LOSS-OF-FUNCTION MUTATIONS IN A CALCIUM-CHANNEL ALPHA(1)-SUBUNIT GENEIN XP11.23 CAUSE INCOMPLETE X-LINKED CONGENITAL STATIONARY NIGHT BLINDNESS

X-linked congenital stationary night blindness (CSNB) is a recessive n on-progressive retinal disorder characterized by night blindness, decr eased visual acuity, myopia, nystagmus and strabismus(1-3). Two distin ct clinical entities of X-linked CSNB have been proposed(4). Patients with complete CSNB show moderate to severe myopia, undetectable rod fu nction and a normal cone response, whereas patients with incomplete CS NB show moderate myopia to hyperopia and subnormal but measurable rod and cone function. The electrophysiological and psychophysical feature s of these clinical entities suggest a defect in retinal neurotransmis sion. The apparent clinical heterogeneity in X-linked CSNB reflects th e recently described genetic heterogeneity in which the locus for comp lete CSNB (CSNB1) was mapped to Xp11.4, and the locus for incomplete C SNB (CSNB2) was refined within Xp11.23 (ref. 5). A novel retina-specif ic gene mapping to the CSNB2 minimal region was characterized and foun d to have similarity to voltage-gated L-type calcium channel alpha(1)- subunit genes. Mutation analysis of this new alpha(1)-subunit gene, CA CNA1F, in 20 families with incomplete CSNB revealed six different muta tions that are all predicted to cause premature protein truncation. Th ese findings establish that loss-of-function mutations in CACNA1F caus e incomplete CSNB, making this disorder an example of a human channelo pathy of the retina.