Incomplete X-linked congenital stationary night blindness: Characterization of mutations in the CACNAIF gene and an assessment of clinical variability

X-linked congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous non-progressive retinal disorder characterized by impaired night vision, decreased visual acuity, myopia, nystagmus, and strabismus. Two loci for CSNB exist on the X chromosome. The locus for complete CSNB (nonrecordable scotopic b-wave and lack of rod dark adaptation) has been mapped to Xp11.4 (Boycott et al. AJHG 62:865-875, 1998), while the gene responsible for incomplete CSNB (subnormal scotopic b-wave and mildly elevated rod adaptation), CACNA1F, has been identified in Xp11.23 (Bech-Hansen et al. Nature Genet. 19:264-267). Our analysis of this retina-specific L-type calcium channel a1-subunit gene has identified a total of 17 different mutations (two-thirds of which are predicted to cause a loss-of-function) in 36 families with incomplete CSNB. One of these mutations, L1045insC, is seen in 15 families of Mennonite ancestry from Western Canada. Clinical variability was examined in 66 patients from these families in terms of night blindness, myopia, visual acuity, congenital nystagmus and strabismus. In 80% of the patients at least one of the main features of CSNB (night blindness, myopia, and nystagmus) was absent. The only clinical feature present in all 66 patients tested was impaired visual acutiy. Among these Patients who shared the common CACNA1F mutation, considerable variability in clinical expression is evident and suggests the presence of genetic modifiers.This research was supported in part by the RP Research Foundation (Canada), the Alberta Heritage Foundation for Medical Research and the Roy Allen Endowment.