RHO – Retinitis Pigmentosa

Rhodopsin (RHO) is a G protein–coupled receptor expressed in rod photoreceptor cells. Heterozygous pathogenic variants in RHO cause autosomal dominant retinitis pigmentosa (adRP), a progressive rod–cone dystrophy marked by nyctalopia and peripheral visual field loss. The inheritance is autosomal dominant, with high penetrance and variable expressivity across families.

Extensive genetic studies have identified RHO mutations in 27 of 150 unrelated adRP patients ([PMID:2215617]) and in 39 of 161 additional adRP patients across 17 families ([PMID:1862076]), supporting a definitive gene–disease relationship. Segregation analyses demonstrate co-segregation of RHO variants with disease in multi-generational pedigrees, with LOD scores >3 in several kinships. Affected relatives present classic RP features including bone-spicule pigmentation and extinguished rod responses on electroretinography.

The RHO variant spectrum comprises over 100 distinct alleles: predominantly missense changes (e.g., c.403C>T (p.Arg135Trp), c.1040C>T (p.Pro347Leu)), nonsense mutations causing C-terminal truncation (e.g., c.1030C>T (p.Gln344Ter)), splice-site defects (e.g., c.936+1G>T), and rare copy-number gains. Founder alleles such as p.Pro347Leu recur in diverse populations. Recurrent variants have allele frequencies up to 18% in some adRP cohorts.

Functional assays reveal multiple pathogenic mechanisms. Class II mutants misfold and accumulate in the endoplasmic reticulum, inducing ER stress and apoptosis. Active-state mutants at the Schiff base or counterion sites (e.g., c.269G>A (p.Gly90Asp)) constitutively activate transducin and undergo aberrant phosphorylation/arrestin binding ([PMID:8107847]). Transgenic mouse models of class I (P347S) and class II (T17M) mutations recapitulate photoreceptor degeneration and elevated cAMP, with rescue by chromophore supplementation in class II ([PMID:9751768]). Patient-derived iPSC models further confirm ER stress and autophagy defects in RHO-mutant photoreceptors.

No conflicting evidence has substantially challenged the RHO–RP association. Rare cases of stationary night blindness (G90D, A292E) illustrate allelic phenotypic heterogeneity but do not dispute the role of RHO in RP. Overall, genetic and experimental data reach a ClinGen definitive classification.

Key take-home: RHO sequencing is essential for adRP diagnosis and genetic counseling, guiding prognosis and potential chromophore-based therapies.

References

• The New England Journal of Medicine • 1990 • Mutations within the rhodopsin gene in patients with autosomal dominant retinitis pigmentosa PMID:2215617
• Proceedings of the National Academy of Sciences of the United States of America • 1991 • Rhodopsin mutations in autosomal dominant retinitis pigmentosa PMID:1862076
• Nature • 1994 • Rhodopsin mutation G90D and a molecular mechanism for congenital night blindness PMID:8107847
• Proceedings of the National Academy of Sciences of the United States of America • 1998 • Effect of vitamin A supplementation on rhodopsin mutants threonine-17 → methionine and proline-347 → serine in transgenic mice and in cell cultures PMID:9751768

Evidence Based Scoring (AI generated)