rs72474224 — GJB2 V37I

Connexin 26 missense variant causing partial loss of cochlear gap junction function; the leading cause of mild-to-moderate hereditary hearing loss in East Asian populations

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Connexin 26 V37I — The Hidden Cause of Progressive Hearing Loss in East Asia

The cochlea — the spiral hearing organ of the inner ear — depends on a precise ionic environment to convert sound waves into electrical nerve signals. Connexin 26, encoded by GJB211 Connexin 26, encoded by GJB2
Gap Junction Protein Beta-2; the most common cause of hereditary non-syndromic hearing loss worldwide forms the molecular channels that maintain this environment. The V37I variant (rs72474224, c.109G>A, p.Val37Ile) is a missense substitution that partially disrupts this channel function, and it is the single most important genetic cause of mild-to-moderate sensorineural hearing loss in East Asian populations.

Unlike the severe c.35delG variant that dominates European deaf populations, V37I does not eliminate channel function entirely — it reduces it. This subtlety produces a distinct clinical signature: hearing loss that is often absent at birth, detected only by audiogram in childhood or adulthood, and inexorably progressive across the lifespan.

The Mechanism

Connexin 26 proteins form hexameric hemichannels (connexons) in the membranes of cochlear supporting cells22 Connexin 26 proteins form hexameric hemichannels (connexons) in the membranes of cochlear supporting cells
These cells surround and protect the hair cells that detect sound. Two hemichannels from adjacent cells dock together to create a complete gap junction channel, enabling the rapid intercellular recycling of potassium ions that is essential for maintaining the endocochlear potential33 endocochlear potential
A +80–100 mV electrical gradient in the cochlear fluid that powers mechanosensory transduction by hair cells.

The V37I substitution replaces the nonpolar amino acid valine with the larger, slightly polar isoleucine at position 37, located in the first transmembrane domain of connexin 26. Functional studies show that V37I gap junction plaques are shorter than wild-type, reducing the total cross-sectional area available for ion transport. Knock-in mouse studies confirm that homozygous V37I animals develop a measurable reduction in endocochlear potential44 measurable reduction in endocochlear potential
Approximately 12 mV below wild-type, impaired cochlear amplification, and increased calcium current in inner hair cells — the last finding suggesting that K+ accumulation around hair cells causes excitotoxic damage over time.

The partial nature of the functional loss explains why V37I causes milder, later-onset hearing loss compared to truncating mutations. The residual gap junction activity is sufficient for normal hearing in infancy but insufficient to sustain the cochlea indefinitely against aging and acoustic stress.

The Evidence

The pathogenicity of homozygous V37I was confirmed by a meta-analysis of 33 studies with 14,398 hearing loss cases and 8,699 controls55 meta-analysis of 33 studies with 14,398 hearing loss cases and 8,699 controls
Shen et al. 2017, Oncotarget, PMID 28489599 that found an odds ratio of 7.14 (95% CI 3.01–16.95) for the TT genotype and OR 3.63 (95% CI 1.38–9.54) for compound heterozygotes (V37I plus another pathogenic GJB2 allele). Critically, single heterozygous carriers (CT genotype) did not show elevated hearing loss risk, establishing the autosomal recessive inheritance pattern.

The variant's progressive nature was documented in a population-based longitudinal study of 30,122 individuals aged 0–97 years in Shanghai66 population-based longitudinal study of 30,122 individuals aged 0–97 years in Shanghai
Chen et al. 2022, Genetics in Medicine, PMID 35016843. Among biallelic V37I carriers: 43.9% passed newborn hearing screening (hearing appears normal at birth), but hearing loss prevalence rose with age — 9.5% of children aged 7–15, 23.1% of adults aged 20–40, 59.4% of those aged 40–60, and 80% of those aged 60–85 had moderate or greater hearing loss. The average progression rate was 0.40 dB per year, affecting high frequencies first.

In a Chinese Han cohort of 3,864 hearing-impaired patients, a Chinese-specific study77 Chinese-specific study
Liu et al. 2015, PMC4463851 found that among 106 individuals with biallelic V37I or V37I plus other pathogenic mutations, 66% had mild-to-moderate hearing loss while 28–41% progressed to severe-profound loss. A prospective newborn screening study88 newborn screening study
Li et al. 2012, PMID 22574200 found the biallelic V37I genotype confers an odds ratio of 62.92 for postnatal permanent childhood hearing impairment in Chinese Han newborns — confirming that subclinical hearing impairment at birth frequently evolves into detectable loss during childhood.

Mouse model experiments confirm heightened vulnerability to secondary insults: knock-in mice carrying homozygous V37I99 knock-in mice carrying homozygous V37I
Aging journal study, PMID 31562289 showed significantly greater threshold shifts than wild-type animals after noise exposure, furosemide injection, and KCl administration. This mechanistically explains why environmental factors accelerate hearing decline in biallelic V37I carriers.

Practical Implications

Biallelic carriers (TT genotype) require structured audiological surveillance throughout life, beginning in childhood. Because the variant passes standard newborn hearing screening in roughly 44% of affected infants, genetic testing is the most reliable early detection method in at-risk East Asian families. Once hearing loss develops, amplification with properly fitted hearing aids is the first-line intervention. The mild-to-moderate severity profile of most V37I hearing loss makes hearing aids highly effective for most affected individuals.

Avoiding ototoxic insults is particularly important for biallelic carriers. Noise-induced permanent threshold shifts are compounded by impaired K+ recycling, meaning occupational or recreational high-level noise exposure should be minimized and hearing protection used consistently. Ototoxic drugs (aminoglycosides, platinum-based chemotherapy) that further impair cochlear ion homeostasis pose magnified risk and should prompt heightened monitoring or alternative choices when possible.

Single heterozygous carriers (CT genotype) have normal hearing and carry no elevated personal hearing loss risk. Their clinical relevance is as parents: two CT carriers have a 25% chance of producing a biallelic (TT) child with hearing loss.

Interactions

V37I can produce compound heterozygous hearing loss when inherited alongside other pathogenic GJB2 variants on the opposite chromosome, including c.35delG (rs80338939, the most common European deafness allele), c.235delC (rs80338943 — predominant in East Asian populations), and c.299_300delAT. Compound V37I/35delG heterozygotes typically show milder hearing loss (median threshold ~40 dB) than 35delG homozygotes, consistent with V37I being a partial loss-of-function allele. In audiologically normal individuals of East Asian descent, discovering V37I heterozygosity should prompt clinical investigation for a second GJB2 pathogenic variant on the opposite allele if the clinical presentation is consistent with sensorineural hearing loss.

Large genomic deletions in the neighbouring GJB6 gene1010 GJB6 gene
Encodes connexin 30, which forms heteromeric gap junctions with connexin 26 — particularly the del(GJB6-D13S1830) deletion — also act as pathogenic second alleles in trans with GJB2 variants including V37I, contributing to DFNB1-spectrum hearing loss.

Genotype Interpretations

What each possible genotype means for this variant.

CC Non-carrier Normal

No GJB2 V37I variant; normal connexin 26 function

You have two copies of the common C allele of GJB2 at this position. Your connexin 26 protein is unaffected by the V37I substitution, and your cochlear gap junction function is not impaired by this variant. The vast majority of people worldwide share this genotype (>99% globally), including essentially all individuals of European and African descent. Any sensorineural hearing loss you experience is not attributable to this variant.

CT Carrier Carrier

Single copy of V37I — normal hearing, reproductive relevance

The autosomal recessive nature of GJB2 V37I means two non-functional alleles are required to impair connexin 26 function enough to cause hearing loss. Large-scale meta-analyses confirm that OR for hearing loss in heterozygous carriers is approximately 1.18 — not statistically significant and not clinically meaningful. Your risk of hearing loss from this variant is equivalent to the general population.

The reproductive significance is real: if your partner also carries a GJB2 pathogenic variant (whether V37I or another allele such as c.35delG or c.235delC), each pregnancy carries a 25% chance of producing a biallelic child with hearing loss. Carrier testing of a partner is straightforward and can guide reproductive decision-making.

TT Homozygous Homozygous

Two copies of V37I — elevated risk for progressive mild-to-moderate sensorineural hearing loss

The TT genotype is rare in most populations (homozygous frequency roughly 0.7% in East Asians based on Hardy-Weinberg from 8.3% allele frequency) but is the most common cause of hereditary mild-to-moderate hearing loss in Chinese, Japanese, Korean, and Southeast Asian populations. The V37I substitution reduces gap junction plaque length, lowering the cross- sectional area available for K+ transport without eliminating it entirely — this partial impairment explains why hearing loss is milder and later-onset than with truncating GJB2 mutations.

Population data from 30,122 individuals aged 0–97 years shows the full natural history: normal or borderline hearing in newborns, progressively increasing prevalence with age, reaching 80% with moderate or greater hearing loss by age 60–85. Males appear to progress slightly faster than females. The audiogram typically shows a downward-sloping pattern, with high-frequency thresholds (2–8 kHz) affected before low-frequencies.

Biallelic V37I carriers also show heightened susceptibility to noise-induced hearing loss and ototoxic drug effects (aminoglycosides, cisplatin), as their cochlear K+ recycling capacity has reduced reserve to cope with additional insults.