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 : 000495 ( PubMed/Corpus ); précédent : 000494; suivant : 000496A 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 ; 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 LiuSource :
- Human genetics [ 1432-1203 ] ; 2016.
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 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.
DOI: 10.1007/s00439-016-1657-7
PubMed: 27023905
PubMed Central: PMC4836961
Links to Exploration step
pubmed:27023905Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">A mutation in SLC22A4 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><nlm:affiliation>Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Route sidimansour Km 6, BP '1177', 3018, Sfax, Tunisia.</nlm:affiliation></affiliation></author><author><name sortKey="Grati, M Hamed" sort="Grati, M Hamed" uniqKey="Grati M" first="M'Hamed" last="Grati">M'Hamed Grati</name><affiliation><nlm:affiliation>Department of Otolaryngology (D-48), University of Miami Miller School of Medicine, 1666 NW 12th Avenue, Miami, FL, 33136, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Ishimoto, Takahiro" sort="Ishimoto, Takahiro" uniqKey="Ishimoto T" first="Takahiro" last="Ishimoto">Takahiro Ishimoto</name><affiliation><nlm:affiliation>Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, 920-1192, Japan.</nlm:affiliation></affiliation></author><author><name sortKey="Zou, Bing" sort="Zou, Bing" uniqKey="Zou B" first="Bing" last="Zou">Bing Zou</name><affiliation><nlm:affiliation>Department of Otolaryngology (D-48), University of Miami Miller School of Medicine, 1666 NW 12th Avenue, Miami, FL, 33136, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Chakchouk, Imen" sort="Chakchouk, Imen" uniqKey="Chakchouk I" first="Imen" last="Chakchouk">Imen Chakchouk</name><affiliation><nlm:affiliation>Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Route sidimansour Km 6, BP '1177', 3018, Sfax, Tunisia.</nlm:affiliation></affiliation></author><author><name sortKey="Ma, Qi" sort="Ma, Qi" uniqKey="Ma Q" first="Qi" last="Ma">Qi Ma</name><affiliation><nlm:affiliation>Department of Otolaryngology (D-48), University of Miami Miller School of Medicine, 1666 NW 12th Avenue, Miami, FL, 33136, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Yao, Qi" sort="Yao, Qi" uniqKey="Yao Q" first="Qi" last="Yao">Qi Yao</name><affiliation><nlm:affiliation>Department of Otolaryngology (D-48), University of Miami Miller School of Medicine, 1666 NW 12th Avenue, Miami, FL, 33136, USA.</nlm:affiliation></affiliation><affiliation><nlm:affiliation>Department of Biology, University of Miami, Miami, FL, 33146, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Hammami, Bouthaina" sort="Hammami, Bouthaina" uniqKey="Hammami B" first="Bouthaina" last="Hammami">Bouthaina Hammami</name><affiliation><nlm:affiliation>Service Otorhinolaryngologie, Hôpital Universitaire Habib Bourguiba, Sfax, Tunisia.</nlm:affiliation></affiliation></author><author><name sortKey="Yan, Denise" sort="Yan, Denise" uniqKey="Yan D" first="Denise" last="Yan">Denise Yan</name><affiliation><nlm:affiliation>Department of Otolaryngology (D-48), University of Miami Miller School of Medicine, 1666 NW 12th Avenue, Miami, FL, 33136, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Mittal, Rahul" sort="Mittal, Rahul" uniqKey="Mittal R" first="Rahul" last="Mittal">Rahul Mittal</name><affiliation><nlm:affiliation>Department of Otolaryngology (D-48), University of Miami Miller School of Medicine, 1666 NW 12th Avenue, Miami, FL, 33136, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Nakamichi, Noritaka" sort="Nakamichi, Noritaka" uniqKey="Nakamichi N" first="Noritaka" last="Nakamichi">Noritaka Nakamichi</name><affiliation><nlm:affiliation>Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, 920-1192, Japan.</nlm:affiliation></affiliation></author><author><name sortKey="Ghorbel, Abdelmonem" sort="Ghorbel, Abdelmonem" uniqKey="Ghorbel A" first="Abdelmonem" last="Ghorbel">Abdelmonem Ghorbel</name><affiliation><nlm:affiliation>Service Otorhinolaryngologie, Hôpital Universitaire Habib Bourguiba, Sfax, Tunisia.</nlm:affiliation></affiliation></author><author><name sortKey="Neng, Lingling" sort="Neng, Lingling" uniqKey="Neng L" first="Lingling" last="Neng">Lingling Neng</name><affiliation><nlm:affiliation>Oregon Hearing Research Center, Department of Otolaryngology/Head and Neck Surgery, Oregon Health and Science University, Portland, OR, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Tekin, Mustafa" sort="Tekin, Mustafa" uniqKey="Tekin M" first="Mustafa" last="Tekin">Mustafa Tekin</name><affiliation><nlm:affiliation>Department of Otolaryngology (D-48), University of Miami Miller School of Medicine, 1666 NW 12th Avenue, Miami, FL, 33136, USA.</nlm:affiliation></affiliation><affiliation><nlm:affiliation>Dr. John T. Macdonald Foundation Department of Human Genetics, and John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, 33136, USA.</nlm:affiliation></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><nlm:affiliation>Oregon Hearing Research Center, Department of Otolaryngology/Head and Neck Surgery, Oregon Health and Science University, Portland, OR, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Kato, Yukio" sort="Kato, Yukio" uniqKey="Kato Y" first="Yukio" last="Kato">Yukio Kato</name><affiliation><nlm:affiliation>Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, 920-1192, Japan.</nlm:affiliation></affiliation></author><author><name sortKey="Masmoudi, Saber" sort="Masmoudi, Saber" uniqKey="Masmoudi S" first="Saber" last="Masmoudi">Saber Masmoudi</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Lu, Zhongmin" sort="Lu, Zhongmin" uniqKey="Lu Z" first="Zhongmin" last="Lu">Zhongmin Lu</name><affiliation><nlm:affiliation>Department of Biology, University of Miami, Miami, FL, 33146, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Hmani, Mounira" sort="Hmani, Mounira" uniqKey="Hmani M" first="Mounira" last="Hmani">Mounira Hmani</name><affiliation><nlm:affiliation>Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Route sidimansour Km 6, BP '1177', 3018, Sfax, Tunisia.</nlm:affiliation></affiliation></author><author><name sortKey="Liu, Xuezhong" sort="Liu, Xuezhong" uniqKey="Liu X" first="Xuezhong" last="Liu">Xuezhong Liu</name><affiliation><nlm:affiliation>Department of Otolaryngology (D-48), University of Miami Miller School of Medicine, 1666 NW 12th Avenue, Miami, FL, 33136, USA. xliu@med.miami.edu.</nlm:affiliation></affiliation><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation><affiliation><nlm:affiliation>Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, Hunan, China. xliu@med.miami.edu.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2016">2016</date><idno type="RBID">pubmed:27023905</idno><idno type="pmid">27023905</idno><idno type="doi">10.1007/s00439-016-1657-7</idno><idno type="pmc">PMC4836961</idno><idno type="wicri:Area/PubMed/Corpus">000495</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000495</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">A mutation in SLC22A4 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><nlm:affiliation>Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Route sidimansour Km 6, BP '1177', 3018, Sfax, Tunisia.</nlm:affiliation></affiliation></author><author><name sortKey="Grati, M Hamed" sort="Grati, M Hamed" uniqKey="Grati M" first="M'Hamed" last="Grati">M'Hamed Grati</name><affiliation><nlm:affiliation>Department of Otolaryngology (D-48), University of Miami Miller School of Medicine, 1666 NW 12th Avenue, Miami, FL, 33136, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Ishimoto, Takahiro" sort="Ishimoto, Takahiro" uniqKey="Ishimoto T" first="Takahiro" last="Ishimoto">Takahiro Ishimoto</name><affiliation><nlm:affiliation>Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, 920-1192, Japan.</nlm:affiliation></affiliation></author><author><name sortKey="Zou, Bing" sort="Zou, Bing" uniqKey="Zou B" first="Bing" last="Zou">Bing Zou</name><affiliation><nlm:affiliation>Department of Otolaryngology (D-48), University of Miami Miller School of Medicine, 1666 NW 12th Avenue, Miami, FL, 33136, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Chakchouk, Imen" sort="Chakchouk, Imen" uniqKey="Chakchouk I" first="Imen" last="Chakchouk">Imen Chakchouk</name><affiliation><nlm:affiliation>Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Route sidimansour Km 6, BP '1177', 3018, Sfax, Tunisia.</nlm:affiliation></affiliation></author><author><name sortKey="Ma, Qi" sort="Ma, Qi" uniqKey="Ma Q" first="Qi" last="Ma">Qi Ma</name><affiliation><nlm:affiliation>Department of Otolaryngology (D-48), University of Miami Miller School of Medicine, 1666 NW 12th Avenue, Miami, FL, 33136, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Yao, Qi" sort="Yao, Qi" uniqKey="Yao Q" first="Qi" last="Yao">Qi Yao</name><affiliation><nlm:affiliation>Department of Otolaryngology (D-48), University of Miami Miller School of Medicine, 1666 NW 12th Avenue, Miami, FL, 33136, USA.</nlm:affiliation></affiliation><affiliation><nlm:affiliation>Department of Biology, University of Miami, Miami, FL, 33146, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Hammami, Bouthaina" sort="Hammami, Bouthaina" uniqKey="Hammami B" first="Bouthaina" last="Hammami">Bouthaina Hammami</name><affiliation><nlm:affiliation>Service Otorhinolaryngologie, Hôpital Universitaire Habib Bourguiba, Sfax, Tunisia.</nlm:affiliation></affiliation></author><author><name sortKey="Yan, Denise" sort="Yan, Denise" uniqKey="Yan D" first="Denise" last="Yan">Denise Yan</name><affiliation><nlm:affiliation>Department of Otolaryngology (D-48), University of Miami Miller School of Medicine, 1666 NW 12th Avenue, Miami, FL, 33136, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Mittal, Rahul" sort="Mittal, Rahul" uniqKey="Mittal R" first="Rahul" last="Mittal">Rahul Mittal</name><affiliation><nlm:affiliation>Department of Otolaryngology (D-48), University of Miami Miller School of Medicine, 1666 NW 12th Avenue, Miami, FL, 33136, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Nakamichi, Noritaka" sort="Nakamichi, Noritaka" uniqKey="Nakamichi N" first="Noritaka" last="Nakamichi">Noritaka Nakamichi</name><affiliation><nlm:affiliation>Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, 920-1192, Japan.</nlm:affiliation></affiliation></author><author><name sortKey="Ghorbel, Abdelmonem" sort="Ghorbel, Abdelmonem" uniqKey="Ghorbel A" first="Abdelmonem" last="Ghorbel">Abdelmonem Ghorbel</name><affiliation><nlm:affiliation>Service Otorhinolaryngologie, Hôpital Universitaire Habib Bourguiba, Sfax, Tunisia.</nlm:affiliation></affiliation></author><author><name sortKey="Neng, Lingling" sort="Neng, Lingling" uniqKey="Neng L" first="Lingling" last="Neng">Lingling Neng</name><affiliation><nlm:affiliation>Oregon Hearing Research Center, Department of Otolaryngology/Head and Neck Surgery, Oregon Health and Science University, Portland, OR, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Tekin, Mustafa" sort="Tekin, Mustafa" uniqKey="Tekin M" first="Mustafa" last="Tekin">Mustafa Tekin</name><affiliation><nlm:affiliation>Department of Otolaryngology (D-48), University of Miami Miller School of Medicine, 1666 NW 12th Avenue, Miami, FL, 33136, USA.</nlm:affiliation></affiliation><affiliation><nlm:affiliation>Dr. John T. Macdonald Foundation Department of Human Genetics, and John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, 33136, USA.</nlm:affiliation></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><nlm:affiliation>Oregon Hearing Research Center, Department of Otolaryngology/Head and Neck Surgery, Oregon Health and Science University, Portland, OR, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Kato, Yukio" sort="Kato, Yukio" uniqKey="Kato Y" first="Yukio" last="Kato">Yukio Kato</name><affiliation><nlm:affiliation>Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, 920-1192, Japan.</nlm:affiliation></affiliation></author><author><name sortKey="Masmoudi, Saber" sort="Masmoudi, Saber" uniqKey="Masmoudi S" first="Saber" last="Masmoudi">Saber Masmoudi</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Lu, Zhongmin" sort="Lu, Zhongmin" uniqKey="Lu Z" first="Zhongmin" last="Lu">Zhongmin Lu</name><affiliation><nlm:affiliation>Department of Biology, University of Miami, Miami, FL, 33146, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Hmani, Mounira" sort="Hmani, Mounira" uniqKey="Hmani M" first="Mounira" last="Hmani">Mounira Hmani</name><affiliation><nlm:affiliation>Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Route sidimansour Km 6, BP '1177', 3018, Sfax, Tunisia.</nlm:affiliation></affiliation></author><author><name sortKey="Liu, Xuezhong" sort="Liu, Xuezhong" uniqKey="Liu X" first="Xuezhong" last="Liu">Xuezhong Liu</name><affiliation><nlm:affiliation>Department of Otolaryngology (D-48), University of Miami Miller School of Medicine, 1666 NW 12th Avenue, Miami, FL, 33136, USA. xliu@med.miami.edu.</nlm:affiliation></affiliation><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation><affiliation><nlm:affiliation>Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, Hunan, China. xliu@med.miami.edu.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Human genetics</title><idno type="eISSN">1432-1203</idno><imprint><date when="2016" type="published">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="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Organic Cation Transport Proteins</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="metabolism" xml:lang="en"><term>Cochlea</term><term>Endothelium</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></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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. </div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">27023905</PMID><DateCompleted><Year>2016</Year><Month>08</Month><Day>31</Day></DateCompleted><DateRevised><Year>2020</Year><Month>12</Month><Day>09</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1432-1203</ISSN><JournalIssue CitedMedium="Internet"><Volume>135</Volume><Issue>5</Issue><PubDate><Year>2016</Year><Month>May</Month></PubDate></JournalIssue><Title>Human genetics</Title><ISOAbbreviation>Hum Genet</ISOAbbreviation></Journal><ArticleTitle>A mutation in SLC22A4 encoding an organic cation transporter expressed in the cochlea strial endothelium causes human recessive non-syndromic hearing loss DFNB60.</ArticleTitle><Pagination><MedlinePgn>513-524</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1007/s00439-016-1657-7</ELocationID><Abstract><AbstractText>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. </AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Ben Said</LastName><ForeName>Mariem</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Route sidimansour Km 6, BP '1177', 3018, Sfax, Tunisia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Grati</LastName><ForeName>M'hamed</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Otolaryngology (D-48), University of Miami Miller School of Medicine, 1666 NW 12th Avenue, Miami, FL, 33136, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ishimoto</LastName><ForeName>Takahiro</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, 920-1192, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zou</LastName><ForeName>Bing</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Department of Otolaryngology (D-48), University of Miami Miller School of Medicine, 1666 NW 12th Avenue, Miami, FL, 33136, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chakchouk</LastName><ForeName>Imen</ForeName><Initials>I</Initials><AffiliationInfo><Affiliation>Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Route sidimansour Km 6, BP '1177', 3018, Sfax, Tunisia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ma</LastName><ForeName>Qi</ForeName><Initials>Q</Initials><AffiliationInfo><Affiliation>Department of Otolaryngology (D-48), University of Miami Miller School of Medicine, 1666 NW 12th Avenue, Miami, FL, 33136, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Yao</LastName><ForeName>Qi</ForeName><Initials>Q</Initials><AffiliationInfo><Affiliation>Department of Otolaryngology (D-48), University of Miami Miller School of Medicine, 1666 NW 12th Avenue, Miami, FL, 33136, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Biology, University of Miami, Miami, FL, 33146, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hammami</LastName><ForeName>Bouthaina</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Service Otorhinolaryngologie, Hôpital Universitaire Habib Bourguiba, Sfax, Tunisia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Yan</LastName><ForeName>Denise</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Department of Otolaryngology (D-48), University of Miami Miller School of Medicine, 1666 NW 12th Avenue, Miami, FL, 33136, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mittal</LastName><ForeName>Rahul</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Department of Otolaryngology (D-48), University of Miami Miller School of Medicine, 1666 NW 12th Avenue, Miami, FL, 33136, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Nakamichi</LastName><ForeName>Noritaka</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, 920-1192, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ghorbel</LastName><ForeName>Abdelmonem</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Service Otorhinolaryngologie, Hôpital Universitaire Habib Bourguiba, Sfax, Tunisia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Neng</LastName><ForeName>Lingling</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Oregon Hearing Research Center, Department of Otolaryngology/Head and Neck Surgery, Oregon Health and Science University, Portland, OR, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tekin</LastName><ForeName>Mustafa</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Otolaryngology (D-48), University of Miami Miller School of Medicine, 1666 NW 12th Avenue, Miami, FL, 33136, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Dr. John T. Macdonald Foundation Department of Human Genetics, and John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, 33136, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Shi</LastName><ForeName>Xiao Rui</ForeName><Initials>XR</Initials><AffiliationInfo><Affiliation>Oregon Hearing Research Center, Department of Otolaryngology/Head and Neck Surgery, Oregon Health and Science University, Portland, OR, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kato</LastName><ForeName>Yukio</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, 920-1192, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Masmoudi</LastName><ForeName>Saber</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lu</LastName><ForeName>Zhongmin</ForeName><Initials>Z</Initials><AffiliationInfo><Affiliation>Department of Biology, University of Miami, Miami, FL, 33146, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hmani</LastName><ForeName>Mounira</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Route sidimansour Km 6, BP '1177', 3018, Sfax, Tunisia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Liu</LastName><ForeName>Xuezhong</ForeName><Initials>X</Initials><AffiliationInfo><Affiliation>Department of Otolaryngology (D-48), University of Miami Miller School of Medicine, 1666 NW 12th Avenue, Miami, FL, 33136, USA. xliu@med.miami.edu.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>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.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, Hunan, China. xliu@med.miami.edu.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>R01 DC012115</GrantID><Acronym>DC</Acronym><Agency>NIDCD NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01DC005575</GrantID><Acronym>DC</Acronym><Agency>NIDCD NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01DC012115</GrantID><Acronym>DC</Acronym><Agency>NIDCD NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R21DC012398</GrantID><Acronym>DC</Acronym><Agency>NIDCD NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>2P50DC000422</GrantID><Acronym>DC</Acronym><Agency>NIDCD NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01DC009645</GrantID><Acronym>DC</Acronym><Agency>NIDCD NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 DC005575</GrantID><Acronym>DC</Acronym><Agency>NIDCD NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01DC010844</GrantID><Acronym>DC</Acronym><Agency>NIDCD NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R21DC009879</GrantID><Acronym>DC</Acronym><Agency>NIDCD NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 DC012546</GrantID><Acronym>DC</Acronym><Agency>NIDCD NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2016</Year><Month>03</Month><Day>29</Day></ArticleDate></Article><MedlineJournalInfo><Country>Germany</Country><MedlineTA>Hum Genet</MedlineTA><NlmUniqueID>7613873</NlmUniqueID><ISSNLinking>0340-6717</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D027701">Organic Cation Transport Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C109807">SLC22A4 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D027981">Symporters</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000595" MajorTopicYN="N">Amino Acid Sequence</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002478" MajorTopicYN="N">Cells, Cultured</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D003051" MajorTopicYN="N">Cochlea</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000473" MajorTopicYN="Y">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D003241" MajorTopicYN="Y">Consanguinity</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004727" MajorTopicYN="N">Endothelium</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000473" MajorTopicYN="Y">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D059472" MajorTopicYN="N">Exome</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005808" MajorTopicYN="N">Genes, Recessive</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D057809" MajorTopicYN="N">HEK293 Cells</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D034381" MajorTopicYN="N">Hearing Loss</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D059014" MajorTopicYN="N">High-Throughput Nucleotide Sequencing</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008810" MajorTopicYN="N">Mice, Inbred C57BL</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008969" MajorTopicYN="N">Molecular Sequence Data</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009154" MajorTopicYN="N">Mutation</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D027701" MajorTopicYN="N">Organic Cation Transport Proteins</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010375" MajorTopicYN="N">Pedigree</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D016133" MajorTopicYN="N">Polymerase Chain Reaction</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012150" MajorTopicYN="N">Polymorphism, Restriction Fragment Length</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D051381" MajorTopicYN="N">Rats</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017207" MajorTopicYN="N">Rats, Sprague-Dawley</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017386" 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