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X‐linked juvenile retinoschisis (XLRS) is a hereditary retinal disorder caused by mutations in the RS1 gene, encoding the secreted discoidin‐domain protein retinoschisin. Affected males present with early‐onset foveal schisis, reduced visual acuity, and characteristic spoke‐wheel macular changes. Female carriers are typically asymptomatic. The inheritance mode is X‐linked recessive, with hemizygous males manifesting full disease and heterozygous females often unaffected.
Multiple case series and population studies have established RS1 as the causative gene for XLRS. In 14 Japanese males from 11 families, six novel missense and a nonsense mutation were identified in RS1 in all affected probands, including a founder Glu72Lys variant in four families, confirming non‐Caucasian involvement (14 probands) (PMID:9760195). Detailed analysis of Danish families uncovered two large founder deletions spanning RS1 exons and adjacent genes in one‐third of patients, all with typical XLRS phenotype (PMID:11013441). A South Indian cohort of 22 probands underwent Sanger sequencing, revealing 12 hemizygous RS1 mutations with consistent OCT and ERG findings (PMID:38317323). A recent case series described three affected siblings with variable severity, all harboring the same RS1 mutation, illustrating intrafamilial phenotype heterogeneity (PMID:39304024). Collectively these studies encompass over 250 unrelated XLRS cases worldwide.
The RS1 variant spectrum is broad, with more than 108 unique pathogenic alleles reported across cohorts, including missense, nonsense, splice‐site, frameshift, and gross deletions (PMID:35456481). Recurrent and founder variants such as c.305G>A (p.Arg102Gln) have been observed in diverse populations, underscoring mutational hotspots (c.305G>A (p.Arg102Gln)) (PMID:31006083).
Functional and experimental studies demonstrate that most RS1 missense and truncating mutations disrupt proper folding, oligomerisation, and secretion of retinoschisin. In COS‐7 cells, disease‐associated mutants (e.g., Leu12His, Cys59Ser, Gly70Ser, Arg102Trp) are retained intracellularly or degraded, whereas wild‐type protein is efficiently secreted (PMID:12417531). Structural modelling and in vitro assays reveal that mutations affecting conserved cysteines impair octamer formation and galactose‐binding, disrupting cell‐surface adhesion functions (PMID:16361673). In Rs1‐knockout mice, adeno‐associated virus‐mediated RS1 gene delivery restores retinoschisin expression, retinal structure, and ERG b‐wave amplitude, providing rescue evidence supportive of haploinsufficiency mechanism (PMID:17525175).
A minority of reports describe atypical electrophysiological findings that do not diminish the overall gene–disease association. One family with an Arg213Trp mutation exhibited a normal scotopic b‐wave in a young male, illustrating phenotypic variability but not refuting causality (PMID:10458173).
In sum, RS1 mutations cause XLRS through a loss‐of‐function mechanism characterized by intracellular retention and absence of secreted retinoschisin. The genetic and functional concordance across multiple independent studies supports a Definitive gene‐disease association, with Strong genetic and Strong functional evidence according to ClinGen criteria. Molecular diagnosis of RS1 variants enables accurate prognostic counselling and informs eligibility for emerging gene therapy approaches.
Gene–Disease AssociationDefinitive
Genetic EvidenceStrongMultiple independent cohorts (14 Japanese, 22 Indian, Danish, familial series) with >108 unique RS1 variants and recurrent/founder alleles Functional EvidenceStrongIn vitro secretion/oligomerisation assays, knockout mouse rescue by gene therapy demonstrating loss-of-function mechanism |