SLC17A8 – Autosomal dominant nonsyndromic hearing loss 25

Autosomal dominant nonsyndromic hearing loss 25 (DFNA25) is caused by heterozygous variants in SLC17A8, which encodes the vesicular glutamate transporter 3 (VGLUT3). In two unrelated families, a missense variant, c.632C>T (p.Ala211Val), segregates with progressive high-frequency sensorineural hearing loss and is absent in 267 controls (PMID:18674745). Linkage‐disequilibrium analysis suggests a distant common ancestor in these pedigrees.

Additional screening in 87 Korean patients with autosomal dominant nonsyndromic hearing loss identified a novel heterozygous frameshift variant, c.616dup (p.Met206AsnfsTer4), not observed in 100 controls, supporting the variant spectrum in DFNA25 (PMID:26797701).

Knockout mice lacking Slc17a8 exon 2 exhibit absent auditory‐nerve responses to acoustic stimuli while preserving robust otoacoustic emissions, implicating a specific defect in vesicular glutamate uptake at inner hair cell ribbon synapses (PMID:18674745). Cellular models of the p.Ala211Val mutation show a ~70% reduction in VGLUT3 expression with minimal alteration of transport activity, and super‐resolution microscopy reveals fewer VGLUT3-positive synaptic vesicles per terminal (PMID:28314816).

A knock‐in mouse model carrying the orthologous p.Ala224Val mutation recapitulates progressive hearing loss, collapse of inner hair cell stereocilia bundles, oversized synaptic ribbons, and increased sustained exocytosis rate, confirming dominant‐negative effects on mechano‐transduction and synaptic transfer (PMID:34783032).

Taken together, SLC17A8 variants cause DFNA25 through a haploinsufficient/dominant‐negative mechanism, with robust genetic segregation and concordant in vivo and in vitro functional data. Key Take-home: SLC17A8 testing informs diagnosis of progressive autosomal dominant nonsyndromic hearing loss and guides genetic counseling.

References

• American journal of human genetics • 2008 • Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice. PMID:18674745
• BMC Medical Genetics • 2016 • Screening of the SLC17A8 gene as a causative factor for autosomal dominant non-syndromic hearing loss in Koreans. PMID:26797701
• The Journal of Neuroscience • 2017 • Characterization of a Human Point Mutation of VGLUT3 (p.A211V) in the Rodent Brain Suggests a Nonuniform Distribution of the Transporter in Synaptic Vesicles. PMID:28314816
• The Journal of Physiology • 2021 • VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons. PMID:34783032

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