Rhodopsin – Congenital Stationary Night Blindness

Autosomal dominant congenital stationary night blindness (CSNB) is a non‐progressive retinal dysfunction characterized by impaired rod photoreceptor signaling under low-light conditions (HP:0007642). The RHO gene encodes rhodopsin, a G protein-coupled receptor essential for phototransduction in rod outer segments. Heterozygous missense variants in RHO have been implicated in CSNB through both familial segregation and functional assays.

In one report, a singleton patient presenting with lifelong night vision deficit harbored RHO NM_000539.3:c.875C>A (p.Ala292Glu), which exhibited light-independent transducin activation in vitro, consistent with constitutive opsin activity ([PMID:8358437]). A second Irish family segregating autosomal dominant CSNB was found to carry NM_000539.3:c.281C>T (p.Thr94Ile), with disease co‐segregation across multiple affected relatives, and structural modeling supporting aberrant transducin stimulation ([PMID:9888392]).

In a multi‐cohort screening of 361 subjects (282 retinitis pigmentosa, 76 Leber congenital amaurosis, 3 CSNB), three CSNB probands were among those with RHO mutations clustered near the retinal attachment site, implicating a recurrent mutational hotspot in the CSNB phenotype ([PMID:8317502]). Together, these findings yield at least five unrelated CSNB probands with RHO variants.

Mechanistic in vitro studies demonstrate that CSNB-associated RHO variants disrupt the salt-bridge between Lys296 and Glu113, leading to constitutive activation of opsin and continuous G protein signaling in the absence of light and chromophore. This gain-of-function mechanism contrasts with the loss-of-function defects seen in many retinitis pigmentosa–associated alleles.

No conflicting clinical or genetic evidence has been reported that refutes RHO’s role in autosomal dominant CSNB. The concordance of genetic segregation across two pedigrees, multiple sporadic cases, and in vitro functional concordance supports a moderate level of clinical validity.

Key Take-home: Heterozygous gain-of-function RHO variants cause autosomal dominant CSNB via constitutive opsin activation, informing genetic testing and potential targeted therapies.

References

• Nature Genetics • 1993 • Heterozygous missense mutation in the rhodopsin gene as a cause of congenital stationary night blindness. PMID:8358437
• Human Mutation • 1999 • A novel mutation within the rhodopsin gene (Thr-94-Ile) causing autosomal dominant congenital stationary night blindness. PMID:9888392
• American Journal of Human Genetics • 1993 • Identification of novel rhodopsin mutations responsible for retinitis pigmentosa: implications for the structure and function of rhodopsin. PMID:8317502

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