A summary of 20 CACNA1F mutations identified in 36 families with incomplete X-linked congenital stationary night blindness, and characterization of splice variants

Abstract

Incomplete X-linked congenital stationary night blindness (CSNB) is a recessive, non-progressive eye disorder characterized by abnormal electroretinogram and psychophysical testing and can include impaired night vision, decreased visual acuity, myopia, nystagmus, and strabismus. Including the 20 families previously reported (Bech-Hansen et al. 1998b), we have now analyzed patients from a total of 36 families with incomplete CSNB and identified 20 different mutations in the calcium channel gene CACNA1F. Three of the mutations account for incomplete CSNB in two or more families, and a founder effect is clearly demonstrable for one of these mutations. Of the 20 mutations identified, 14 (70%) are predicted to cause premature protein truncation and six (30%) to cause amino acid substitutions or deletions at conserved positions in the alpha1F protein. In characterizing transcripts of CACNA1F we have identified several splice variants and defined a prototypical sequence based on the location of mutations in splice variants and comparison with the mouse orthologue, Cacnalf.

Thirty distinct CACNA1F mutations in 33 families with incomplete type of XLCSNB and Cacna1f expression profiling in mouse retina

“…From eight mutations published recently, 9 the mutation 3133insC has been found in Mennonite families which have been emigrated since 1683 from Germany, Netherlands, Poland and Russia to North America. 11,30 No overlap is found between our mutation spectrum and the mutation pattern in five Japanese families carrying the incomplete type of CSNB. 12 In this study, one missense, one nonsense, one splice site mutation, a single nucleotide insertion and a del/ins combination could be detected.…”

“…Two stop mutations (R82X and R1288X) have also been identified in other populations 11 and might be caused by the frequent C-to-T transition 29 rather than by a founder mutation. From eight mutations published recently, 9 the mutation 3133insC has been found in Mennonite families which have been emigrated since 1683 from Germany, Netherlands, Poland and Russia to North America.…”

“…Its expression is restricted to the retina and initial mutation analyses revealed loss of function as well as missense mutations. 9 So far, mutation spectra have been published only for mixed populations 10,11 or few Japanese families. 12 In order to establish a mutation spectrum for the German population and to further support the strong association of the CACNA1F gene with CSNB2, we completed analysis in 10 families partially characterised previously 9 and included another 24 CSNB2 families to the study.…”

Thenob2mouse, a null mutation inCacna1f: Anatomical and functional abnormalities in the outer retina and their consequences on ganglion cell visual responses

“…The incomplete form, CSNB2, is caused by mutations in the Cacna1f gene, encoding the α 1F subunit of VDCCs (Bech-Hansen et al, 1998;Strom et al, 1998;Boycott et al, 2001;Wutz et al, 2002). In the outer retina, expression of the α 1F subunit has been localized to the OPL where it is concentrated on the presynaptic side in the terminals of the photoreceptors at their "active zones," which are specialized to mediate continuous calcium-dependent neurotransmitter release (Morgans et al, 2001).…”

Mutations in theCACNA1F andNYX genes in British CSNBX families

“…The single base deletion in exon 9 detected in family C3532 results in a frameshift at amino acid position 341 resulting in loss of domains and motifs downstream from domain I and predicted loss of function. This mutation was previously identified in one other family (Bech-Hansen et al, 1998, Boycott et al 2001. The third mutation (nonsense) identified in exon 24 (family A1397) was also previously identified in a single family (Strom et al, 1998) and occurs in domain III resulting in protein truncation.…”