ADGRV1 – Usher syndrome type 2C

ADGRV1 (formerly VLGR1/GPR98) encodes the largest adhesion G protein-coupled receptor, localizing to the periciliary membrane complex in photoreceptors and to stereocilia of inner-ear hair cells. Autosomal recessive loss-of-function (LoF) variants in ADGRV1 underlie Usher syndrome type 2C (USH2C), a dual sensory disorder characterized by congenital sensorineural hearing loss and progressive retinitis pigmentosa (PMID:14740321). Pathogenic alleles predominantly truncate key Calx-β and seven-transmembrane domains, abrogating protein interactions.

Initial evidence came from a multi-center study that screened 10 unrelated USH2C probands and identified four isoform-specific VLGR1 mutations across three families and two sporadic cases (PMID:14740321). A follow-up clinical study described three affected siblings segregating a nonsense variant c.6901C>T (p.Gln2301Ter) (PMID:15671307). Subsequent reports include two male probands and an affected sister carrying novel LoF alleles (PMID:19357117), a consanguineous Chinese pedigree homozygous for c.6912dupG (p.Leu2305ValfsTer4) (PMID:29890953), and a Chinese family with compound heterozygous frameshift variants c.15008delG (p.Gly5003AlafsTer13) and c.18386_18389dup (p.His6130GlnfsTer84) (PMID:29883260).

Segregation analyses confirm autosomal recessive inheritance with at least 5 additional affected relatives across sibships and consanguineous pedigrees co-segregating LoF ADGRV1 variants with the USH2C phenotype (PMID:15671307; PMID:19357117; PMID:29890953; PMID:29883260).

The variant spectrum is dominated by nonsense, frameshift, canonical splice-site, and small indel mutations, all predicted to produce truncated proteins. No recurrent founder alleles have been reported, and missense changes are exceedingly rare.

Functional assays elucidate the pathogenic mechanism: ADGRV1 assembles with WHRN and USH2A into an obligatory periciliary membrane complex (PMC) in photoreceptors. Ablation of the whirlin long isoform in mice disrupts PMC integrity, recapitulates retinal degeneration and hearing loss, and destabilizes USH2 proteins (PMID:20502675). Biochemical and cell-based studies confirm that truncating variants in ADGRV1 abrogate complex formation and mediate haploinsufficiency (PMID:14740321).

Collectively, ADGRV1 exhibits a definitive gene–disease relationship with Usher syndrome type 2C, supported by extensive autosomal recessive LoF variant identification, robust co-segregation, and concordant functional data. ADGRV1 testing should be included in diagnostic panels for USH2 patients of both sexes. Key take-home: loss-of-function variants in ADGRV1 cause Usher syndrome type 2C, informing diagnosis, genetic counseling, and potential therapeutic development.

References

• American Journal of Human Genetics • 2004 • Mutations in the VLGR1 gene implicate G-protein signaling in the pathogenesis of Usher syndrome type II. PMID:14740321
• Investigative Ophthalmology & Visual Science • 2005 • Disease expression in Usher syndrome caused by VLGR1 gene mutation (USH2C) and comparison with USH2A phenotype. PMID:15671307
• Journal of Medical Genetics • 2009 • GPR98 mutations cause Usher syndrome type 2 in males. PMID:19357117
• BMC Medical Genetics • 2018 • A novel homozygous variant of GPR98 causes usher syndrome type IIC in a consanguineous Chinese family by next generation sequencing. PMID:29890953
• Ophthalmic Genetics • 2018 • Identification of two novel compound heterozygous mutations of ADGRV1 in a Chinese family with Usher syndrome type IIC. PMID:29883260
• PLoS Genetics • 2010 • Ablation of whirlin long isoform disrupts the USH2 protein complex and causes vision and hearing loss. PMID:20502675

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