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

Hideki Mutai, Koichiro Wasano, Yukihide Momozawa, Yoichiro Kamatani, Fuyuki Miya, Sawako Masuda, Noriko Morimoto, Kiyomitsu Nara, Satoe Takahashi, Tatsuhiko Tsunoda, Kazuaki Homma, Michiaki Kubo, Tatsuo Matsunaga

研究成果: Article査読

18 被引用数 (Scopus)

抄録

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.

本文言語English
論文番号e1008643
ジャーナルPLoS Genetics
16
4
DOI
出版ステータスPublished - 2020 4月
外部発表はい

ASJC Scopus subject areas

  • 生態、進化、行動および分類学
  • 分子生物学
  • 遺伝学
  • 遺伝学(臨床)
  • 癌研究

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