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Other entities represented in this entry:
HGNC Approved Gene Symbol: CRYBB2
Cytogenetic location: 22q11.23 Genomic coordinates (GRCh38): 22:25,211,661-25,231,869 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q11.23 | Cataract 3, multiple types | 601547 | Autosomal dominant | 3 |
Chambers and Russell (1993) reported the sequence of full-length cDNA clones for human CRYB2. The full-length cDNA comprises 1,721 bp and codes for a 23-kD protein of 205 amino acids.
Sun et al. (2013) stated that Crybb2 is expressed in different regions of the mouse brain, including hippocampus, olfactory bulb, cerebellum, and cerebral cortex, in addition to ocular lens.
The alpha-crystallin subunits alpha-A (123580) and alpha-B (123590) each can form an oligomer by itself or with the other. Fu and Liang (2002) used a 2-hybrid system to study heterogeneous interactions among lens crystallins of different classes. They found interactions between alpha-A- (or alpha-B-) and beta-B2- or gamma-C-(123680) crystallins, but the intensity of interaction was one-third that of alpha-A-alpha-B interactions. HSP27 (602195), a member of the small heat-shock protein family, showed similar interaction properties with alpha-B-crystallin. Experiments with N- and C-terminal domain-truncated mutants demonstrated that both N- and C-terminal domains were important in alpha-A-crystallin self-interaction, but that only the C-terminal domain was important in alpha-B-crystallin self-interaction.
Using a bovine cDNA clone as a probe, Sparkes et al. (1987) assigned the CRYB2 gene to 22q11.2-q12.2 by somatic cell hybridization and in situ hybridization.
Bijlsma et al. (1993) found that all crystallin genes map to a very small region on chromosome 22 that is physically separate from the NF2 gene (607379) by at least 160 kb of DNA. They concluded, therefore, that the cataracts that occur in many NF2 patients are probably not the primary consequence of rearrangements on chromosome 22 that involve both the NF2 gene and a nearby beta-crystallin gene.
Hulsebos et al. (1995) demonstrated by interspecific backcross analysis that the homologs of the CRYBB2, CRYBB3, and CRYBA4 (123631) genes are located in the central region of mouse chromosome 5. Kerscher et al. (1995) confirmed the assignment to mouse chromosome 5.
Pseudogenes
Aarts et al. (1987) found 2 copies of the CRYB2 gene in the human genome. They showed that 1 copy is linked to CRYB3 (123630), separated by 20 kb and oriented head-to-tail with respect to transcription. Hulsebos et al. (1991) likewise identified a second CRYB2 gene, not linked to the CRYB2/CRYB3 cluster but localized in the same region, 22q11.2-q12. Brakenhoff et al. (1992) demonstrated that the second CRYB2 gene is a pseudogene (CRYBB2P1). The pseudogene contains a 1-triplet deletion and a mutated splice acceptor site. Furthermore, no transcripts from the second gene could be detected in the human lens.
Litt et al. (1997) demonstrated that affected individuals in a family with congenital cerulean cataract (CTRCT3; 601547) had a chain-terminating mutation in the CRYBB2 gene (Q155X; 123620.0001).
Gill et al. (2000) identified the Q155X mutation in a 4-generation Swiss family with autosomal dominant Coppock-like cataract (601547).
In affected members of a 5-generation Indian family that exhibited sutural cataract with punctate and cerulean opacities (601547), Vanita et al. (2001) identified the Q155X mutation and also found a second variant in the CRYBB2 gene, a silent 483C-T transition (123620.0002) that cosegregated with the phenotype. Vanita et al. (2001) suggested that these alterations represented a gene conversion event between CRYBB2 and its nearby pseudogene, CRYBB2P1.
In a 4-generation Chilean family (ADC53) segregating autosomal dominant cataract with variable location, morphology, color, and density of the opacities among affected family members, Bateman et al. (2007) identified the Q155X mutation and the previously reported 483C-T silent polymorphism. No mutations were found in the CRYBB1 gene. In the affected individuals examined, morphology and density were the same in each eye. Cataracts included pulverulent embryonal cataract, pulverulent cortical opacities, dense posterior star-shaped subcapsular cataract with pulverulent opacities in the cortical and embryonal regions, and dense embryonal cataracts.
To investigate the role of Crybb2 in brain, Sun et al. (2013) studied homozygous male O377 mice. The O377 mutation is an A-to-T substitution that forms an alternative splice site, resulting in a 57-bp insertion in Crybb2 mRNA and an additional loop near the C terminus of Crybb2 protein. O377 mutant mice have dominant progressive cataracts. Homozygous male O377 mice showed elevated social investigation, reduced prepulse inhibition, and reduced acoustic startle response. O377 mutants have reduced hippocampal size due to elevated apoptosis. They also had reduced density of parvalbumin (PVALB; 168890)-positive interneurons in hippocampus, but not in prefrontal cortex; hippocampal cell loss did not appear to be due to apoptosis. O377 hippocampus showed elevated free intracellular Ca(2+) content and calpain-3 (114240) expression, and dentate gyrus showed increased input-to-output neuronal activity. Expression of NMDA receptor subunits (see GRIN1, 138249) was downregulated in mutant hippocampus. Sun et al. (2013) concluded that Crybb2 has a role in mouse hippocampal function.
In a family segregating congenital cerulean cataract (CTRCT3; 601547) mapped to chromosome 22 by Kramer et al. (1996), Litt et al. (1997) found that affected individuals had a heterozygous chain-terminating mutation in CRYBB2. Of the 3 crystallin genes in the critical region, only CRYBB2 is strongly expressed in the adult lens. Hence, they chose this gene as the initial target for mutation screening. Detection of the mutation was assisted by the availability of an affected homozygote who was found to have a G-to-A transition in the antisense strand at the position of the first base of the codon normally encoding glutamine residue 155. This mutation created a stop codon that truncated the beta-B2-crystallin polypeptide by 51 residues (Q155X). The mutation also created a BfaI site, allowing convenient testing for its presence in family members. This family was originally reported by Bodker et al. (1990), who found that visual acuity was normal to mildly decreased until adult life except in 1 female, the product of affected first cousins, who was born with bilateral microphthalmia. They speculated that this represented the homozygous state.
Gill et al. (2000) studied a 4-generation Swiss family with autosomal dominant Coppock-like cataract (604307) and mapped the phenotype to the 22q11.2-q13.1 region by linkage analysis. Direct cycle sequencing of exons 1 through 6 of the CRYBB2 gene identified a C-to-T transition at nucleotide 14 of exon 6, which results in an in-frame premature stop codon that truncates the beta-B2 crystallin polypeptide by 51 residues. Penetrance appeared to be complete. The study of Gill et al. (2000) demonstrated that the Coppock-like cataract phenotype is genetically heterogeneous; causative mutation had been found in the CRYGC gene (123680.0001).
In affected members of a 5-generation Indian family that exhibited sutural cataract with punctate and cerulean opacities (601547), Vanita et al. (2001) identified the Q155X mutation and also found a second variant in the CRYBB2 gene, a silent 483C-T transition in exon 6 (123620.0002) that was in complete cosegregation with the phenotype. Alignment of the crystallin gene sequences showed that the Q155X and 483C-T alterations defined a fragment of at least 9 bp in the CRYBB2 mutant that were identical to the 'normal' sequence in the CRYBB2P1 pseudogene, and the fragment was flanked upstream by 28 bp and downstream by 67 bp where the gene and pseudogene are identical. Vanita et al. (2001) concluded that both variants had arisen by a gene conversion event between the CRYBB2 and its nearby pseudogene, CRYBB2P1.
In affected members of a 4-generation Chilean family (ADC53) segregating autosomal dominant cataract with variable location, morphology, color, and density of the opacities (601547) among affected family members, Bateman et al. (2007) identified the Q155X mutation and the 483C-T silent polymorphism. Because the Indian family reported by Vanita et al. (2001) and this Chilean family had the same exon 6 CRYBB2 sequence but different haplotypes, Bateman et al. (2007) postulated that the alterations in each family were caused by independent gene conversion events.
For discussion of the 483C-T transition in the CRYBB2 gene that was found in compound heterozygous state in patients with autosomal dominant cataract by Vanita et al. (2001) and Bateman et al. (2007), see 123620.0001.
Aarts, H. J. M., Den Dunnen, J. T., Lubsen, N. H., Schoenmakers, J. G. G. Linkage between the beta-B2 and beta-B3 crystallin genes in man and rat: a remnant of an ancient beta-crystallin gene cluster. Gene 59: 127-135, 1987. [PubMed: 3436525] [Full Text: https://doi.org/10.1016/0378-1119(87)90273-3]
Bateman, J. B., von-Bischhoffshaunsen, F. R. B., Richter, L., Flodman, P., Burch, D., Spence, M. A. Gene conversion mutation in crystallin, beta-B2 (CRYBB2) in a Chilean family with autosomal dominant cataract. Ophthalmology 114: 425-432, 2007. [PubMed: 17234267] [Full Text: https://doi.org/10.1016/j.ophtha.2006.09.013]
Bijlsma, E. K., Delattre, O., Juyn, J. A., Melot, T., Westerveld, A., Dumanski, J. P., Thomas, G., Hulsebos, T. J. M. Regional fine mapping of the beta-crystallin genes on chromosome 22 excludes these genes as physically linked markers for neurofibromatosis type 2. Genes Chromosomes Cancer 8: 112-118, 1993. [PubMed: 7504514] [Full Text: https://doi.org/10.1002/gcc.2870080208]
Bodker, F. S., Lavery, M. A., Mitchell, T. N., Lovrien, E. W., Maumenee, I. H. Microphthalmos in the presumed homozygous offspring of a first cousin marriage and linkage analysis of a locus in a family with autosomal dominant cerulean congenital cataracts. Am. J. Med. Genet. 37: 54-59, 1990. [PubMed: 2240043] [Full Text: https://doi.org/10.1002/ajmg.1320370113]
Brakenhoff, R. H., Aarts, H. J. M., Schuren, F., Lubsen, N. H., Schoenmakers, J. G. G. The second human beta-B(2)-crystallin gene is a pseudogene. Exp. Eye Res. 54: 803-806, 1992. [PubMed: 1623966] [Full Text: https://doi.org/10.1016/0014-4835(92)90036-r]
Chambers, C., Russell, P. Sequence of the human lens beta-B2-crystallin-encoding cDNA. Gene 133: 295-299, 1993. [PubMed: 8224918] [Full Text: https://doi.org/10.1016/0378-1119(93)90655-m]
Fu, L., Liang, J. J.-N. Detection of protein-protein interactions among lens crystallins in a mammalian two-hybrid system assay. J. Biol. Chem. 277: 4255-4260, 2002. [PubMed: 11700327] [Full Text: https://doi.org/10.1074/jbc.M110027200]
Gill, D., Klose, R., Munier, F. L., McFadden, M., Priston, M., Billingsley, G., Ducrey, N., Schorderet, D. F., Heon, E. Genetic heterogeneity of the Coppock-like cataract: a mutation in CRYBB2 on chromosome 22q11.2. Invest. Ophthal. Vis. Sci. 41: 159-165, 2000. [PubMed: 10634616]
Hulsebos, T. J. M., Bijlsma, E. K., Geurts van Kessel, A. H. M., Brakenhoff, R. H., Westerveld, A. Direct assignment of the human beta-B2 and beta-B3 and crystallin genes to 22q11.2-q12: markers for neurofibromatosis 2. Cytogenet. Cell Genet. 56: 171-175, 1991. [PubMed: 2055112] [Full Text: https://doi.org/10.1159/000133080]
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]
Kerscher, S., Church, R. L., Boyd, Y., Lyon, M. F. Mapping of four mouse genes encoding eye lens-specific structural, gap junction, and integral membrane proteins: Cryba1 (crystallin-beta-A3/A1), Crybb2 (crystallin-beta-B2), Gja8 (MP70), and Lim2 (MP19). Genomics 29: 445-450, 1995. [PubMed: 8666393] [Full Text: https://doi.org/10.1006/geno.1995.9983]
Kramer, P., Yount, J., Mitchell, T., LaMorticella, D., Carrero-Valenzuela, R., Lovrien, E., Maumenee, I., Litt, M. A second gene for cerulean cataracts maps to the beta crystallin region on chromosome 22. Genomics 35: 539-542, 1996. [PubMed: 8812489] [Full Text: https://doi.org/10.1006/geno.1996.0395]
Litt, M., Carrero-Valenzuela, R., LaMorticella, D. M., Schultz, D. W., Mitchell, T. N., Kramer, P., Maumenee, I. H. Autosomal dominant cerulean cataract is associated with a chain termination mutation in the human beta-crystallin gene CRYBB2. Hum. Molec. Genet. 6: 665-668, 1997. [PubMed: 9158139] [Full Text: https://doi.org/10.1093/hmg/6.5.665]
Sparkes, R. S., Hogg, D., Gorin, M. B., Heinzmann, C., Zollman, S., Mohandas, T., Tsui, L.-C., Breitman, M., Horwitz, J. Assignment of a second human beta-crystallin gene (CRYB2) to 22q11.2-q12.2. (Abstract) Cytogenet. Cell Genet. 46: 696 only, 1987.
Sun, M., Holter, S. M., Stepan, J., Garrett, L., Genius, J., Kremmer, E., Hrabe de Angelis, M., Wurst, W., Lie, D. C., Bally-Cuif, L., Eder, M., Rujescu, D., Graw, J. Crybb2 coding for beta-B2 crystallin affects sensorimotor gating and hippocampal function. Mammalian Genome 24: 333-348, 2013. [PubMed: 24096375] [Full Text: https://doi.org/10.1007/s00335-013-9478-7]
Vanita, Sarhadi, V., Reis, A., Jung, M., Singh, D., Sperling, K., Singh, J. R., Burger, J. A unique form of autosomal dominant cataract explained by gene conversion between beta-crystallin B2 and its pseudogene. (Letter) J. Med. Genet. 38: 392-396, 2001. [PubMed: 11424921] [Full Text: https://doi.org/10.1136/jmg.38.6.392]