RP1L1 – Retinitis Pigmentosa

RP1L1 encodes a photoreceptor‐specific ciliary protein implicated in autosomal recessive rod–cone dystrophy. Initial linkage and exome sequencing in a consanguineous family identified a homozygous frameshift, c.603del (p.Lys203ArgfsTer28), segregating with early‐onset RP in two siblings ([PMID:23281133]). A second independent homozygous missense, c.1637G>C (p.Ser546Thr), was found in an unrelated proband with arRP and confirmed by segregation ([PMID:23281133]).

A large cohort study of 1204 Japanese RP patients identified four East Asian–specific pathogenic alleles in autosomal recessive genes, including a recurrent RP1L1 stop variant p.Arg658Ter observed in ≥10 unrelated individuals, supporting a recurrent founder effect ([PMID:31213501]). Together these account for at least 12 unrelated probands with biallelic RP1L1 variants demonstrating consistent recessive inheritance.

Clinically, RP1L1‐associated RP presents with nyctalopia (HP:0000662), progressive visual field constriction and attenuated ERG responses. Digenic models combining heterozygous RP1L1 null alleles with C2orf71 loss have been reported in syndromic RP with hearing impairment (HP:0000365), ataxia (HP:0001251), and cerebellar atrophy (HP:0001272), suggesting gene–gene interaction modulates penetrance ([PMID:27029556]).

Functional assays demonstrate retina‐specific RP1L1 expression and polymorphism without phenotype in adRP cohorts ([PMID:12724644]). In vivo zebrafish rp1l1 knockdown recapitulates reduced eye size, rhodopsin loss and cerebellar disorganization, concordant with human syndromic features, confirming a loss‐of‐function mechanism ([PMID:27029556]).

Heterozygous RP1L1 missense variants have been detected in unaffected relatives and fail linkage for dominant RP or OCMD, arguing against sole dominant‐negative effects and highlighting incomplete penetrance in heterozygotes ([PMID:23281133]).

Overall, autosomal recessive RP1L1 loss‐of‐function has strong clinical validity for retinitis pigmentosa, supported by multiple unrelated probands, segregation, founder alleles and functional concordance. Additional modifiers and digenic interactions may influence phenotypic expressivity. Key take‐home: RP1L1 should be included in AR RP genetic testing, particularly in East Asian populations.

References

• Ophthalmic genetics • 2017 • Putative digenic inheritance of heterozygous RP1L1 and C2orf71 null mutations in syndromic retinal dystrophy PMID:27029556
• Human Mutation • 2013 • RP1L1 variants are associated with a spectrum of inherited retinal diseases including retinitis pigmentosa and occult macular dystrophy PMID:23281133
• Journal of Medical Genetics • 2019 • Genetic characteristics of retinitis pigmentosa in 1204 Japanese patients PMID:31213501
• Molecular Vision • 2003 • Characterization of RP1L1, a highly polymorphic paralog of the retinitis pigmentosa 1 (RP1) gene PMID:12724644

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