GRK1 – Oguchi Disease

GRK1 has been strongly implicated in Oguchi disease, a rare autosomal recessive form of congenital stationary night blindness characterized by specific fundus changes and night blindness. Multiple independent studies have reported that mutations in GRK1 impair its function in the phototransduction cascade, critically supporting its role in disease pathogenesis (PMID:19753316).

Genetic evidence indicates that diverse variant types—including loss‑of‑function and missense mutations—segregate with Oguchi disease in affected families. For example, a novel nonsense mutation, c.614C>A (p.Ser205Ter), was shown to segregate in eight affected members of a consanguineous Pakistani family, and additional case reports across different populations have corroborated these findings (PMID:19753316, PMID:27511724).

The inheritance pattern for GRK1‑associated Oguchi disease is autosomal recessive, with robust segregation observed in multiple families. Case series and multi‑patient studies further validate that both truncating and missense variants in GRK1 contribute to the disease phenotype, emphasizing the genetic heterogeneity and reproducibility of these genetic findings (PMID:33252155).

Functional studies provide moderate but compelling support for pathogenicity. Biochemical assays have demonstrated that GRK1 mutants exhibit markedly reduced or absent rhodopsin kinase activity. In vitro experiments reveal that such loss‑of‑function effects disrupt the normal deactivation of photoactivated rhodopsin, aligning with the clinical manifestations of night blindness and the characteristic Mizuo phenomenon (PMID:9501174).

Integration of the genetic and functional data presents a coherent narrative: multiple independent mutations in GRK1, confirmed by segregation in affected families and supported by experimental loss‑of‑function findings, establish a strong gene‑disease relationship. This cumulative evidence exceeds the threshold required by ClinGen criteria and supports diagnostic decision‑making and clinical applications.

Key take‑home: Comprehensive GRK1 genetic testing is a valuable diagnostic tool for Oguchi disease, benefiting both clinical practice and future research by providing clear molecular insights that inform treatment and genetic counseling.

References

• Molecular vision • 2009 • A novel mutation in GRK1 causes Oguchi disease in a consanguineous Pakistani family PMID:19753316
• Molecular medicine reports • 2016 • A novel missense mutation of the GRK1 gene in Oguchi disease PMID:27511724
• Human mutation • 2021 • New variants and in silico analyses in GRK1 associated Oguchi disease PMID:33252155
• Proceedings of the National Academy of Sciences of the United States of America • 1998 • Biochemical evidence for pathogenicity of rhodopsin kinase mutations correlated with the oguchi form of congenital stationary night blindness PMID:9501174

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