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

PLoS Genet. 2020 Apr 15;16(4):e1008643. doi: 10.1371/journal.pgen.1008643.

Hideki Mutai ¹, Koichiro Wasano ¹ ², Yukihide Momozawa ³, Yoichiro Kamatani ⁴ ⁵, Fuyuki Miya ⁶ ⁷, Sawako Masuda ⁸, Noriko Morimoto ⁹, Kiyomitsu Nara ¹, Satoe Takahashi ², Tatsuhiko Tsunoda ⁶ ⁷ ¹⁰, Kazuaki Homma ² ¹¹, Michiaki Kubo ¹², Tatsuo Matsunaga ¹ ¹³

Affiliations

1 Division of Hearing and Balance Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Meguro, Tokyo, Japan.
2 Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
3 Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
4 Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
5 Kyoto-McGill International Collaborative School in Genomic Medicine, Graduate School of Medicine, Kyoto University, Yoshidakonoecho, Kyoto, Japan.
6 Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
7 Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo, Japan.
8 Department of Otorhinolaryngology, National Hospital Organization Mie National Hospital, Tsu, Mie, Japan.
9 Department of Otorhinolaryngology, National Center for Child Health and Development, Setagaya, Tokyo, Japan.
10 Laboratory for Medical Science Mathematics, Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Bunkyo, Tokyo, Japan.
11 The Hugh Knowles Center for Clinical and Basic Science in Hearing and Its Disorders, Northwestern University, Evanston, Illinois, United States of America.
12 RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
13 Medical Genetics Center, National Hospital Organization Tokyo Medical Center, Meguro, Tokyo, Japan.

PMID: 32294086 DOI: 10.1371/journal.pgen.1008643

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.

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