ArticlePLoS genetics2020
Variants encoding a restricted carboxy-terminal domain of SLC12A2 cause hereditary hearing loss in humans.
Article in PLoS genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers, 1 of them a synthesis that pooled it.
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Who cites it
38 citing papers in PubMed, 1 synthesis or guideline pooled it, 58 citations in OpenAlex.
- A Systematic Review on the Role of the Stria Vascularis in Menière's Disease Pathogenesis.Journal of the Association for Research in Otolaryngology : JARO · 2025Pooled it
- Mutation Spectrum and Novel Rare Variants in a Han Chinese Hearing Loss Cohort Using a Tiered Sequencing Strategy.Molecular genetics & genomic medicine · 2026Article
- Chasing the ghost in the code: highlighting the mystery of a rare genetic condition.American journal of physiology. Cell physiology · 2026Review
- Association Between Genetically Proxied SLC12A2 Inhibition and Inflammatory Bowel Disease: A Mendelian Randomization Study.Biochemical genetics · 2026Article
- A spatial long-read approach at near-single-cell resolution reveals developmental regulation of splicing and polyadenylation sites in distinct cortical layers and cell types.Nature communications · 2025Article
- Hearing Loss and Audiogenic Seizures Induced by Hypofunctional Prestin Variants.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- Complete omission of exon 21 from Slc12a2 transcripts in mice results in hearing loss.Scientific reports · 2025Article
- Genetic landscape in undiagnosed patients with syndromic hearing loss revealed by whole exome sequencing and phenotype similarity search.Human genetics · 2025Article
- Identification of Novel Disease-Modifying Agents for Pelvic Organ Prolapse by Systematic Druggable Genome-Wide Mendelian Randomization.International journal of women's health · 2025Article
- Genetic investigations on singleton school aged children reveal novel variants and new candidate genes for hearing loss.Scientific reports · 2024Article
- Gap Junction Beta-2 p.Val84Met Can Cause Autosomal Dominant Syndromic Hearing Loss With Keratoderma.Cureus · 2024Article
- The role ofJournal of pharmaceutical analysis · 2023Review
- NKCC1 in human diseases: is theAmerican journal of physiology. Cell physiology · 2023Article
- Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review.Biomedicines · 2023Review
- Correlation between genotype and phenotype with special attention to hearing in 14 Japanese cases of NF2-related schwannomatosis.Scientific reports · 2023Article
- Mapping the Constrained Coding Regions in the Human Genome to Their Corresponding Proteins.Journal of molecular biology · 2023Article
- Inhibition mechanism of NKCC1 involves the carboxyl terminus and long-range conformational coupling.Science advances · 2022Article
- Loss of NKCC1 function increases epithelial tight junction permeability by upregulating claudin-2 expression.American journal of physiology. Cell physiology · 2022Article
- Article
- NKCC1 Deficiency in Forming Hippocampal Circuits Triggers Neurodevelopmental Disorder: Role of BDNF-TrkB Signalling.Brain sciences · 2022Review
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Authors and funding
13 authors at 7 institutions in 2 countries.
Funding
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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