GRK1 – Oguchi disease-2

Oguchi disease-2 is a rare autosomal recessive form of congenital stationary night blindness characterized by the Mizuo–Nakamura phenomenon, a golden-brown fundus discoloration that reverses after prolonged dark adaptation and reappears upon light exposure. Patients present with normal visual acuity and visual fields but exhibit delayed rod photoreceptor recovery and reduced scotopic electroretinogram amplitudes ([PMID:26349155]).

Genetic evidence includes a single Polish case with a homozygous GRK1 frameshift variant, c.1610_1613del (p.Asp537ValfsTer542) ([PMID:26349155]), and twelve additional unrelated probands harboring biallelic GRK1 variants (missense and truncating) in an autosomal recessive pattern ([PMID:33252155]). No segregation data are reported beyond proband status; carrier frequencies are exceedingly low.

The variant spectrum comprises loss-of-function alleles—nonsense (p.Arg19Ter), frameshift (c.1610_1613del (p.Asp537ValfsTer542), c.142_145del (p.Glu48ProfsTer?)), exon 5 deletions—and missense changes clustering in the kinase domain (p.Ser536Leu, p.Arg438Cys). A mutational hotspot around codons 380–537 has been identified through structure-based in silico analyses ([PMID:33252155]).

Functional studies demonstrate that GRK1 mutations abolish or severely reduce kinase activity: the Val380Asp and exon 7 4-bp deletion (codon 536) mutants show near-absent catalytic function in COS7 cells ([PMID:9501174]), and an exon 5 deletion null allele abolishes rhodopsin phosphorylation and slows phototransduction recovery in vivo ([PMID:9419375]).

These data support a loss-of-function mechanism leading to impaired rhodopsin deactivation and the characteristic stationary night blindness phenotype. No conflicting reports have been identified.

Overall, the association between GRK1 and Oguchi disease-2 is classified as Strong based on 13 unrelated probands with concordant biallelic variants and functional concordance. Key take-home: GRK1 loss-of-function mutations reliably predict Oguchi disease-2 in patients with congenital stationary night blindness.

References

• Klinika oczna • 2015 • The first case of Oguchi disease, type 2 in a Polish patient with confirmed GRK1 gene mutation. PMID:26349155
• 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
• Proceedings of the National Academy of Sciences of the United States of America • 1998 • Null mutation in the rhodopsin kinase gene slows recovery kinetics of rod and cone phototransduction in man. PMID:9419375
• Human Mutation • 2021 • New variants and in silico analyses in GRK1 associated Oguchi disease. PMID:33252155

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