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

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

Sodium Transporters in Human Health and Disease

“…Because her fibroblasts were collected, genetic analysis revealed that she carried both her parent's mutations. Evidence is now mounting that de novo (single allele) mutations lead to neurodevelopmental deficits and cochlea-vestibular defects (McNeill et al, 2020;Mutai et al, 2020). Another patient with NKCC1 mutation deserves some attention in the context of this review article.…”

NKCC1, an Elusive Molecular Target in Brain Development: Making Sense of the Existing Data

“…The shaker-with-syndactylism homozygotes are deaf and exhibit vestibular dysfunction [57,58]. So far, several human mutations of NKCC1 have been reported [59][60][61][62][63][64]. Patients with deletion in NKCC1 suffer from multiorgan failure [60] or global developmental delay, together with hearing loss, gastrointestinal abnormalities, and absent salivation (named Kilquist syndrome [59]), while a gain-of-function missense variant of NKCC1 has been linked to schizophrenia [62].…”

NKCC1: Newly Found as a Human Disease-Causing Ion Transporter

“…The affected individuals presented with severe hearing loss. 98 In the first family, a 7-month-old female infant and her twin brother shared a SLC12A2 c.2145C > G variant, resulting in p.Asp981Tyr mutation. In the second family, the affected individual carried a c.2930-2A > G mutation; which affects the splice acceptor site of exon 21.…”

“…Interestingly, all these variants were confined to exon 21 ( Figure 5 ). 98 In addition to the hearing loss, affected infants in two families had difficulties in holding their heads up, maintaining a sitting position, or walking, indicative of minor motor developmental delays. In a second study, we identified three individuals from two independent families with mutations in exon 21 associated with nonsyndromic bilateral sensorineural deafness ( Table 2 ).…”