HGNC Approved Gene Symbol: CRYBA4
Cytogenetic location: 22q12.1 Genomic coordinates (GRCh38): 22:26,590,220-26,630,669 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q12.1 | Cataract 23 | 610425 | Autosomal dominant | 3 |
In the ocular lens, 80 to 90% of the soluble protein fraction comprises crystallins (van Rens et al., 1992). These proteins are thought to play an important role in the maintenance of the transparency and refractive index of the lens. In the mammalian lens, crystallins can be divided into alpha, beta, gamma, and delta families. These in turn can be subdivided into acidic and basic groups.
Lampi et al. (1997) cloned the CRYBA4 gene, which they designated beta-A4, by 3-prime and 5-prime RACE-PCR of lens RNA with primers based on the sequence of bovine CRYBA4. The beta-A4 gene encodes a predicted 196-amino acid protein; the initial methionine is posttranslationally removed. The conserved crystallin domain is 92 to 94% identical to rat and bovine beta-A4, and there is an unrelated 10-amino acid N-terminal region ('N-terminal extension'). The calculated 22,285-dalton molecular weight of the protein matched the value determined experimentally by mass spectrometry and by analysis of tryptic peptides. Lampi et al. (1997) found that there are 11 major soluble proteins in the young human lens, and that beta-A4 constitutes approximately 5% of the total.
See 123610 for background on the crystallin gene family.
The beta-A4 gene, an acidic crystallin, was mapped to 22q11.2-q13.1 by van Rens et al. (1992) by study of somatic cell hybrids including some containing translocated chromosome 22 segments. The CRYBB2 (123620) and the CRYBB3 (123630) genes have also been assigned to this region of chromosome 22. Hulsebos et al. (1995) demonstrated by interspecific backcross analysis that the homologs of the CRYBB2, CRYBB3, and CRYBA4 genes are located in the central region of mouse chromosome 5.
Billingsley et al. (2006) identified CRYBA4 as a 'cataract gene' in a large Indian family with an autosomal dominant cataract phenotype (CTRCT23; 610425). After a genomewide screen, linkage analysis identified a maximum lod score of 3.20 with marker D22S1167 of the beta-crystallin gene cluster on chromosome 22. To that time, CRYBA4 was the only gene in this cluster not associated with either human or murine cataracts. A heterozygous pathogenic mutation was identified in exon 4 (123631.0001). Considering that CRYBA4 associates with CRYBB2 (123620) and that the latter protein had been implicated in microphthalmia (see 123620.0001), mutation analysis of CRYBA4 was performed in 32 patients affected with microphthalmia. In 1 patient, Billingsley et al. (2006) identified a heterozygous leu69-to-pro mutation (123631.0002) that was predicted to disrupt the beta-sheet structure in CRYBA4.
In a Chinese father and son with congenital nuclear cataract and microcornea, Zhou et al. (2010) identified heterozygosity for a missense mutation (G64W; 123631.0003) in the CRYBA4 gene. The mutation segregated with the disease in the family.
In an Indian family (C132) with autosomal dominant lamellar (stationary and nonprogressive) cataract (610425) in 3 generations (Santhiya et al., 2004), Billingsley et al. (2006) demonstrated a heterozygous 317T-C transition in the CRYBA4 gene, resulting in a phe94-to-ser (F94S) substitution. Modeling suggested that this substitution would significantly reduce the intrinsic stability of the crystalline monomer, which would impair its ability to form the association modes critical for lens transparency. The age at onset/diagnosis in affected individuals in the 3 generations of this family was 4 years.
In a patient with cataract and bilateral microphthalmia (610425), Billingsley et al. (2006) identified heterozygosity for a 242T-C transition in exon 1 of the CRYBA4 gene that was predicted to result in a leu69-to-pro (L69P) substitution. As there was no family history of eye anomalies, the mutation was presumed to be de novo. The mutation was predicted to disrupt the beta-sheet structure of CRYBA4. Protein folding would consequently be impaired, most probably leading to a structure with reduced stability in the mutant.
In a Chinese father and son with congenital nuclear cataract and microcornea (CTRCT23; 610425), Zhou et al. (2010) identified heterozygosity for a c.225G-T transversion in exon 4 of the CRYBA4 gene, resulting in a gly64-to-trp (G64W) substitution. The mutation segregated with the disease in the family and was not found in 100 controls.
Billingsley, G., Santhiya, S. T., Paterson, A. D., Ogata, K., Wodak, S., Hosseini, S. M., Manisastry, S. M., Vijayallakshmi, P., Gopinath, P. M., Graw, J., Heon, E. CRYBA4, a novel human cataract gene, is also involved in microphthalmia. Am. J. Hum. Genet. 79: 702-709, 2006. [PubMed: 16960806] [Full Text: https://doi.org/10.1086/507712]
Hulsebos, T. J. M., Jenkins, N. A., Gilbert, D. J., Copeland, N. G. The beta crystallin genes on human chromosome 22 define a new region of homology with mouse chromosome 5. Genomics 25: 574-576, 1995. [PubMed: 7789995] [Full Text: https://doi.org/10.1016/0888-7543(95)80062-q]
Lampi, K. J., Ma, Z., Shih, M., Shearer, T. R., Smith, J. B., Smith, D. L., David, L. L. Sequence analysis of beta-A3, beta-B3, and beta-A4 crystallins completes the identification of the major proteins in young human lens. J. Biol. Chem. 272: 2268-2275, 1997. [PubMed: 8999933] [Full Text: https://doi.org/10.1074/jbc.272.4.2268]
Santhiya, S. T., Manisastry, S. M., Rawlley, D., Malathi, R., Anishetty, S., Gopinath, P. M., Vijayalakshmi, P., Namperumalsamy, P., Adamski, J., Graw, J. Mutation analysis of congenital cataracts in Indian families: identification of SNPs and a new causative allele in CRYBB2 gene. Invest. Ophthal. Vis. Sci. 45: 3599-3607, 2004. [PubMed: 15452067] [Full Text: https://doi.org/10.1167/iovs.04-0207]
van Rens, G. L. M., Geurts van Kessel, A. H. M., Bloemendal, H. Localization of the beta-A4-crystallin gene (CRYBA4) on human chromosome 22 in the region q11.2-q13.1. Cytogenet. Cell Genet. 61: 180-183, 1992. [PubMed: 1424806] [Full Text: https://doi.org/10.1159/000133403]
Zhou, G., Zhou, N., Hu, S., Zhao, L., Zhang, C., Qi, Y. A missense mutation in CRYBA4 associated with congenital cataract and microcornea. Molec. Vision 16: 1019-1024, 2010. [PubMed: 20577656]