HGNC Approved Gene Symbol: CACNA1F
Cytogenetic location: Xp11.23 Genomic coordinates (GRCh38): X:49,205,063-49,233,340 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp11.23 | Aland Island eye disease | 300600 | X-linked | 3 |
| Cone-rod dystrophy, X-linked, 3 | 300476 | X-linked recessive | 3 | |
| Night blindness, congenital stationary (incomplete), 2A, X-linked | 300071 | X-linked | 3 |
The human Xp11.23-p11.22 interval is involved in several hereditary diseases. Fisher et al. (1997) noted that in constructing YAC contigs spanning this region, it was found that the region of Xp surrounding the synaptophysin gene (SYP; 313475) was refractory to cloning in YACs, but highly stable in cosmids. Preliminary analysis of the cosmid suggested a high density of coding sequences and prompted complete sequencing of an SYP-containing cosmid. Fisher et al. (1997) identified 29 putative exons organized into 3 genes, in addition to the 7 exons of the complete SYP coding region, all mapping within a 44-kb interval. Two genes were novel: one (CACNA1F) shows high homology to alpha-1 subunits of calcium channels (see CACNA2; 114204), whereas the other (LMO6; 300111) encodes a product with significant similarity to LIM-domain proteins. RT-PCR and Northern blot studies confirmed that these loci were indeed transcribed. The third locus (A4; 300112) had been previously described but not localized to a specific chromosomal site. The region has an elevated GC content (more than 53%), and Fisher et al. (1997) identified CpG islands associated with the 5-prime ends of SYP, A4, and LMO6.
Naylor et al. (2000) cloned the mouse Cacna1f gene. The deduced 1,985-amino acid channel protein shares 90% identity with the 1,977-amino acid human protein, with almost perfect conservation between the functional domains and only a single amino acid substitution within the transmembrane segments. RT-PCR of several mouse tissues detected Cacna1f expression only in eye. In situ hybridization detected Cacna1f in the outer nuclear layer, the inner nuclear layer, and the ganglion cell layer of mouse retina.
To study the electrophysiologic and pharmacologic properties of the L-type calcium channel CACNA1F, Baumann et al. (2004) cloned and functionally expressed the complete Cacna1f cDNA from the mouse retina. The data indicated that CACNA1F 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.
Liu et al. (2010) combined electrophysiology to characterize channel regulation with optical fluorescence resonance energy transfer sensor determination of free-apocalmodulin (CALM1; 114180) concentration in live cells. This approach translates quantitative calmodulin biochemistry from the traditional test-tube context into the realm of functioning holochannels within intact cells. From this perspective, Liu et al. (2010) found that long splice forms of Ca(V)1.3 (CACNA1D; 114206) and Ca(V)1.4 (CACNA1F) channels include a distal carboxy tail that resembles an enzyme competitive inhibitor that retunes channel affinity for apocalmodulin such that natural calmodulin variations affect the strength of Ca(2+) feedback modulation. Given the ubiquity of these channels, the connection between ambient calmodulin levels and Ca(2+) entry through channels is broadly significant for Ca(2+) homeostasis.
Fisher et al. (1997) determined that the order of loci in the Xp11.23-p11.22 interval is Xpter-A4-LMO6-SYP-CACNA1F-Xcen, with intergenic distances ranging from approximately 300 bp to approximately 5 kb. The density of transcribed sequences in this area (more than 80%) is comparable to that found in the highly gene-rich band Xq28.
Naylor et al. (2000) mapped the mouse Cacna1f gene to a region of the X chromosome that shows homology of synteny to human chromosome Xp11.23.
Incomplete Congenital Stationary Night Blindness, Type 2A
Conducting mutation analysis in 13 families with the incomplete form of X-linked congenital stationary night blindness (CSNB2A; 300071), Strom et al. (1998) identified 9 different mutations in 10 families, including 3 nonsense and 1 frameshift mutation. 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.
Boycott et al. (2001) summarized 20 CACNA1F mutations that had been identified in 36 families with incomplete X-linked congenital stationary night blindness. Three of the mutations accounted for incomplete CSNB in 2 or more families, and a founder effect was demonstrable for one of these mutations. Of the 20 mutations identified, 14 (70%) were predicted to cause premature protein truncation and 6 (30%) to cause amino acid substitutions or deletions at conserved positions in the alpha-1F protein.
Wutz et al. (2002) reported comprehensive mutation analysis of the 48 exons of the CACNA1F gene in 34 unrelated cases (33 families and 1 sporadic case) diagnosed with the incomplete form of X-linked congenital stationary night blindness, based on ERG data and dark adaptation tests. Ten of the families had been partially characterized previously (Strom et al., 1998). The patients were of German (32), Belgian (1), and French (1) origin. Mutation analysis was also performed in 2 patients with an Aland Island disease (300600)-related phenotype. A total of 30 different mutations (20 of which were novel) were identified in 33 patients, 31 CSNB2 familial cases, and the 2 patients with an AIED-like phenotype. Reevaluation of the AIED-like phenotype indicated full compatibility of the patients' ophthalmologic findings with CSNB2. The mutations were equally distributed over the entire gene sequence and included 13 missense, 8 nonsense, 5 splice site, 3 deletion, and 1 insertion mutations. RT-PCR experiments in mouse strains with photoreceptor degeneration showed that the Cacna1f gene is not exclusively expressed in photoreceptors but in the outer nuclear, the inner nuclear, and the ganglion cell layer as well.
Nakamura et al. (2003) described 2 Japanese brothers with retinal and optic disc atrophy and progressive decrease of visual function with increasing age. Although these clinical features are atypical of patients with incomplete CSNB, both patients had an in-frame mutation with deletion and insertion in exon 4 of the CACNA1F gene. In both patients, the bright flash, mixed rod-cone ERG had a negative configuration, characteristic of incomplete CSNB. However, the full-field scotopic and photopic ERGs were nonrecordable, indicating severe, diffuse retinal malfunction, not typical of incomplete CSNB. These findings underscored the phenotypic variability of incomplete CSNB.
Hemara-Wahanui et al. (2005) identified an ile745-to-thr mutation (I745T; 300110.0006) in the CACNA1F gene in a New Zealand family with a visual disorder more severe than typical CSNB2.
Cone-Rod Dystrophy 3
In a large Finnish family with X-linked cone-rod dystrophy-3 (CORDX3; 300476), originally described by Mantyjarvi et al. (2001), Jalkanen et al. (2006) identified a splice site mutation in the CACNA1F gene (300110.0007).
By whole-exome sequencing in 47 Chinese probands with CORD, Huang et al. (2013) identified 1 male proband with a missense mutation in the CACNA1F gene (G848S; 300110.0009).
In affected males and unaffected female carriers from a large German family with cone-rod dystrophy mapping to chromosome Xp11.3-p11.23, Hauke et al. (2013) identified hemizygosity or heterozygosity, respectively, for a large in-frame deletion encompassing exons 18 to 26 of the CACNA1F gene (300110.0010).
Aland Island Eye Disease
In affected members of the original family with Aland Island eye disease (300600) described by Forsius and Eriksson (1964), Jalkanen et al. (2007) identified homozygosity for a 425-bp deletion mutation encompassing exon 30 and portions of adjacent introns of the CACNA1F gene (300110.0008). The mutation was found in heterozygous state in carrier females of this family and was not found in samples from 121 Finnish male control subjects.
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.
Using a large-scale mutagenesis screen for defects in visual behavior in zebrafish, Jia et al. (2014) identified the 'wait until dark' (wud) mutant and isolated 5 wud alleles. Wud mutants were viable but displayed complete loss of sight. Compared with wildtype, wud mutants showed thinning of the outer plexiform layer of the retina and had ERGs consistent with defective synaptic transmission from cone photoreceptors. Transmission electron microscopy revealed complete absence of synaptic ribbons and mislocalization of the synaptic ribbon protein ribeye (CTBP2; 602619) in wud mutants. Using a positional cloning strategy and sequence analysis, Jia et al. (2014) discovered mutations in 1 of the 2 zebrafish CACNA1F orthologs, cacna1fa, in the 2 wud alleles examined. Both mutations introduced premature stop codons and produced null alleles. Jia et al. (2014) noted that the zebrafish cacna1fa and cacna1fb genes are expressed in the photoreceptor layer and inner retina, respectively, in contrast with the single mouse and human CACNA1F genes, which are expressed throughout many layers of the retina.
One of the missense mutations identified by Strom et al. (1998) in cases of incomplete X-linked congenital stationary night blindness (CSNB2A; 300071) was a gly369-to-asp (G369D) amino acid substitution resulting from a transition of nucleotide 1106 in exon 8.
One of the nonsense mutations identified in families with incomplete X-linked congenital stationary night blindness (CSNB2A; 300071) by Strom et al. (1998) was an arg958-to-ter (R958X) mutation due to a C-to-T transition of nucleotide 2172 in exon 24.
In 15 families with congenital stationary night blindness type 2A (CSNB2A; 300071) and the common Mennonite haplotype, suggesting that these families share a founder mutation (Boycott et al. (1998)), Bech-Hansen et al. (1998) found insertion of a single C nucleotide at codon 991 for leucine (L991insC). The insertion caused a frameshift with stop codon 1001.
Among families with congenital stationary night blindness type 2A (CSNB2A; 300071), one of the truncating mutations found by Bech-Hansen et al. (1998) was a C-to-T transition in exon 21 of the CACNA1F gene, resulting in an arg830-to-ter (R830X) nonsense amino acid change.
In 2 affected members of a French family segregating X-linked congenital stationary night blindness type 2A (CSNB2A; 300071), Jacobi et al. (2003) identified a 1-bp deletion (C) at nucleotide 4548 in the CACNA1F gene, resulting in a frameshift with a predicted premature termination at codon 1524.
Hemara-Wahanui et al. (2005) identified a C-to-T transition at nucleotide 2234 in exon 17 of the CACNA1F gene in a New Zealand family with a retinal disorder similar to, but more severe than, X-linked congenital stationary night blindness-2 (CSNB2A; 300071). The transition resulted in the substitution of a conserved isoleucine with threonine at residue 745 (I745T) within transmembrane segment IIS6. Affected males had congenital nystagmus, decreased visual acuity, frequent hypermetropia, and normal fundi. Female family members had congenital nystagmus, decreased visual acuity, and frequent high myopia, in contrast to typical CSNB2A families, in which female heterozygotes are unaffected. Electroretinography showed CSNB2A-like features in males and similar, but less severe, features in females. In addition, some visually impaired males had intellectual impairment and were autistic. Hemara-Wahanui et al. (2005) found that the I745T mutation caused altered channel activity following expression in human embryonic kidney cells. The channel showed a dramatic shift of about -30 mV in the voltage dependence of activation and significantly slower inactivation kinetics. Hemara-Wahanui et al. (2005) concluded that the I745T mutation increases the number of mutant channels open at physiologic membrane potential and allows for persistent Ca(2+) entry due to reduced channel inactivation, resulting in a gain-of-function defect.
In a large Finnish family with X-linked cone-rod dystrophy-3 (CORDX3; 300476), previously reported by Mantyjarvi et al. (2001), Jalkanen et al. (2006) identified a deletion/insertion (IVS28-1 GCGTC-TGG) at -1 position in the splice acceptor site of intron 28 of the CACNA1F gene. The mutation cosegregated completely with the disease phenotype in the family, which included 7 affected males, 10 carrier females, and 33 unaffected family members; it was not found in 200 control chromosomes. RNA studies revealed that the mutation caused altered splicing of the CACNA1F transcript, resulting in 5 variants with predicted premature termination and exonic deletions of the encoded protein.
In affected members of the original family with Aland Island eye disease (300600) described by Forsius and Eriksson (1964), Jalkanen et al. (2007) identified homozygosity for a 425-bp deletion mutation encompassing exon 30 and portions of adjacent introns of the CACN1F gene. The mutation was found in heterozygous state in carrier females of this family and was not found in samples from 121 Finnish male control subjects. The mutation is predicted to cause a deletion of the transmembrane domain IVS2 and the preceding extracellular loop and consequently an altered membrane topology for the C-terminal part of the protein.
In a Chinese male proband with cone-rod dystrophy (CORDX3; 300476), Huang et al. (2013) identified hemizygosity for a c.2542G-A transition (c.2542G-A, NM_005183.2) in the CACNA1F gene, resulting in a gly848-to-ser (G848S) substitution.
In affected male members over 3 generations of a large German family with slowly progressive cone-rod dystrophy (CORDX3; 300476), Hauke et al. (2013) identified hemizygosity for a large intragenic in-frame deletion encompassing exons 18 to 26 of the CACNA1F gene (EX18-27del, NM_005183.2). The deletion is flanked by AluSx repeat sequences on both sides, suggesting that it results from Alu-Alu repeat-mediated nonhomologous recombination. Sequencing of truncated transcripts from affected individuals revealed the aberrant junction of exon 17 to exon 27, representing the loss of 267 amino acids (residues 77-1041), including 4 transmembrane helices within the homologous domain III. The deletion segregated with disease in the family, with asymptomatic female carriers being heterozygous for the deletion.
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Hemara-Wahanui, A., Berjukow, S., Hope, C. I., Dearden, P. K., Wu, S.-B., Wilson-Wheeler, J., Sharp, D. M., Lundon-Treweek, P., Clover, G. M., Hoda, J.-C., Striessnig, J., Marksteiner, R., Hering, S., Maw, M. A. A CACNA1F mutation identified in an X-linked retinal disorder shifts the voltage dependence of Ca(v)1.4 channel activation. Proc. Nat. Acad. Sci. 102: 7553-7558, 2005. [PubMed: 15897456] [Full Text: https://doi.org/10.1073/pnas.0501907102]
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Jacobi, F. K., Hamel, C. P., Arnaud, B., Blin, N., Broghammer, M., Jacobi, P. C., Apfelstedt-Sylla, E., Pusch, C. M. A novel CACNA1F mutation in a French family with the incomplete type of X-linked congenital stationary night blindness. Am. J. Ophthal. 135: 733-736, 2003. [PubMed: 12719097] [Full Text: https://doi.org/10.1016/s0002-9394(02)02109-8]
Jalkanen, R., Bech-Hansen, N. T., Tobias, R., Sankila, E.-M., Mantyjarvi, M., Forsius, H., de la Chapelle, A., Alitalo, T. A novel CACNA1F gene mutation causes Aland Island eye disease. Invest. Ophthal. Vis. Sci. 48: 2498-2502, 2007. [PubMed: 17525176] [Full Text: https://doi.org/10.1167/iovs.06-1103]
Jalkanen, R., Demirci, F. Y., Tyynismaa, H., Bech-Hansen, T., Meindl, A., Peippo, M., Mantyjarvi, M., Gorin, M. B., Alitalo, T. A new genetic locus for X linked progressive cone-rod dystrophy. J. Med. Genet. 40: 418-423, 2003. [PubMed: 12807962] [Full Text: https://doi.org/10.1136/jmg.40.6.418]
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Jia, S., Muto, A., Orisme, W., Henson, H. E., Parupalli, C., Ju, B., Baier, H., Taylor, M. R. Zebrafish Cacna1fa is required for cone photoreceptor function and synaptic ribbon formation. Hum. Molec. Genet. 23: 2981-2994, 2014. [PubMed: 24419318] [Full Text: https://doi.org/10.1093/hmg/ddu009]
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Nakamura, M., Ito, S., Piao, C-H., Terasaki, H., Miyake, Y. Retinal and optic disc atrophy associated with a CACNA1F mutation in a Japanese family. Arch. Ophthal. 121: 1028-1033, 2003. [PubMed: 12860808] [Full Text: https://doi.org/10.1001/archopht.121.7.1028]
Naylor, M. J., Rancourt, D. E., Bech-Hansen, N. T. Isolation and characterization of a calcium channel gene, Cacna1f, the murine orthologue of the gene for incomplete X-linked congenital stationary night blindness. Genomics 66: 324-327, 2000. [PubMed: 10873387] [Full Text: https://doi.org/10.1006/geno.2000.6204]
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Wutz, K., Sauer, C., Zrenner, E., Lorenz, B., Alitalo, T., Broghammer, M., Hergersberg, M., de la Chapelle, A., Weber, B. H. F., Wissinger, B., Meindl, A., Pusch, C. M. Thirty distinct CACNA1F mutations in 33 families with incomplete type of XLCSNB and Cacna1f expression profiling in mouse retina. Europ. J. Hum. Genet. 10: 449-456, 2002. [PubMed: 12111638] [Full Text: https://doi.org/10.1038/sj.ejhg.5200828]