Loss-of-function mutations in a calcium-channel α1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness

Abstract

X-linked congenital stationary night blindness (CSNB) is a recessive non-progressive retinal disorder characterized by night blindness, decreased visual acuity, myopia, nystagmus and strabismus1,2,3. Two distinct clinical entities of X-linked CSNB have been proposed4. Patients with complete CSNB show moderate to severe myopia, undetectable rod function and a normal cone response, whereas patients with incomplete CSNB show moderate myopia to hyperopia and subnormal but measurable rod and cone function. The electrophysiological and psychophysical features of these clinical entities suggest a defect in retinal neurotransmission. The apparent clinical heterogeneity in X-linked CSNB reflects the recently described genetic heterogeneity in which the locus for complete CSNB (CSNB1) was mapped to Xp11.4, and the locus for incomplete CSNB (CSNB2) was refined within Xp11.23 (ref. 5). A novel retina-specific gene mapping to the CSNB2 minimal region was characterized and found to have similarity to voltage-gated L-type calcium channel α1-subunit genes. Mutation analysis of this new α1-subunit gene, CACNA1F , in 20 families with incomplete CSNB revealed six different mutations that are all predicted to cause premature protein truncation. These findings establish that loss-of-function mutations in CACNA1F cause incomplete CSNB, making this disorder an example of a human channelopathy of the retina.

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Figure 1: The predicted protein sequence of JMC8.
Figure 2: JMC8 expression.
Figure 3: Two examples of mutation analysis of CACNA1F in families with incomplete X-linked CSNB.
Figure 4: Evolutionary tree of representative classes of calcium channel genes.
Figure 5: Predicted membrane topology of the L-type calcium channel α1F-subunit encoded by CACNA1F.

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Acknowledgements

We thank the participating families and especially the large Mennonite kindred that initiated our interest in identifying the CSNB2 gene. We also thank L. MacLaren, T. Mah, K. McElligott, M.L. Klimek and S. Scott for facilitating the collection of blood samples, and R. Winkfein, S. Barnes, P. Mains, D. Rancourt, W. Stell, M. Walter and G. Zamponi for helpful discussions. R. Winkfein and P. Schnetkamp provided us with first-strand cDNA from human retinal mRNA. This research was supported in part by the RP Research Foundation (Canada) (operating grants to N.T.B.-H. and Studentship to K.M.B.), the Canadian Genome Analysis and Technology Program and the I.D. Bebensee Foundation. N.T.B.-H. was supported by the Department of Ophthalmology (University of Alberta) and The Alberta Children's Hospital Foundation. K.M.B. is the recipient of an Alberta Heritage Foundation for Medical Research Postdoctoral Fellowship.

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Correspondence to N. Torben Bech-Hansen.

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Bech-Hansen, N., Naylor, M., Maybaum, T. et al. Loss-of-function mutations in a calcium-channel α1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness . Nat Genet 19, 264–267 (1998). https://doi.org/10.1038/947

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