ADGRV1 – Usher syndrome type 2

Usher syndrome type 2 (USH2) is an autosomal recessive disorder characterized by congenital moderate to severe sensorineural hearing loss and progressive retinitis pigmentosa. The ADGRV1 gene (formerly GPR98/VLGR1) encodes a very large adhesion G protein–coupled receptor essential for cochlear and retinal function. Patients typically present with nyctalopia (HP:0000662) and cystoid macular edema (HP:0011505), with electroretinographic evidence of photoreceptor dysfunction preceding funduscopic changes.

Multiple studies of USH2A‐negative cohorts have established ADGRV1 as a minor but definitive contributor to USH2. In a cohort of 31 unrelated patients not linked to USH2A, ADGRV1 mutations were found in 10 individuals ([PMID:22147658]). A multicentric study of 222 USH2 patients identified 18 ADGRV1 cases out of 222 individuals ([PMID:34638692]). A Spanish series of 19 USH2A-negative patients yielded 7 ADGRV1-mutated cases, five of which were homozygous ([PMID:23441107]). Two siblings from a Japanese family harbored compound heterozygous ADGRV1 alleles ([PMID:25743181]), and a consanguineous Chinese pedigree demonstrated a novel homozygous c.6912dupG (p.Leu2305ValfsTer4) variant segregating with USH2C ([PMID:29890953]).

All reported ADGRV1 disease alleles follow autosomal recessive inheritance with co-segregation in sib pairs and consanguineous families. Homozygous and compound heterozygous LoF variants—nonsense, frameshift, and essential splice site changes—predominate, with only two genuine missense changes described among the core cohorts. Segregation in multiple families and absence in ethnically matched controls underscore pathogenicity.

The variant spectrum in ADGRV1 is dominated by truncating mutations; for example, the novel c.6912dupG (p.Leu2305ValfsTer4) LoF allele was shown to abolish critical Calx-β, EPTP, and 7TM domains, leading to receptor instability and loss of function ([PMID:29890953]). Missense variants at Calx-β motifs have been reported in non-syndromic epilepsy cohorts but are rare in USH2 cases.

Functional assays in cellular and animal models support a loss-of-function mechanism. Denaturing HPLC and sequencing identified VLGR1 nonsense and frameshift alleles that segregate with the USH2C phenotype ([PMID:14740321]). Ablation of whirlin’s long isoform in mice disrupts the USH2 protein complex (USH2A–WHRN–ADGRV1) at the periciliary membrane, reproducing retinal and cochlear defects, and highlighting an obligatory complex for sensory cell function ([PMID:20502675]).

Integration of genetic and experimental data meets criteria for a definitive gene–disease relationship. ADGRV1 should be included in molecular diagnostic panels for USH2, enabling early diagnosis, tailored counseling, and potential intervention before visual decline. Key take-home: Autosomal recessive LoF variants in ADGRV1 cause Usher syndrome type 2, supporting its clinical utility in genetic testing.

References

• Human mutation • 2012 • Non-USH2A mutations in USH2 patients. PMID:22147658
• International journal of molecular sciences • 2021 • Characteristics of Retinitis Pigmentosa Associated with ADGRV1 and Comparison with USH2A in Patients from a Multicentric Usher Syndrome Study Treatrush. PMID:34638692
• Molecular vision • 2013 • The contribution of GPR98 and DFNB31 genes to a Spanish Usher syndrome type 2 cohort. PMID:23441107
• The Annals of otology, rhinology, and laryngology • 2015 • USH2 caused by GPR98 mutation diagnosed by massively parallel sequencing in advance of the occurrence of visual symptoms. PMID:25743181
• 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
• 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
• 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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