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

Autoři: Hideki Mutai aff001;  Koichiro Wasano aff001;  Yukihide Momozawa aff003;  Yoichiro Kamatani aff004;  Fuyuki Miya aff006;  Sawako Masuda aff008;  Noriko Morimoto aff009;  Kiyomitsu Nara aff001;  Satoe Takahashi aff002;  Tatsuhiko Tsunoda aff006;  Kazuaki Homma aff002;  Michiaki Kubo aff012;  Tatsuo Matsunaga aff001
Působiště autorů: Division of Hearing and Balance Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Meguro, Tokyo, Japan aff001;  Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America aff002;  Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan aff003;  Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan aff004;  Kyoto-McGill International Collaborative School in Genomic Medicine, Graduate School of Medicine, Kyoto University, Yoshidakonoecho, Kyoto, Japan aff005;  Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan aff006;  Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo, Japan aff007;  Department of Otorhinolaryngology, National Hospital Organization Mie National Hospital, Tsu, Mie, Japan aff008;  Department of Otorhinolaryngology, National Center for Child Health and Development, Setagaya, Tokyo, Japan aff009;  Laboratory for Medical Science Mathematics, Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Bunkyo, Tokyo, Japan aff010;  The Hugh Knowles Center for Clinical and Basic Science in Hearing and Its Disorders, Northwestern University, Evanston, Illinois, United States of America aff011;  RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan aff012;  Medical Genetics Center, National Hospital Organization Tokyo Medical Center, Meguro, Tokyo, Japan aff013
Vyšlo v časopise: Variants encoding a restricted carboxy-terminal domain of SLC12A2 cause hereditary hearing loss in humans. PLoS Genet 16(4): e32767. doi:10.1371/journal.pgen.1008643
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008643


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.

Klíčová slova:

Audiology – Cell membranes – Cochlea – Deafness – Dideoxy DNA sequencing – Exon mapping – Reverse transcriptase-polymerase chain reaction – Yellow fluorescent protein


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