HGNC Approved Gene Symbol: CRYBA2
Cytogenetic location: 2q35 Genomic coordinates (GRCh38): 2:218,990,190-218,993,422 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q35 | ?Cataract 42 | 115900 | Autosomal dominant | 3 |
The alpha-, beta-, and gamma-crystallins are major constituents of the lens and are important for its transparency and light reflection properties. Hereditary cataracts in humans and mice are often the result of mutations in the genes producing these proteins. The beta-crystallin family consists of 4 acidic (A) and 3 basic (B) members. One of these is beta-A2 (CRYBA2) (summary by Hulsebos et al., 1995).
Beta-A2 crystallin was identified in human by Hulsebos et al. (1995), who designed primers based on the bovine sequence to amplify a portion of the human gene.
By HPLC separation of beta-crystallins isolated from human lenses, followed by peptide digestion and mass spectrometry of a protein that coeluted with crystallin beta-A1/A3 (CRYBA1; 123610), Lapko et al. (2003) identified crystallin beta-A2. The deduced 196-amino acid protein had an apparent molecular mass of about 22 kD by HPLC and electrospray ionization (ESI) mass spectrometry. The ESI mass spectrum showed 2 additional, slightly larger peaks, likely resulting from secondary modification. Crystallin beta-A2 accounted for approximately 1.5% of lens crystallins in both 11-day-old and adult lenses.
Reis et al. (2013) studied expression of the CRYBA2 orthologs cryba2a and cryba2b in zebrafish embryos and detected a strong and specific presence of both transcripts at early stages of lens development: at 22 hours postfertilization (hpf), cryba2 was expressed in the posterior region of the lens mass that delaminates from the head ectoderm (corresponding to human lens vesicle formation/separation), and at 48 hpf, robust expression was observed in the developing lens fiber cells.
Using a portion of the human CRYBA2 gene to screen a panel of human-rodent hybrid cell DNAs, Hulsebos et al. (1995) mapped the gene to chromosome 2q34-q36. Interspecific backcross mapping was used to map the mouse gene to the central portion of chromosome 1, a region with homology of synteny to the distal half of the long arm of human chromosome 2.
In 7 affected members of a large 4-generation Uruguayan family segregating autosomal dominant cataract (CTRCT42; 115900) with incomplete penetrance, Reis et al. (2013) analyzed 8 crystallin genes not previously linked to cataract in humans and identified a heterozygous mutation in the CRYBA2 gene (V50M; 600836.0001).
Puk et al. (2011) identified the first mutation in the Cryba2 gene in the mouse. The S46P mutation was found in a breeding colony of mice characterized by small lenses and no changes in corneal thickness, anterior chamber depth, or aqueous humor volume. In homozygous mice, the mutation caused cortical cataracts and led to a total cataract at the age of 25 weeks. Puk et al. (2011) suggested that the human CRYBA2 gene should be considered a strong candidate gene for age-related cataracts, and that the slightly smaller size of the lens might be recognized as an early biomarker for age-related cataract.
In 7 affected members of a large 4-generation Uruguayan family segregating autosomal dominant cataract (CTRCT42; 115900) with incomplete penetrance, Reis et al. (2013) identified heterozygosity for a c.148G-A transition in the CRYBA2 gene, resulting in a val50-to-met (V50M) substitution at a highly conserved residue within the beta-strand 4 of the Greek key motif I. The mutation was also detected in 3 unaffected obligate carriers but was not found in 2 unaffected spouses, in an unaffected child, or in 12,948 control chromosomes from the Exome Variant Server database.
Hulsebos, T. J. M., Cerosaletti, K. M., Fournier, R. E. K., Sinke, R. J., Rocchi, M., Marzella, R., Jenkins, N. A., Gilbert, D. J., Copeland, N. G. Identification of the human beta-A2 crystallin gene (CRYBA2): localization of the gene on human chromosome 2 and of the homologous gene on mouse chromosome 1. Genomics 28: 543-548, 1995. [PubMed: 7490092] [Full Text: https://doi.org/10.1006/geno.1995.1186]
Lapko, V. N., Smith, D. L., Smith, J. B. Expression of beta-A2-crystallin in human lenses. (Letter) Exp. Eye Res. 77: 383-385, 2003. [PubMed: 12907171] [Full Text: https://doi.org/10.1016/s0014-4835(03)00156-8]
Puk, O., Ahmad, N., Wagner, S., de Angelis, M. H., Graw, J. First mutation in the beta-A2-crystallin encoding gene is associated with small lenses and age-related cataracts. Invest. Ophthal. Vis. Sci. 52: 2571-2576, 2011. [PubMed: 21212184] [Full Text: https://doi.org/10.1167/iovs.10-6443]
Reis, L. M., Tyler, R. C., Muheisen, S., Raggio, V., Salviati, L., Han, D. P., Costakos, D., Yonath, H., Hall, S., Power, P., Semina, E. V. Whole exome sequencing in dominant cataract identifies a new causative factor, CRYBA2, and a variety of novel alleles in known genes. Hum. Genet. 132: 761-770, 2013. [PubMed: 23508780] [Full Text: https://doi.org/10.1007/s00439-013-1289-0]