HGNC Approved Gene Symbol: CABP4
Cytogenetic location: 11q13.2 Genomic coordinates (GRCh38) : 11:67,452,403-67,461,752 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.2 | Cone-rod synaptic disorder, congenital nonprogressive | 610427 | Autosomal recessive | 3 |
By searching databases for sequences similar to CABPs, Haeseleer et al. (2000) identified a CABP4 genomic clone. Like other CABP family members, the deduced CABP4 protein contains 4 EF-hand motifs.
Haeseleer et al. (2004) obtained a full-length human CABP4 cDNA by PCR of a retina cDNA library. The deduced 275-amino acid protein has a calculated molecular mass of 30.4 kD. Haeseleer et al. (2004) noted that the second EF-hand motif of CABP4 cannot coordinate Ca(2+) because the lysine residue in position 1 is not suitable for Ca(2+) coordination. Human, bovine, mouse, and rat CABP4 are highly homologous in their C-terminal regions, but are less conserved in their N-terminal regions. Northern blot analysis of several human tissues and rat retina and brain detected 1.6- and 3.8-kb transcripts only in retina. RT-PCR of mouse tissues detected expression only in retina. In situ hybridization and immunocytochemical analysis of monkey retina detected Cabp4 only in photoreceptors. Analysis of mouse retina found Cabp4 in rod spherules and cone pedicles, where it colocalized with synaptic vesicle proteins.
Haeseleer et al. (2004) found that CABP4 associated with the C-terminal domain of Ca(V)4.1 alpha-1 (CACNA1F; 300110) and shifted the activation of the channel to hyperpolarized voltages following cotransfection in human embryonic kidney cells.
Haeseleer et al. (2000) determined that the CABP4 gene contains 6 exons. Haeseleer et al. (2004) determined that the CABP4 gene spans about 4 kb.
By genomic sequence analysis, Haeseleer et al. (2004) mapped the CABP4 gene to chromosome 11q13.1. CABP4 lies in the opposite orientation and is separated from CABP2 (607314) by 4 genes and about 60 kb.
In 2 Swiss brothers who had decreased visual acuity without night blindness (CRSD; 610427) and who exhibited ERG findings consistent with CSNB2 (300071) but were negative for mutation in the CACNA1F gene (300110), Zeitz et al. (2006) identified homozygosity for a 2-bp deletion in the CABP4 gene (800delAG; 608965.0001). In addition, a 15-year-old boy from an unrelated family of Swiss ancestry, who did experience night blindness and whose ERG showed a pattern typical for CSNB in general, was compound heterozygous for the 2-bp deletion and a missense mutation in CABP4 (R124C; 608965.0002). He was also hemizygous for an N735T missense mutation in the CACNA1F gene, as was his unaffected brother, and his mother was a heterozygous carrier of the variant. Zeitz et al. (2006) concluded that the CACNA1F variant was not itself disease-causing but might modify the phenotype. Zeitz et al. (2006) showed that these mutations reduced CABP4 transcript levels to 30 to 40% of those in controls. On the basis of haplotype reconstruction and the Swiss ancestry of both families, a common origin of the 2-bp deletion in all 3 apparently unrelated individuals was considered possible.
In a Dutch brother and sister with decreased visual acuity and nystagmus due to CRSD, Littink et al. (2009) identified homozygosity for a nonsense mutation in the CABP4 gene (R216X; 608965.0003).
In 4 Bedouin sibs from a consanguineous family with decreased visual acuity from infancy and extinguished or markedly reduced ERG responses, Aldahmesh et al. (2010) identified homozygosity for a 1-bp insertion in CABP4 (81insA; 608965.0004).
In 7 patients from 3 consanguineous Saudi families with early-onset retinal dysfunction, Khan et al. (2013) identified homozygosity for the same 1-bp insertion (81insA) previously reported in 4 Bedouin sibs by Aldahmesh et al. (2010).
Haeseleer et al. (2004) developed Cabp4-null mice. The outer plexiform layer, which contains the photoreceptor synapses with secondary neurons, was thinner in mutant mice than in control mice. Cabp4 -/- retinas had ectopic synapses originating from rod bipolar and horizontal cells that extended into the outer nuclear layer. Rod bipolars were reduced in sensitivity about 100-fold, and electroretinograms indicated reduced cone and rod synaptic function. The phenotype of Cabp4-null mice was similar to that of patients with incomplete congenital stationary night blindness (300071). Similar morphologic and functional alterations were observed in the retinas of Cacna1f-mutant mice (Mansergh et al., 2005).
In 2 Swiss brothers with congenital nonprogressive cone-rod synaptic disorder (CRSD; 610427), Zeitz et al. (2006) identified homozygosity for a 2-bp deletion (800_801delAG) at the junction of intron 5 and exon 6 of the CABP4 gene. This deletion, which removes 1 of the AG dinucleotides, was predicted either to cause a translational frameshift or to affect transcript splicing by altering the acceptor site. A computational search led the authors to conclude that deletion of 1 of the 2 tandem AG nucleotides might not dramatically alter splicing efficiency, and RT-PCR experiments confirmed that the deletion did not cause aberrant splicing of CABP4. However, quantitative RT-PCR revealed a 60 to 70% reduction in patient CABP4 transcript levels compared to controls. The brothers' unaffected parents and 3 unaffected sibs were heterozygous for the mutation, which was not found in 216 control alleles. In a 15-year-old boy from an unrelated family of Swiss ancestry with a similar ocular phenotype, Zeitz et al. (2006) identified compound heterozygosity for the 2-bp deletion and a missense mutation in CABP4 (R124C; 608965.0002). SNP analysis revealed that the 2-bp deletion arose on the same haplotype in both families, suggesting a common origin.
In a 15-year-old boy of Swiss ancestry with congenital nonprogressive cone-rod synaptic disorder (CRSD; 610427), Zeitz et al. (2006) identified compound heterozygosity for a 2-bp deletion in the CABP4 gene (608965.0001) and a c.370C-T transition in exon 2, predicted to introduce a binding site for SRp55 (SRSF6; 601944) and influence splicing, or to result in an arg124-to-cys (R124C) substitution. His unaffected parents were each heterozygous for 1 of the mutations, which were not found in 216 or 228 control alleles, respectively. The patient exhibited CABP4 transcript levels 30 to 40% of those found in controls.
In a Dutch brother and sister with congenital nonprogressive cone-rod synaptic disorder (CRSD; 610427), Littink et al. (2009) identified homozygosity for a c.646C-T transition (c.646C-T, NM_14500) in exon 4 of the CABP4 gene, resulting in an arg216-to-ter (R216X) substitution that deletes the functional EF-hands 3 and 4. The unaffected parents were heterozygous for the mutation, which was not found in 300 ethnically matched alleles.
In a female Dutch patient with low visual acuity, hyperopia, severe nonspecific color vision defects, and photophobia, Bijveld et al. (2013) identified homozygosity for the R216X mutation in CABP4.
In 4 Bedouin sibs with congenital nonprogressive cone-rod synaptic disorder (CRSD; 610427), Aldahmesh et al. (2010) identified homozygosity for a 1-bp insertion (c.81_82insA, NM_145200.2), causing a frameshift predicted to add 44 novel amino acids before premature termination (Pro28ThrfsTer44). Their unaffected first-cousin parents and 1 unaffected brother were heterozygous for the insertion. The sibs had had severely decreased visual acuity from infancy, with extinguished or markedly reduced responses on electroretinography.
In 7 patients from 3 consanguineous Saudi families with early-onset retinal dysfunction, Khan et al. (2013) identified homozygosity for this 1-bp insertion.
Aldahmesh, M. A., Al-Owain, M., Alqahtani, F., Hazzaa, S., Alkuraya, F. S. A null mutation in CABP4 causes Leber's congenital amaurosis-like phenotype. Molec. Vision 16: 207-212, 2010. [PubMed: 20157620]
Bijveld, M. M. C., Florijn, R. J., Bergen, A. A. B., van den Born, L. I., Kamermans, M., Prick, L., Riemslag, F. C. C., van Schooneveld, M. J., Kappers, A. M. L., van Genderen, M. M. Genotype and phenotype of 101 Dutch patients with congenital stationary night blindness. Ophthalmology 120: :2072-2081, 2013. [PubMed: 23714322] [Full Text: https://doi.org/10.1016/j.ophtha.2013.03.002]
Haeseleer, F., Imanishi, Y., Maeda, T., Possin, D. E., Maeda, A., Lee, A., Rieke, F., Palczewski, K. Essential role of Ca(2+)-binding protein 4, a Ca(V)1.4 channel regulator, in photoreceptor synaptic function. Nature Neurosci. 7: 1079-1087, 2004. [PubMed: 15452577] [Full Text: https://doi.org/10.1038/nn1320]
Haeseleer, F., Sokal, I., Verlinde, C. L. M. J., Erdjument-Bromage, H., Tempst, P., Pronin, A. N., Benovic, J. L., Fariss, R. N., Palczewski, K. Five members of a novel Ca(2+)-binding protein (CABP) subfamily with similarity to calmodulin. J. Biol. Chem. 275: 1247-1260, 2000. [PubMed: 10625670] [Full Text: https://doi.org/10.1074/jbc.275.2.1247]
Khan, A. O., Alrashed, M., Alkuraya, F. S. Clinical characterisation of the CABP4-related retinal phenotype. Brit. J. Ophthal. 97: 262-265, 2013. [PubMed: 23099293] [Full Text: https://doi.org/10.1136/bjophthalmol-2012-302186]
Littink, K. W., van Genderen, M. M., Collin, R. W. J., Roosing, S., de Brouwer, A. P. M., Riemslag, F. C. C., Venselaar, H., Thiadens, A. A. H. J., Hoyng, C. B., Rohrschneider, K., den Hollander, A. I., Cremers, F. P. M., van den Born, L. I. A novel homozygous nonsense mutation in CABP4 causes congenital cone-rod synaptic disorder. Invest. Ophthal. Vis. Sci. 50: 2344-2350, 2009. [PubMed: 19074807] [Full Text: https://doi.org/10.1167/iovs.08-2553]
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]
Zeitz, C., Kloeckener-Gruissem, B., Forster, U., Kohl, S., Magyar, I., Wissinger, B., Matyas, G., Borruat, F.-X., Schorderet, D. F., Zrenner, E., Munier, F. L., Berger, W. Mutations in CABP4, the gene encoding the Ca(2+)-binding protein 4, cause autosomal recessive night blindness. Am. J. Hum. Genet. 79: 657-667, 2006. [PubMed: 16960802] [Full Text: https://doi.org/10.1086/508067]