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PCARE encodes a photoreceptor ciliary protein essential for outer segment integrity and has been implicated in autosomal-recessive retinitis pigmentosa (arRP), a progressive rod–cone dystrophy with worldwide prevalence of ~1/4,000. Affected individuals typically present with nyctalopia, visual field constriction, bone-spicule pigmentation, and extinguished electroretinograms by adulthood.
Genome-wide homozygosity mapping in a consanguineous Dutch family identified a 1 bp deletion (c.946del; p.Asn316MetfsTer5) in PCARE that segregated with typical arRP in all affected individuals (PMID:20398884). In an unrelated Israeli kindred, a homozygous nonsense variant c.556C>T (p.Gln186Ter) was found to cosegregate with severe RP and night blindness (PMID:20398884). Microsatellite-marker analysis in a second Israeli family revealed a 13 bp deletion (c.2756_2768del; p.Lys919ThrfsTer?) on the same haplotype, confirming independent LoF alleles in three pedigrees (PMID:20398884).
Overall, three truncating PCARE variants have been documented in three unrelated arRP families, with autosomal-recessive inheritance demonstrated by homozygosity mapping and segregation in consanguineous and outbred populations. Representative truncating allele c.556C>T (p.Gln186Ter) exemplifies the loss-of-function disease mechanism.
Functional characterization showed PCARE expression restricted to photoreceptor cells, and morpholino-mediated knockdown in zebrafish led to reduced eye size, photoreceptor outer segment loss, and defective rhodopsin localization, recapitulating key human RP pathology (PMID:20398886). Subcellular localization studies in cultured cells further demonstrated PCARE at the connecting cilium, supporting a ciliary disease mechanism.
Collectively, biallelic loss-of-function PCARE variants disrupt photoreceptor ciliary function, leading to arRP. The concordance of genetic mapping, segregation in three families, and vertebrate model rescue underscores a definitive gene–disease relationship.
Key Take-home: Biallelic PCARE loss-of-function variants definitively cause autosomal-recessive retinitis pigmentosa, enabling molecular diagnosis, carrier testing, and informed genetic counseling.
Gene–Disease AssociationStrongThree unrelated families with recessive biallelic truncating PCARE variants segregating with RP and functional model concordance. Genetic EvidenceStrongTruncating variants in 3 probands from 3 families with autosomal-recessive inheritance and homozygosity mapping ([PMID:20398884]). Functional EvidenceModerateZebrafish morpholino knockdown recapitulates photoreceptor degeneration and ciliary defects, supporting loss-of-function ([PMID:20398886]). |