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HGNC Approved Gene Symbol: CRYGA
Cytogenetic location: 2q33.3 Genomic coordinates (GRCh38): 2:208,160,740-208,163,589 (from NCBI)
The transparency and high refractive index of the normal eye lens necessary for focusing visible light on the retina is achieved by a regular arrangement of the lens fiber cells during growth of the lenticular body and by the high concentration and the supramolecular organization of the alpha- (see 123580), beta- (see 123610), and gamma-crystallins, the major protein components of the vertebrate eye lens (summary by Moormann et al., 1982).
The gamma-crystallins, which constitute about 40% of the total protein of the rodent lens, are monomeric; at least 5 closely related gamma crystallins have been identified in bovine and rat lens. In the rat, 2 distinct gamma-crystallin genes showed extensive sequence homology suggesting derivation from a common primordial gene (Moormann et al., 1982).
Siezen et al. (1987) isolated the individual gamma-crystallins expressed in young human lenses and identified with which of the 6 known human gamma-crystallin genes they each correspond. The authors found that at least 90% of the gamma-crystallins synthesized in the young human lens are the products of genes gamma-G3 and gamma-G4. They demonstrated that gamma-G4-crystallin undergoes a temperature-dependent phase separation, whereas gamma-G3-crystallin failed to show this phenomenon even at lower temperatures and higher concentrations. Gamma-G2 and gamma-G1 in the human lens are pseudogenes. If they were expressed, it is likely that they would produce proteins with high phase separation temperatures. Thus, these 2 genes may have been 'turned off' during human evolution because their translation products exhibited a disadvantageous physical property. Siezen et al. (1987) speculated that some inherited human cataracts may involve a genetic alteration in which one or both of the pseudogenes are expressed.
By study of somatic hybrid cells, gamma-crystallin genes were assigned to 2p12-qter by den Dunnen et al. (1985).
Tsui et al. (1985) assigned at least 6 of the human gamma-crystallin genes to chromosome 2; in studies of cells with chromosome 2 rearrangements and by in situ hybridization, they showed that all are clustered in the region 2q33-q35.
Shiloh et al. (1986) localized the gamma-crystallin genes to 2q33-q36, most probably 2q34-q35, by Southern analysis of DNA from somatic cell hybrids and by in situ hybridization.
Skow et al. (1988) used RFLPs in the gamma-crystallin sequences to localize the genes to the proximal region of chromosome 1 of the mouse. Zneimer and Womack (1988) mapped gamma-crystallin genes to mouse chromosome 1 by in situ hybridization. Vidal et al. (1992) identified and mapped 6 microdissected genomic DNA probes to the proximal region of mouse chromosome 1, and by RFLP analysis mapped the probes with respect to 12 marker loci usually assigned to this portion of mouse chromosome 1 in a panel of Mus spretus x C57BL/6J interspecific backcross mice. The Len-2 (lens crystalline protein) gene mapped in the following position: cen--Col3a1 (120180)--8.8 cM--Len-2--4.2 cM--Fn-1 (135600)--tel. Len-2 presumably corresponds to CRYG2 (123670).
The gamma-crystallin gene cluster located in region 2q33-q35 consists of 6 genes: gamma-A through gamma-F and a quarter gene fragment, gamma-G (review by Brakenhoff et al., 1994). Gamma-E (CRYGEP1) and gamma-F (CRYGFP1) are pseudogenes by virtue of an in-frame stop codon; the gamma-F gene lacks a promoter as well. Only 2 of the genes, gamma-C (CRYGC; 123680) and gamma-D (CRYGD; 123690), encode abundant proteins. The gamma-B (CRYGB; 123670), gamma-C and psi-gamma-E genes are physically linked on a 40-kb DNA segment; the exact location within the cluster of the gamma-A and the psi-gamma-F genes, as well as the psi-gamma-G gene fragment, remains to be determined.
Hejtmancik (1998) presented a table of 9 loci, including this one, which had been implicated in nonsyndromal cataract and mapped to specific chromosomal sites.
Pseudogenes
CRYG5, also known as gamma-E-crystallin (CRYGEP1), is a pseudogene. It is located directly downstream from the CRYG4 gene (CRYGD; 123690). The predicted protein product of the CRYG5 pseudogene is a 6-kD N-terminal gamma-crystallin fragment. Brakenhoff et al. (1994) found that in hereditary Coppock-like cataract (604307), the CRYG4 gene was not abnormal, whereas the CRYG5 pseudogene contained a cluster of sequence changes within and around its TATA box, affecting its expression as described above and possibly resulting in the cataract phenotype. Heon et al. (1999) identified a mutation in the CRYGC gene in the original Coppock-like cataract family and suggested that the previously reported sequence changes in the CRYG5 promoter region are not causally related to a cataract phenotype.
CRYG6, or gamma-F-crystallin (CRYGFP1), is a promoterless pseudogene located within the gamma-crystallin gene cluster (Shiloh et al., 1986).
Hejtmancik (1998) tabulated 8 animal models of cataract in which molecular defects had been identified.
Klopp et al. (1998) identified the molecular defect in gamma-crystallin genes in 3 different murine cataract mutants. One involved the Cryga gene, 1 the Crygb gene, and 1 the Cryge gene. The 3 mutations were predicted to alter protein folding of the gamma crystallins and result in lens cataract, but the phenotype for each was quite distinctive.
The murine Elo (eye lens obsolescence) mutation confers a dominant phenotype characterized by malformation of the eye lens. The mutation maps to mouse chromosome 1 in close proximity to the gamma-E-crystallin gene, which is a 3-prime-most member of the gamma-crystallin gene cluster. Cartier et al. (1992) analyzed the sequence of this gene from the Elo mouse and identified a single nucleotide deletion that destroys the fourth and last 'Greek key' motif of the protein. This mutation is tightly associated with the phenotype, as no recombination was detected in 274 meioses. In addition, the mutant mRNA is present in the affected lens, providing further support for the authors' hypothesis that the deletion is responsible for the dominant Elo phenotype.
Brakenhoff, R. H., Henskens, H. A. M., van Rossum, M. W. P. C., Lubsen, N. H., Schoenmakers, J. G. G. Activation of the gamma-E-crystallin pseudogene in the human hereditary Coppock-like cataract. Hum. Molec. Genet. 3: 279-283, 1994. [PubMed: 8004095] [Full Text: https://doi.org/10.1093/hmg/3.2.279]
Cartier, M., Breitman, M. L., Tsui, L.-C. A frameshift mutation in the gamma-E-crystallin gene of the Elo mouse. Nature Genet. 2: 42-45, 1992. Note: Erratum: Nature Genet. 2: 343 only, 1992. [PubMed: 1303247] [Full Text: https://doi.org/10.1038/ng0992-42]
den Dunnen, J. T., Jongbloed, R. J. E., Geurts van Kessel, A. H. M., Schoenmakers, J. G. G. Human lens gamma-crystallin sequences are located in the p12-qter region of chromosome 2. Hum. Genet. 70: 217-221, 1985. [PubMed: 2991114] [Full Text: https://doi.org/10.1007/BF00273445]
Hejtmancik, J. F. The genetics of cataract: our vision becomes clearer. (Editorial) Am. J. Hum. Genet. 62: 520-525, 1998. [PubMed: 9497271] [Full Text: https://doi.org/10.1086/301774]
Heon, E., Priston, M., Schorderet, D. F., Billingsley, G. D., Girard, P. O., Lubsen, N., Munier, F. L. The gamma-crystallins and human cataracts: a puzzle made clearer. Am. J. Hum. Genet. 65: 1261-1267, 1999. Note: Erratum: Am. J. Hum. Genet. 66: 753 only, 2000. [PubMed: 10521291] [Full Text: https://doi.org/10.1086/302619]
Klopp, N., Favor, J., Loster, J., Lutz, R. B., Neuhauser-Klaus, A., Prescott, A., Pretsch, W., Quinlan, R. A., Sandilands, A., Vrensen, G. F. J. M., Graw, J. Three murine cataract mutants (Cat2) are defective in different gamma-crystallin genes. Genomics 52: 152-158, 1998. [PubMed: 9782080] [Full Text: https://doi.org/10.1006/geno.1998.5417]
Moormann, R. J. M., den Dunnen, J. T., Bloemendal, H., Schoenmakers, J. G. G. Extensive intragenic sequence homology in two distinct rat lens gamma-crystallin cDNAs suggests duplications of a primordial gene. Proc. Nat. Acad. Sci. 79: 6876-6880, 1982. [PubMed: 6294661] [Full Text: https://doi.org/10.1073/pnas.79.22.6876]
Piatigorsky, J. Lens crystallins and their gene families. Cell 38: 620-621, 1984. [PubMed: 6548413] [Full Text: https://doi.org/10.1016/0092-8674(84)90254-x]
Shiloh, Y., Donlon, T., Bruns, G., Breitman, M. L., Tsui, L.-C. Assignment of the human gamma-crystallin gene cluster (CRYG) to the long arm of chromosome 2, region q33-36. Hum. Genet. 73: 17-19, 1986. [PubMed: 3011643] [Full Text: https://doi.org/10.1007/BF00292656]
Siezen, R. J., Thomson, J. A., Kaplan, E. D., Benedek, G. B. Human lens gamma-crystallins: isolation, identification, and characterization of the expressed gene products. Proc. Nat. Acad. Sci. 84: 6088-6092, 1987. [PubMed: 3476929] [Full Text: https://doi.org/10.1073/pnas.84.17.6088]
Skow, L. C., Donner, M. E., Huang, S.-M., Gardner, J. M., Taylor, B. A., Beamer, W. G., Lalley, P. A. Mapping of mouse gamma crystallin genes on chromosome 1. Biochem. Genet. 26: 557-570, 1988. [PubMed: 3242494] [Full Text: https://doi.org/10.1007/BF02399601]
Tsui, L.-C., Breitman, M. L., Meakin, S. O., Willard, H. F., Shiloh, Y., Donlon, T., Bruns, G. Localization of the human gamma-crystallin gene cluster (CRYG) to the long arm of chromosome 2, region q33-q35. (Abstract) Cytogenet. Cell Genet. 40: 763-764, 1985.
Vidal, S. M., Epstein, D. J., Malo, D., Weith, A., Vekemans, M., Gros, P. Identification and mapping of six microdissected genomic DNA probes to the proximal region of mouse chromosome 1. Genomics 14: 32-37, 1992. [PubMed: 1358796] [Full Text: https://doi.org/10.1016/s0888-7543(05)80279-4]
Willard, H. F., Meakin, S. O., Tsui, L.-C., Breitman, M. L. Assignment of human gamma crystallin multigene family to chromosome 2. Somat. Cell Molec. Genet. 11: 511-516, 1985. [PubMed: 2994242] [Full Text: https://doi.org/10.1007/BF01534846]
Wistow, G., Piatigorsky, J. Recruitment of enzymes as lens structural proteins. Science 236: 1554-1556, 1987. [PubMed: 3589669] [Full Text: https://doi.org/10.1126/science.3589669]
Zneimer, S. M., Womack, J. E. Regional localization of the fibronectin and gamma crystallin genes to mouse chromosome 1 by in situ hybridization. Cytogenet. Cell Genet. 48: 238-241, 1988. [PubMed: 3248380] [Full Text: https://doi.org/10.1159/000132636]