
<affiliation wicri:level="1"><nlm:aff id="A3">Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa 920-1192</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Masmoudi, Saber" sort="Masmoudi, Saber" uniqKey="Masmoudi S" first="Saber" last="Masmoudi">Saber Masmoudi</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Sfax, Tunisia</nlm:aff>
<country xml:lang="fr">Tunisie</country>
<wicri:regionArea>Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Sfax</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Lu, Zhongmin" sort="Lu, Zhongmin" uniqKey="Lu Z" first="Zhongmin" last="Lu">Zhongmin Lu</name>
<affiliation wicri:level="1"><nlm:aff id="A4">Department of Biology, University of Miami, Miami, FL 33146, United States of America</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biology, University of Miami, Miami, FL 33146</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Hmani, Mounira" sort="Hmani, Mounira" uniqKey="Hmani M" first="Mounira" last="Hmani">Mounira Hmani</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Sfax, Tunisia</nlm:aff>
<country xml:lang="fr">Tunisie</country>
<wicri:regionArea>Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Sfax</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Liu, Xuezhong" sort="Liu, Xuezhong" uniqKey="Liu X" first="Xuezhong" last="Liu">Xuezhong Liu</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, United States of America</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A7">Dr. John T. Macdonald Foundation Department of Human Genetics, and John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL 33136, United States of America</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Dr. John T. Macdonald Foundation Department of Human Genetics, and John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL 33136</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A8">Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, Hunan, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, Hunan</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series><title level="j">Human genetics</title>
<idno type="ISSN">0340-6717</idno>
<idno type="eISSN">1432-1203</idno>
<imprint><date when="2016">2016</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acid Sequence (MeSH)</term>
<term>Animals (MeSH)</term>
<term>Cells, Cultured (MeSH)</term>
<term>Cochlea (metabolism)</term>
<term>Cochlea (pathology)</term>
<term>Consanguinity (MeSH)</term>
<term>Endothelium (metabolism)</term>
<term>Endothelium (pathology)</term>
<term>Exome (genetics)</term>
<term>Female (MeSH)</term>
<term>Genes, Recessive (genetics)</term>
<term>HEK293 Cells (MeSH)</term>
<term>Hearing Loss (genetics)</term>
<term>Hearing Loss (pathology)</term>
<term>High-Throughput Nucleotide Sequencing (MeSH)</term>
<term>Humans (MeSH)</term>
<term>Male (MeSH)</term>
<term>Mice (MeSH)</term>
<term>Mice, Inbred C57BL (MeSH)</term>
<term>Molecular Sequence Data (MeSH)</term>
<term>Mutation (genetics)</term>
<term>Organic Cation Transport Proteins (genetics)</term>
<term>Pedigree (MeSH)</term>
<term>Polymerase Chain Reaction (MeSH)</term>
<term>Polymorphism, Restriction Fragment Length (MeSH)</term>
<term>Rats (MeSH)</term>
<term>Rats, Sprague-Dawley (MeSH)</term>
<term>Sequence Homology, Amino Acid (MeSH)</term>
<term>Symporters (MeSH)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux (MeSH)</term>
<term>Cellules HEK293 (MeSH)</term>
<term>Cellules cultivées (MeSH)</term>
<term>Cochlée (anatomopathologie)</term>
<term>Cochlée (métabolisme)</term>
<term>Consanguinité (MeSH)</term>
<term>Données de séquences moléculaires (MeSH)</term>
<term>Endothélium (anatomopathologie)</term>
<term>Endothélium (métabolisme)</term>
<term>Exome (génétique)</term>
<term>Femelle (MeSH)</term>
<term>Gènes récessifs (génétique)</term>
<term>Humains (MeSH)</term>
<term>Mutation (génétique)</term>
<term>Mâle (MeSH)</term>
<term>Pedigree (MeSH)</term>
<term>Perte d'audition (anatomopathologie)</term>
<term>Perte d'audition (génétique)</term>
<term>Polymorphisme de restriction (MeSH)</term>
<term>Rat Sprague-Dawley (MeSH)</term>
<term>Rats (MeSH)</term>
<term>Réaction de polymérisation en chaîne (MeSH)</term>
<term>Similitude de séquences d'acides aminés (MeSH)</term>
<term>Souris (MeSH)</term>
<term>Souris de lignée C57BL (MeSH)</term>
<term>Symporteurs (MeSH)</term>
<term>Séquence d'acides aminés (MeSH)</term>
<term>Séquençage nucléotidique à haut débit (MeSH)</term>
<term>Transporteurs de cations organiques (génétique)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Organic Cation Transport Proteins</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Cochlée</term>
<term>Endothélium</term>
<term>Perte d'audition</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Exome</term>
<term>Genes, Recessive</term>
<term>Hearing Loss</term>
<term>Mutation</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Exome</term>
<term>Gènes récessifs</term>
<term>Mutation</term>
<term>Perte d'audition</term>
<term>Transporteurs de cations organiques</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Cochlea</term>
<term>Endothelium</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Cochlée</term>
<term>Endothélium</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Cochlea</term>
<term>Endothelium</term>
<term>Hearing Loss</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Amino Acid Sequence</term>
<term>Animals</term>
<term>Cells, Cultured</term>
<term>Consanguinity</term>
<term>Female</term>
<term>HEK293 Cells</term>
<term>High-Throughput Nucleotide Sequencing</term>
<term>Humans</term>
<term>Male</term>
<term>Mice</term>
<term>Mice, Inbred C57BL</term>
<term>Molecular Sequence Data</term>
<term>Pedigree</term>
<term>Polymerase Chain Reaction</term>
<term>Polymorphism, Restriction Fragment Length</term>
<term>Rats</term>
<term>Rats, Sprague-Dawley</term>
<term>Sequence Homology, Amino Acid</term>
<term>Symporters</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Cellules HEK293</term>
<term>Cellules cultivées</term>
<term>Consanguinité</term>
<term>Données de séquences moléculaires</term>
<term>Femelle</term>
<term>Humains</term>
<term>Mâle</term>
<term>Pedigree</term>
<term>Polymorphisme de restriction</term>
<term>Rat Sprague-Dawley</term>
<term>Rats</term>
<term>Réaction de polymérisation en chaîne</term>
<term>Similitude de séquences d'acides aminés</term>
<term>Souris</term>
<term>Souris de lignée C57BL</term>
<term>Symporteurs</term>
<term>Séquence d'acides aminés</term>
<term>Séquençage nucléotidique à haut débit</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p id="P2">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 DFNB60 ARNSHL locus. Moreover, we performed whole-exome sequencing on FT13 patient DNA and uncovered aminoacid 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 <italic>Slc22a4</italic>
 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.</p>
</div>
</front>
</TEI>
<affiliations><list><country><li>Japon</li>
<li>République populaire de Chine</li>
<li>Tunisie</li>
<li>États-Unis</li>
</country>
</list>
<tree><country name="Tunisie"><noRegion><name sortKey="Ben Said, Mariem" sort="Ben Said, Mariem" uniqKey="Ben Said M" first="Mariem" last="Ben Said">Mariem Ben Said</name>
</noRegion>
<name sortKey="Chakchouk, Imen" sort="Chakchouk, Imen" uniqKey="Chakchouk I" first="Imen" last="Chakchouk">Imen Chakchouk</name>
<name sortKey="Ghorbel, Abdelmonem" sort="Ghorbel, Abdelmonem" uniqKey="Ghorbel A" first="Abdelmonem" last="Ghorbel">Abdelmonem Ghorbel</name>
<name sortKey="Hammami, Bouthaina" sort="Hammami, Bouthaina" uniqKey="Hammami B" first="Bouthaina" last="Hammami">Bouthaina Hammami</name>
<name sortKey="Hmani, Mounira" sort="Hmani, Mounira" uniqKey="Hmani M" first="Mounira" last="Hmani">Mounira Hmani</name>
<name sortKey="Masmoudi, Saber" sort="Masmoudi, Saber" uniqKey="Masmoudi S" first="Saber" last="Masmoudi">Saber Masmoudi</name>
</country>
<country name="États-Unis"><noRegion><name sortKey="Grati, M Amed" sort="Grati, M Amed" uniqKey="Grati M" first="M Amed" last="Grati">M Amed Grati</name>
</noRegion>
<name sortKey="Liu, Xuezhong" sort="Liu, Xuezhong" uniqKey="Liu X" first="Xuezhong" last="Liu">Xuezhong Liu</name>
<name sortKey="Liu, Xuezhong" sort="Liu, Xuezhong" uniqKey="Liu X" first="Xuezhong" last="Liu">Xuezhong Liu</name>
<name sortKey="Lu, Zhongmin" sort="Lu, Zhongmin" uniqKey="Lu Z" first="Zhongmin" last="Lu">Zhongmin Lu</name>
<name sortKey="Ma, Qi" sort="Ma, Qi" uniqKey="Ma Q" first="Qi" last="Ma">Qi Ma</name>
<name sortKey="Mittal, Rahul" sort="Mittal, Rahul" uniqKey="Mittal R" first="Rahul" last="Mittal">Rahul Mittal</name>
<name sortKey="Neng, Lingling" sort="Neng, Lingling" uniqKey="Neng L" first="Lingling" last="Neng">Lingling Neng</name>
<name sortKey="Shi, Xiao Rui" sort="Shi, Xiao Rui" uniqKey="Shi X" first="Xiao Rui" last="Shi">Xiao Rui Shi</name>
<name sortKey="Tekin, Mustafa" sort="Tekin, Mustafa" uniqKey="Tekin M" first="Mustafa" last="Tekin">Mustafa Tekin</name>
<name sortKey="Tekin, Mustafa" sort="Tekin, Mustafa" uniqKey="Tekin M" first="Mustafa" last="Tekin">Mustafa Tekin</name>
<name sortKey="Yan, Denise" sort="Yan, Denise" uniqKey="Yan D" first="Denise" last="Yan">Denise Yan</name>
<name sortKey="Yao, Qi" sort="Yao, Qi" uniqKey="Yao Q" first="Qi" last="Yao">Qi Yao</name>
<name sortKey="Yao, Qi" sort="Yao, Qi" uniqKey="Yao Q" first="Qi" last="Yao">Qi Yao</name>
<name sortKey="Zou, Bing" sort="Zou, Bing" uniqKey="Zou B" first="Bing" last="Zou">Bing Zou</name>
</country>
<country name="Japon"><noRegion><name sortKey="Ishimoto, Takahiro" sort="Ishimoto, Takahiro" uniqKey="Ishimoto T" first="Takahiro" last="Ishimoto">Takahiro Ishimoto</name>
</noRegion>
<name sortKey="Kato, Yukio" sort="Kato, Yukio" uniqKey="Kato Y" first="Yukio" last="Kato">Yukio Kato</name>
<name sortKey="Nakamichi, Noritaka" sort="Nakamichi, Noritaka" uniqKey="Nakamichi N" first="Noritaka" last="Nakamichi">Noritaka Nakamichi</name>
</country>
<country name="République populaire de Chine"><noRegion><name sortKey="Liu, Xuezhong" sort="Liu, Xuezhong" uniqKey="Liu X" first="Xuezhong" last="Liu">Xuezhong Liu</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>

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

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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