Variants encoding a restricted carboxy-terminal domain of SLC12A2 cause hereditary hearing loss in humans

Hereditary hearing loss is challenging to diagnose because of the heterogeneity of the causative genes. Further, some genes involved in hereditary hearing loss have yet to be identified. Using whole-exome analysis of three families with congenital, severe-to-profound hearing loss, we identified a mi...

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Published inPLoS genetics Vol. 16; no. 4; p. e1008643
Main Authors Mutai, Hideki, Wasano, Koichiro, Momozawa, Yukihide, Kamatani, Yoichiro, Miya, Fuyuki, Masuda, Sawako, Morimoto, Noriko, Nara, Kiyomitsu, Takahashi, Satoe, Tsunoda, Tatsuhiko, Homma, Kazuaki, Kubo, Michiaki, Matsunaga, Tatsuo
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 01.04.2020
Public Library of Science (PLoS)
Subjects
Biology and Life Sciences
Cochlea
Congenital diseases
Deafness
Ears & hearing
Funding
Hair
Hearing loss
Heredity
Homeostasis
Hospitals
Immunohistochemistry
Laboratories
Mathematics
Medical research
Medicine
Medicine and Health Sciences
Multiplication & division
Otolaryngology
Research and Analysis Methods
Software
Supervision
Surgery
Transcription
Twins
Chicago Illinois
United States > US
Illinois
Japan
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Abstract Hereditary hearing loss is challenging to diagnose because of the heterogeneity of the causative genes. Further, some genes involved in hereditary hearing loss have yet to be identified. Using whole-exome analysis of three families with congenital, severe-to-profound hearing loss, we identified a missense variant of SLC12A2 in five affected members of one family showing a dominant inheritance mode, along with de novo splice-site and missense variants of SLC12A2 in two sporadic cases, as promising candidates associated with hearing loss. Furthermore, we detected another de novo missense variant of SLC12A2 in a sporadic case. SLC12A2 encodes Na+, K+, 2Cl- cotransporter (NKCC) 1 and plays critical roles in the homeostasis of K+-enriched endolymph. Slc12a2-deficient mice have congenital, profound deafness; however, no human variant of SLC12A2 has been reported as associated with hearing loss. All identified SLC12A2 variants mapped to exon 21 or its 3'-splice site. In vitro analysis indicated that the splice-site variant generates an exon 21-skipped SLC12A2 mRNA transcript expressed at much lower levels than the exon 21-included transcript in the cochlea, suggesting a tissue-specific role for the exon 21-encoded region in the carboy-terminal domain. In vitro functional analysis demonstrated that Cl- influx was significantly decreased in all SLC12A2 variants studied. Immunohistochemistry revealed that SLC12A2 is located on the plasma membrane of several types of cells in the cochlea, including the strial marginal cells, which are critical for endolymph homeostasis. Overall, this study suggests that variants affecting exon 21 of the SLC12A2 transcript are responsible for hereditary hearing loss in humans.
AbstractList Hereditary hearing loss is challenging to diagnose because of the heterogeneity of the causative genes. Further, some genes involved in hereditary hearing loss have yet to be identified. Using whole-exome analysis of three families with congenital, severe-to-profound hearing loss, we identified a missense variant of SLC12A2 in five affected members of one family showing a dominant inheritance mode, along with de novo splice-site and missense variants of SLC12A2 in two sporadic cases, as promising candidates associated with hearing loss. Furthermore, we detected another de novo missense variant of SLC12A2 in a sporadic case. SLC12A2 encodes Na+, K+, 2Cl− cotransporter (NKCC) 1 and plays critical roles in the homeostasis of K+-enriched endolymph. Slc12a2-deficient mice have congenital, profound deafness; however, no human variant of SLC12A2 has been reported as associated with hearing loss. All identified SLC12A2 variants mapped to exon 21 or its 3’-splice site. In vitro analysis indicated that the splice-site variant generates an exon 21-skipped SLC12A2 mRNA transcript expressed at much lower levels than the exon 21-included transcript in the cochlea, suggesting a tissue-specific role for the exon 21-encoded region in the carboy-terminal domain. In vitro functional analysis demonstrated that Cl− influx was significantly decreased in all SLC12A2 variants studied. Immunohistochemistry revealed that SLC12A2 is located on the plasma membrane of several types of cells in the cochlea, including the strial marginal cells, which are critical for endolymph homeostasis. Overall, this study suggests that variants affecting exon 21 of the SLC12A2 transcript are responsible for hereditary hearing loss in humans.
Hereditary hearing loss is challenging to diagnose because of the heterogeneity of the causative genes. Further, some genes involved in hereditary hearing loss have yet to be identified. Using whole-exome analysis of three families with congenital, severe-to-profound hearing loss, we identified a missense variant of SLC12A2 in five affected members of one family showing a dominant inheritance mode, along with de novo splice-site and missense variants of SLC12A2 in two sporadic cases, as promising candidates associated with hearing loss. Furthermore, we detected another de novo missense variant of SLC12A2 in a sporadic case. SLC12A2 encodes Na+, K+, 2Cl- cotransporter (NKCC) 1 and plays critical roles in the homeostasis of K+-enriched endolymph. Slc12a2-deficient mice have congenital, profound deafness; however, no human variant of SLC12A2 has been reported as associated with hearing loss. All identified SLC12A2 variants mapped to exon 21 or its 3'-splice site. In vitro analysis indicated that the splice-site variant generates an exon 21-skipped SLC12A2 mRNA transcript expressed at much lower levels than the exon 21-included transcript in the cochlea, suggesting a tissue-specific role for the exon 21-encoded region in the carboy-terminal domain. In vitro functional analysis demonstrated that Cl- influx was significantly decreased in all SLC12A2 variants studied. Immunohistochemistry revealed that SLC12A2 is located on the plasma membrane of several types of cells in the cochlea, including the strial marginal cells, which are critical for endolymph homeostasis. Overall, this study suggests that variants affecting exon 21 of the SLC12A2 transcript are responsible for hereditary hearing loss in humans.
Hereditary hearing loss is challenging to diagnose because of the heterogeneity of the causative genes. Further, some genes involved in hereditary hearing loss have yet to be identified. Using whole-exome analysis of three families with congenital, severe-to-profound hearing loss, we identified a missense variant of SLC12A2 in five affected members of one family showing a dominant inheritance mode, along with de novo splice-site and missense variants of SLC12A2 in two sporadic cases, as promising candidates associated with hearing loss. Furthermore, we detected another de novo missense variant of SLC12A2 in a sporadic case. SLC12A2 encodes Na + , K + , 2Cl − cotransporter (NKCC) 1 and plays critical roles in the homeostasis of K + -enriched endolymph. Slc12a2 -deficient mice have congenital, profound deafness; however, no human variant of SLC12A2 has been reported as associated with hearing loss. All identified SLC12A2 variants mapped to exon 21 or its 3’-splice site. In vitro analysis indicated that the splice-site variant generates an exon 21-skipped SLC12A2 mRNA transcript expressed at much lower levels than the exon 21-included transcript in the cochlea, suggesting a tissue-specific role for the exon 21-encoded region in the carboy-terminal domain. In vitro functional analysis demonstrated that Cl − influx was significantly decreased in all SLC12A2 variants studied. Immunohistochemistry revealed that SLC12A2 is located on the plasma membrane of several types of cells in the cochlea, including the strial marginal cells, which are critical for endolymph homeostasis. Overall, this study suggests that variants affecting exon 21 of the SLC12A2 transcript are responsible for hereditary hearing loss in humans. Sounds are perceived by auditory sensory cells, owing to tissues surrounding them, including the cochlear lateral wall. Part of the cochlear lateral wall, the stria vascularis, is critical for production and maintenance of inner-ear fluid with a high potassium concentration, and for generating the positive voltage in the inner ear, important for sound perception, by stimulating secretion of potassium from marginal cells. The gene SLC12A2 encodes a protein involved in sodium, potassium, and chloride transport essential for proper function of specific cells in the stria vascularis; however, human variants of SLC12A2 have not previously been associated with hearing loss. By comprehensive genetic analysis of protein-coding sequences, we identified four candidate changes in SLC12A2 in four families with congenital, severe-to-profound hearing loss. Intriguingly, all four genetic variants were either within or at the 3’-splice site of the exon 21 which encodes a part of the carboxy terminal intracellular domain of SLC12A2. Experiments in cultured cells showed that skipping or mutation of exon 21 significantly decreased chloride influx mediated by the SLC12A2 protein. Overall, our results strongly indicate that mutations influencing exon 21 of SLC12A2 represent a novel mechanism underlying deafness in humans.
Author Mutai, Hideki
Matsunaga, Tatsuo
Wasano, Koichiro
Morimoto, Noriko
Kamatani, Yoichiro
Nara, Kiyomitsu
Takahashi, Satoe
Kubo, Michiaki
Homma, Kazuaki
Miya, Fuyuki
Tsunoda, Tatsuhiko
Masuda, Sawako
Momozawa, Yukihide
AuthorAffiliation 3 Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan
8 Department of Otorhinolaryngology, National Hospital Organization Mie National Hospital, Tsu, Mie, Japan
12 RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan
1 Division of Hearing and Balance Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Meguro, Tokyo, Japan
5 Kyoto-McGill International Collaborative School in Genomic Medicine, Graduate School of Medicine, Kyoto University, Yoshidakonoecho, Kyoto, Japan
10 Laboratory for Medical Science Mathematics, Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Bunkyo, Tokyo, Japan
7 Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo, Japan
9 Department of Otorhinolaryngology, National Center for Child Health and Development, Setagaya, Tokyo, Japan
University
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– name: University of Pennsylvania, UNITED STATES
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  surname: Matsunaga
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  organization: Medical Genetics Center, National Hospital Organization Tokyo Medical Center, Meguro, Tokyo, Japan
BackLink https://www.ncbi.nlm.nih.gov/pubmed/32294086$$D View this record in MEDLINE/PubMed
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ContentType Journal Article
Copyright 2020 Mutai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
2020 Mutai et al 2020 Mutai et al
Copyright_xml – notice: 2020 Mutai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
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SSID ssj0035897
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Snippet Hereditary hearing loss is challenging to diagnose because of the heterogeneity of the causative genes. Further, some genes involved in hereditary hearing loss...
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StartPage e1008643
SubjectTerms Biology and Life Sciences
Cochlea
Congenital diseases
Deafness
Ears & hearing
Funding
Hair
Hearing loss
Heredity
Homeostasis
Hospitals
Immunohistochemistry
Laboratories
Mathematics
Medical research
Medicine
Medicine and Health Sciences
Multiplication & division
Otolaryngology
Research and Analysis Methods
Software
Supervision
Surgery
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Title Variants encoding a restricted carboxy-terminal domain of SLC12A2 cause hereditary hearing loss in humans
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http://dx.doi.org/10.1371/journal.pgen.1008643
Volume 16
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