KCNQ4 – Autosomal Dominant Nonsyndromic Hearing Loss

KCNQ4 encodes the voltage-gated potassium channel Kv7.4, essential for cochlear outer hair cell function and maintaining ion homeostasis. Pathogenic variants cluster in the pore region and underlie DFNA2, an autosomal dominant, progressive, high-frequency sensorineural hearing loss often accompanied by tinnitus and vertigo. The first disease-causing mutation, c.821T>A (p.Leu274His), was identified in a French/Belgian/US/Dutch pedigree linked to DFNA2 (PMID:10925378), confirming the importance of the pore helix. A recurrent hotspot, c.827G>C (p.Trp276Ser), occurred independently in three families from Europe and Japan (PMID:12112653), excluding a single founder origin. In 287 Japanese ADNSHL probands, seven distinct KCNQ4 mutations were found in 19 families (6.62% prevalence), including a c.211delC founder allele in 13 unrelated families (PMID:23717403). A late-onset variant, c.546C>G (p.Phe182Leu), was associated with moderate, progressive hearing loss, tinnitus (41.7%), and vertigo (16.7%) in 12 Taiwanese carriers (PMID:34828318). Prospective patch-clamp of 4,085 possible missense SNVs categorized 1,068 as loss-of-function and demonstrated dominant-negative impact in 516 variants, showing high concordance with murine DFNA2 models (PMID:35760561). Functional assays of pore mutations such as c.886G>A (p.Gly296Ser) revealed impaired surface expression and abolished currents in Xenopus oocytes and mammalian cells, with rescue by KCNQ channel openers (zinc pyrithione + retigabine) and HSP90β overexpression (PMIDs:18030493, 21951272, 23750663). A bi-allelic c.872C>T (p.Pro291Leu) variant exhibited semi-dominant inheritance with prelingual severe hearing loss in homozygotes and late-onset mild loss in heterozygotes, highlighting allelic dosage effects (PMID:31028865). Collectively, strong genetic segregation across 23 probands, diverse variant classes, and concordant functional data establish a definitive gene–disease relationship. Genetic testing of KCNQ4 with targeted functional assays informs diagnosis and provides a framework for mechanism-based therapeutics.

References

• American journal of medical genetics • 2000 • Mutations in the KCNQ4 K+ channel gene, responsible for autosomal dominant hearing loss, cluster in the channel pore region. PMID:10925378
• Human Mutation • 2002 • A mutational hot spot in the KCNQ4 gene responsible for autosomal dominant hearing impairment. PMID:12112653
• PLoS One • 2013 • Comprehensive genetic screening of KCNQ4 in a large autosomal dominant nonsyndromic hearing loss cohort: genotype-phenotype correlations and a founder mutation. PMID:23717403
• Genes • 2021 • A KCNQ4 c.546C>G Genetic Variant Associated with Late Onset Non-Syndromic Hearing Loss in a Taiwanese Population. PMID:34828318
• Genome Research • 2022 • Proactive functional classification of all possible missense single-nucleotide variants in KCNQ4. PMID:35760561
• Human Genetics • 2008 • A novel KCNQ4 pore-region mutation (p.G296S) causes deafness by impairing cell-surface channel expression. PMID:18030493
• British journal of pharmacology • 2012 • Restoration of ion channel function in deafness-causing KCNQ4 mutants by synthetic channel openers. PMID:21951272
• Journal of cellular and molecular medicine • 2013 • Impaired surface expression and conductance of the KCNQ4 channel lead to sensorineural hearing loss. PMID:23750663
• Gene • 2019 • Bi-allelic Pro291Leu variant in KCNQ4 leads to early onset non-syndromic hearing loss. PMID:31028865

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