SAG – Oguchi Disease

SAG (HGNC:10521) encodes visual rod arrestin, a 405–amino acid protein essential for quenching photoactivated rhodopsin and terminating the phototransduction cascade. Pathogenic variants in SAG underlie Oguchi disease (MONDO:0019152), a rare congenital stationary night blindness characterized by nyctalopia and the Mizuo phenomenon (HP:0030824). Patients exhibit normal visual acuity, color vision, and fields, but demonstrate a golden–gray discoloration of the fundus that disappears after prolonged dark adaptation (HP:0000662). Genetic mapping localized Oguchi disease to chromosome 2q, coincident with the SAG locus, implicating arrestin in the recovery phase of rod signaling. The inheritance is strictly autosomal recessive, with affected individuals harboring biallelic loss-of-function alleles.

In the first cohort, six unrelated Japanese probands were found to harbor a homozygous 1-bp deletion at nucleotide 1147 (c.926del (p.Asn309fs)), predicting a frameshift and premature termination ([PMID:7670478]). Subsequent screening of seven families identified nine affected individuals all homozygous for the same 1147delA allele, demonstrating a founder effect in this population ([PMID:9051837]). Two additional unrelated patients also carried the 1147delA homozygous deletion, confirming its high prevalence in Japanese Oguchi disease ([PMID:10420197]). No carriers were reported among unaffected relatives, consistent with recessive segregation. The phenotype in all homozygotes included markedly delayed rod dark adaptation and a positive Mizuo–Nakamura test, with only minor cone involvement in a minority of cases.

Expanded mutation screening in Japanese cohorts uncovered a total of 17 probands from over 14 unrelated families with SAG null alleles, including the recurrent c.926del (p.Asn309fs), and novel nonsense mutations c.523C>T (p.Arg175Ter) and c.874C>T (p.Arg292Ter) ([PMID:15234147]). All reported variants predict protein truncation or disrupted splicing, and none are present in population databases, fulfilling loss-of-function criteria. Segregation analyses uniformly demonstrated that heterozygous carriers are asymptomatic, while homozygotes or compound heterozygotes present with classic Oguchi disease. These data satisfy ClinGen genetic evidence thresholds for a Strong tier association.

Biochemical and cellular assays corroborate a loss-of-function mechanism. Site-directed mutagenesis of arrestin residues within the phosphate-recognition region abolishes binding to phosphorylated rhodopsin, pinpointing key interactions required for signal termination ([PMID:7890732]). Mouse rods lacking arrestin (Arr–/–) exhibit prolonged photoresponses that are normalized by transgenic expression of full-length arrestin, confirming functional rescue in vivo ([PMID:16421323]). Splice variants such as p44 display altered rhodopsin binding kinetics, and structural studies reveal that null mutations prevent the conformational changes necessary for high-affinity receptor interaction. Together, these functional assays support a Moderate tier for mechanistic evidence.

Genetic heterogeneity in Oguchi disease is evidenced by GRK1 mutations in patients without SAG defects, indicating at least two molecular subtypes of stationary night blindness ([PMID:9020843]). However, no studies dispute the pathogenic role of SAG null alleles in classic Oguchi disease, and no alternative phenotypes have been ascribed to SAG loss-of-function. The totality of genetic segregation, recurrent founder alleles, and concordant functional data warrant a Definitive ClinGen classification for SAG–Oguchi disease.

Key take-home: Biallelic loss-of-function variants in SAG cause autosomal recessive Oguchi disease via impaired rhodopsin quenching; the recurrent c.926del (p.Asn309fs) allele is frequent in Japanese patients, and comprehensive SAG testing is recommended in diagnostic panels for congenital stationary night blindness.

References

• Nature genetics • 1995 • A homozygous 1-base pair deletion in the arrestin gene is a frequent cause of Oguchi disease in Japanese. [PMID:7670478]
• Retina (Philadelphia, Pa.) • 1997 • Oguchi disease: phenotypic characteristics of patients with the frequent 1147delA mutation in the arrestin gene. [PMID:9051837]
• Ophthalmic genetics • 1999 • 1147 del A mutation in the arrestin gene in Japanese patients with Oguchi disease. [PMID:10420197]
• Ophthalmology • 2004 • Novel mutations in the arrestin gene and associated clinical features in Japanese patients with Oguchi's disease. [PMID:15234147]
• Nature genetics • 1997 • Defects in the rhodopsin kinase gene in the Oguchi form of stationary night blindness. [PMID:9020843]
• The Journal of biological chemistry • 1995 • Visual arrestin binding to rhodopsin. Diverse functional roles of positively charged residues within the phosphorylation-recognition region of arrestin. [PMID:7890732]
• The Journal of neuroscience : the official journal of the Society for Neuroscience • 2006 • Deactivation of phosphorylated and nonphosphorylated rhodopsin by arrestin splice variants. [PMID:16421323]

Evidence Based Scoring (AI generated)