Phenotypic variability of a dominant CRX mutation and molecular insights into pathogenesis

Background Mutations in the cone-rod homeobox (CRX) gene cause dominantly inherited retinopathies with striking phenotypic variability. We define the clinical spectrum and molecular mechanism of a Class III CRX frameshift variant (c.590del, p.(Pro197Argfs*22); CRXP197Rfs) segregating in a four-generation family.Materials and methods Six family members underwent genetic testing by a retinal dystrophy panel with Sanger confirmation. Carriers received longitudinal phenotyping, including visual acuity, fundus autofluorescence, optical coherence tomography (OCT), and full-field electroretinography (ffERG). Variant function was assessed by rhodopsin-promoter reporter assays in HEK293 cells and Crx−/− mouse retinal explants.Results Three carriers shared the identical variant yet showed cone-rod dystrophy in variable severity and adult-onset ages. The proband developed progressive central vision loss, nyctalopia, outer-retinal atrophy, and reduced ffERG responses. Two carriers remained asymptomatic with preserved acuity and normal ffERG, exhibiting only mild outer nuclear layer thinning and abnormal autofluorescence. CRXP197Rfs lacked transactivation activity and suppressed wild-type CRX function in a dose-dependent manner.Conclusions CRXP197Rfs is a dominant-negative allele that produces cone-rod dystrophy with variable intrafamilial phenotypes. These findings caution against genotype-based prognostication and support mutant-allele knockdown with gene augmentation as therapeutic strategies.