Alternative titles; symbols
ORPHA: 215; DO: 0110871;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp11.23 | Night blindness, congenital stationary (incomplete), 2A, X-linked | 300071 | X-linked | 3 | CACNA1F | 300110 |
A number sign (#) is used with this entry because of evidence that type 2 (incomplete) X-linked congenital stationary night blindness is caused by mutation in the retina-specific calcium channel alpha-1-subunit gene (CACNA1F; 300110). Aland Island eye disease (300600), which has a similar phenotype, is caused by mutation in the same gene.
For a general phenotypic description and discussion of genetic heterogeneity of congenital stationary night blindness, see CSNB1A (310500).
X-linked congenital stationary night blindness is a nonprogressive retinal disorder characterized by decreased visual acuity and loss of night vision. Bergen et al. (1995) stated that X-linked CSNB (CSNBX) is clinically heterogeneous with respect to the involvement of retinal rods and/or cones in the disease. The classic form of X-linked congenital stationary night blindness (CSNB1; 310500) is associated with myopia.
All affected members of the family mapped by Bergen et al. (1996) to Xp21.1 had myopia and a fine horizontal nystagmus. None of them experienced deterioration, during an average follow-up of 5 years, of their visual acuity or ERG recordings. The 6 obligate carriers and 1 possible carrier had normal visual acuity, no myopia, and no abnormalities on ERG. The affected males, apart from night blindness as shown by the dark adaptation curves, had no clinical or electrophysiologic signs of retinitis pigmentosa.
The classic form of X-linked congenital stationary night blindness, CSNB1, shows mapping to Xp11.3. Bergen et al. (1995) localized a new locus for CSNBX to Xp21.1, thus providing evidence that X-linked CSNB is genetically as well as clinically heterogeneous. No clear correlation could be found between phenotypic differences and different map locations. The new CSNBX gene was closely linked to the RP3 gene region (see 312610), which supported the hypothesis that there is a functional relationship between congenital stationary night blindness and retinitis pigmentosa. Such a relationship is indicated by the fact that some mutations in the rhodopsin gene (RHO; 180380) cause congenital stationary night blindness (see 610445), although most cause retinitis pigmentosa. Autosomal dominant congenital stationary night blindness has also been related to mutations in the PDEB gene (180072), which maps to 4p16.3. Other mutations in the PDEB gene cause autosomal recessive retinitis pigmentosa.
Bergen et al. (1996) reported findings they considered conclusive evidence for a distinct congenital stationary night blindness locus in Xp21.1. They described the results of linkage analysis in another large family, confirming the findings in the first family. The second locus is closely linked to the X-linked retinitis pigmentosa type 3 gene (RPGR; 312610) in Xp21.1.
Boycott et al. (1998) studied 32 families with X-linked CSNB, including 11 families with the complete form of CSNB and 21 families with the incomplete form. Critical recombination events in the families with complete CSNB localized a disease gene to the region between DXS556 and DXS8083, in Xp11.4-p11.3. The critical recombination events in the set of families with incomplete CSNB localized a disease gene to the region between DXS722 and DXS8023 in Xp11.23. Further analysis of the incomplete CSNB families by means of disease associated-haplotype construction identified 17 families of apparent Mennonite ancestry that shared portions of an ancestral chromosome. The results of this analysis refined the location of the gene for incomplete CSNB to the region between DXS722 and DXS255, a distance of 1.2 Mb. Genetic and clinical analyses of this set of 32 families with X-linked CSNB, together with the family studies reported in the literature, strongly suggest that 2 loci, 1 for complete (CSNB1; 310500) and 1 for incomplete (CSNB2) X-linked CSNB, can account for all reported mapping information.
Hardcastle et al. (1997) used the symbol CSNB4 for a second form of CSNB encoded by a gene on Xp. They described a new location for the form of CSNB on the proximal part of Xp, Xp11.4-p11.3, between the RP2 (312600) and RP3 loci. They found that 'CSNB4' is not allelic with any previously reported X-linked RP loci; however, the interval overlapped the locus reported to contain the CORDX1 gene (304020).
Conducting mutation analysis in 13 families with the incomplete form of X-linked congenital stationary night blindness type 2, Strom et al. (1998) identified 9 different mutations in the CACNA1F gene in 10 families, including 3 nonsense and 1 frameshift mutation (see, e.g., 300110.0001-300110.0002). Similarly, by mutation analysis of the CACNA1F gene in 20 families with incomplete CSNB, Bech-Hansen et al. (1998) found 6 different mutations, all of which predicted premature protein truncation (see, e.g., 300110.0003-300110.0004).
In 7 Japanese patients from 5 unrelated families with incomplete CSNB, Nakamura et al. (2001) identified 5 different mutations in the CACNA1F gene. Clinically, each patient had essentially normal fundi, mildly reduced corrected visual acuity, and slight myopia or hyperopia with astigmatism. Electrophysiologically, the mixed rod-cone ERG showed a negative configuration with recordable oscillatory potentials. The rod ERG was recordable but subnormal, and the cone and 30-Hz flicker ERGs were markedly depressed. Nakamura et al. (2001) concluded that in most Japanese patients with incomplete CSNB, the phenotype is caused by mutation in the CACNA1F gene.
The key symptoms of CSNB2 are impaired night vision and decreased visual acuity. The electrophysiologic hallmark is the Schubert and Bornschein type electroretinogram, in which the amplitude of the scotopic b-wave is smaller than that of the normal-sized a-wave. This finding suggests that the pathologic correlate of the disease is localized most likely at the photoreceptor-to-bipolar synapse. Baumann et al. (2004) found that the CACNA1F protein constitutes the major molecular correlate of the retinal L-type calcium current. Its intrinsic biophysical properties, in particular its unique inactivation properties, enable it to provide a sustained calcium current over the voltage range required for tonic glutamate release at the photoreceptor synapse.
Mansergh et al. (2005) generated a mouse with a loss-of-function mutation in exon 7 of the mouse Cacna1f gene. Electroretinography of the mutant mouse revealed a scotopic a-wave of marginally reduced amplitude compared with the wildtype mouse and absence of the postreceptoral b-wave and oscillatory potentials. Cone ERG responses together with visual evoked potentials and multi-unit activity in the superior colliculus were also absent. Calcium imaging of retinal slices depolarized with KCl showed 90% less peak signal in the photoreceptor synapses of the Cacna1f mutant than in wildtype mice. The absence of postreceptoral ERG responses and the diminished photoreceptor calcium signals were consistent with a loss of Ca(2+) channel function in photoreceptors. Immunocytochemistry showed no detectable Cav1.4 protein in the outer plexiform layer of Cacna1f-mutant mice, profound loss of photoreceptor synapses, and abnormal dendritic sprouting of second-order neurons in the photoreceptor layer. Mansergh et al. (2005) concluded that the Cav1.4 calcium channel is vital for the functional assembly and/or maintenance and synaptic functions of photoreceptor ribbon synapses.
Baumann, L., Gerstner, A., Zong, X., Biel, M., Wahl-Schott, C. Functional characterization of the L-type Ca(2+) channel Cav1.4-alpha-1 from the mouse retina. Invest. Ophthal. Vis. Sci. 45: 708-713, 2004. [PubMed: 14744918] [Full Text: https://doi.org/10.1167/iovs.03-0937]
Bech-Hansen, N. T., Naylor, M. J., Maybaum, T. A., Pearce, W. G., Koop, B., Fishman, G. A., Mets, M., Musarella, M. A., Boycott, K. M. Loss-of-function mutations in a calcium-channel alpha-1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness. Nature Genet. 19: 264-267, 1998. [PubMed: 9662400] [Full Text: https://doi.org/10.1038/947]
Bergen, A. A. B., ten Brink, J. B., Riemslag, F., Schuurman, E. J. M., Meire, F., Tijmes, N., de Jong, P. T. V. M. Conclusive evidence for a distinct congenital stationary night blindness locus in Xp21.1. J. Med. Genet. 33: 869-872, 1996. [PubMed: 8933343] [Full Text: https://doi.org/10.1136/jmg.33.10.869]
Bergen, A. A. B., ten Brink, J. B., Riemslag, F., Schuurman, E. J. M., Tijmes, N. Localization of a novel X-linked congenital stationary night blindness locus: close linkage to the RP3 type retinitis pigmentosa gene region. Hum. Molec. Genet. 4: 931-935, 1995. [PubMed: 7633454] [Full Text: https://doi.org/10.1093/hmg/4.5.931]
Boycott, K. M., Pearce, W. G., Musarella, M. A., Weleber, R. G., Maybaum, T. A., Birch, D. G., Miyake, Y., Young, R. S. L., Bech-Hansen, N. T. Evidence for genetic heterogeneity in X-linked congenital stationary night blindness. Am. J. Hum. Genet. 62: 865-875, 1998. [PubMed: 9529339] [Full Text: https://doi.org/10.1086/301781]
Hardcastle, A. J., David-Gray, Z. K., Jay, M., Bird, A. C., Bhattacharya, S. S. Localization of CSNBX (CSNB4) between the retinitis pigmentosa loci RP2 and RP3 on proximal Xp. Invest. Ophthal. Vis. Sci. 38: 2750-2755, 1997. [PubMed: 9418727]
Mansergh, F., Orton, N. C., Vessey, J. P., Lalonde, M. R., Stell, W. K., Tremblay, F., Barnes, S., Rancourt, D. E., Bech-Hansen, N. T. Mutation of the calcium channel gene Cacna1f disrupts calcium signaling, synaptic transmission and cellular organization in mouse retina. Hum. Molec. Genet. 14: 3035-3046, 2005. [PubMed: 16155113] [Full Text: https://doi.org/10.1093/hmg/ddi336]
Nakamura, M., Ito, S., Terasaki, H., Miyake, Y. Novel CACNA1F mutations in Japanese patients with incomplete congenital stationary night blindness. Invest. Ophthal. Vis. Sci. 42: 1610-1616, 2001. [PubMed: 11381068]
Strom, T. M., Nyakatura, G., Apfelstedt-Sylla, E., Hellebrand, H., Lorenz, B., Weber, B. H. F., Wutz, K., Gutwillinger, N., Ruther, K., Drescher, B., Sauer, C., Zrenner, E., Meitinger, T., Rosenthal, A., Meindl, A. An L-type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness. Nature Genet. 19: 260-263, 1998. [PubMed: 9662399] [Full Text: https://doi.org/10.1038/940]