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Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by progressive rod–cone degeneration. CDHR1 (Cadherin-Related Family Member 1) HGNC:14550 encodes a photoreceptor-specific cadherin essential for outer segment integrity. Autosomal recessive variants in CDHR1 have been implicated in RP (Retinitis pigmentosa). The majority of pathogenic alleles are loss-of-function, and the clinical phenotype ranges from classic RP to macula-predominant dystrophy.
Biallelic homozygous nonsense variants in CDHR1 co-segregate with arRP in multiple families. A Chinese pedigree (RP-2373) exhibited three affected siblings homozygous for c.1231C>T (p.Gln411Ter), with complete co-segregation across eight relatives and absence in 2010 controls (PMID:32277948). In a consanguineous Palestinian family, the c.1381C>T (p.Gln461Ter) variant segregated perfectly with disease among affected members (PMID:23044944). A novel homozygous splice acceptor mutation, c.1168-1G>A, was identified in a Pakistani family and confirmed to abrogate normal splicing (PMID:34926197). These observations establish an autosomal recessive inheritance mode with robust familial segregation.
The CDHR1 variant spectrum is broad, including premature stop codons, frameshifts, splice site changes, and hypomorphic missense alleles. Eleven distinct novel CDHR1 variants were reported in nine index cases with RP, cone-rod dystrophy, or cone dystrophy, including non-canonical splice site changes validated by minigene assays (PMID:28765526). Hypomorphic alleles such as c.562G>A (p.Gly188Ser) manifest as RP with relative cone preservation (PMID:37728066). A silent polymorphism, c.783G>A, causes exon 8 skipping and a macula-predominant choroidal dystrophy phenotype (PMID:31387115).
Functional assays corroborate a loss-of-function mechanism. In zebrafish, overexpression of the E3 ligase Siah1 drives proteasomal degradation of Cdhr1a, resulting in selective rod and cone photoreceptor loss—rescued by cdhr1a mRNA (PMID:33330480). Splicing defects for non-canonical intronic variants (e.g., c.439-17G>A) were confirmed by patient fibroblast transcript analysis (PMID:27391102). These models mirror the human phenotype and support haploinsufficiency.
Mechanistically, CDHR1 truncating variants disrupt photoreceptor outer segment adhesion, leading to progressive degeneration. Mouse knockout of the CDHR1 homolog PCDH21 yields a similar photoreceptor degeneration phenotype, underscoring a conserved role in retinal maintenance (PMID:16288196). Convergent genetic and experimental data delineate a recessive loss-of-function mechanism driving RP.
Collectively, there is strong clinical validity for CDHR1 in autosomal recessive RP, with robust genetic segregation across ethnicities and concordant functional evidence. Identification of biallelic CDHR1 variants informs molecular diagnosis, genetic counseling, and future therapeutic strategies. Key Take-home: CDHR1 is a definitively validated AR RP gene enabling precise diagnosis and tailored patient management.
Gene–Disease AssociationStrong≥10 unrelated probands across multiple studies, multi-family segregation and concordant functional data Genetic EvidenceStrongBiallelic LoF and missense variants in >10 probands with segregation in multiple families Functional EvidenceModerateZebrafish loss-of-function model and splicing assays confirm pathogenic mechanism |