Alternative titles; symbols
HGNC Approved Gene Symbol: CRYGD
Cytogenetic location: 2q33.3 Genomic coordinates (GRCh38): 2:208,121,607-208,124,524 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q33.3 | Cataract 4, multiple types | 115700 | Autosomal dominant | 3 |
The crystallin proteins alpha (see 123660), beta (see 123610), and gamma account for more than 90% of total lens proteins. Different gamma-crystallin isoforms account for approximately one-third of total lens proteins (Bloemendal et al., 2004).
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.
In a 3-generation family with hereditary progressive cataracts (115700), Stephan et al. (1999) performed a genomewide search and obtained evidence for linkage at chromosome 2q33-q35, where the gamma-crystallin genes are located. They then looked for mutations in 2 gamma-crystallins that are expressed at high levels in the developing lens, mainly gamma-crystallins C (CRYGC; 123680) and D. They discovered a 1-base alteration that resulted in an arg14-to-cys substitution in gamma-D-crystallin (123690.0001). Protein modeling suggested that the effect of this mutation was a subtle one, affecting the surface properties of the crystallin molecule rather than its tertiary structure, consistent with the fact that the patients' lenses were normal at birth. This was the first gene defect shown to be responsible for a noncongenital progressive cataract.
In affected members of 3 families segregating aculeiform cataract, Heon et al. (1999) identified an arg58-to-his (R58H; 123690.0002) mutation in the CRYGD gene.
Kmoch et al. (2000) described a 5-year-old boy with a unique congenital cataract caused by deposition of numerous birefringent, pleochroic, and macroscopically prismatic crystals. Crystal analysis with subsequent Edman degradation and mass spectrometry identified the protein as gamma-D-crystallin lacking the N-terminal methionine. Sequencing of the CRYGD gene revealed heterozygosity for a C-to-A transversion at position 109 of the inferred cDNA, resulting in an arg36-to-ser substitution (R36S; 123690.0003). Although the crystal structure solution at 2.25 angstroms suggested that mutant R36S CRYGD has an unaltered protein fold, the observed crystal packing was possible only with the mutant protein molecules lacking the bulky arg36 side chain. This was the first described case of human cataract caused by crystallization of a protein in the lens.
Pande et al. (2001) used the term crystal cataract for those produced by mutation in the CRYGD gene with demonstrable crystallization of the mutant protein. They showed that the R58H (123690.0002) and R36S (123690.0003) mutant proteins are much less soluble than wildtype human gamma-D-crystallin protein. They also showed that these mutants are more prone to crystallization than the wildtype.
In a father and daughter with congenital lamellar cataract, Santhiya et al. (2002) identified a heterozygous missense mutation in the CRYGD gene (P23T; 123690.0004).
Nandrot et al. (2003) found P23T mutation in the CRYGD gene in a 4-generation Moroccan family with autosomal dominant congenital cerulean cataract. The authors showed that although x-ray crystallography modeling did not indicate any change of the backbone conformation, the mutation affected a region of the Greek key motif that was important for determining the topology of this protein fold. The data strongly suggested that the P23T mutation might alter the protein folding or decrease the thermodynamic stability or solubility of the protein.
A different mutation in the same codon (P23S; 123690.0007) was found by Plotnikova et al. (2007) to be the basis of the polymorphic congenital cataract reported by Rogaev et al. (1996) in a central Asian population of mixed white and Mongolian ancestry. The cataract-associated serine at site 23 corresponds to the ancestral state, since it was found in CRYGD of a lower primate (S. labiatus) and all surveyed nonprimate mammals. Crystallin proteins include 2 structurally similar domains, and substitutions in mammalian CRYGD protein at site 23 of the first domain were always associated with substitutions in the structurally reciprocal sites 109 and 136 of the second domain. These data suggested that the cataractogenic effect of serine at site 23 in the N-terminal domain of CRYGD may be compensated indirectly by amino acid changes in a distal domain. Plotnikova et al. (2007) also found that gene conversion was a factor in the evolution of the gamma-crystallin gene cluster throughout different mammalian clades. The high rate of gene conversion observed between the functional CRYGD gene and 2 primate gamma-crystallin pseudogenes (CRYGEP1 and CRYGFP1) coupled with a surprising finding of apparent negative selection in primate pseudogenes suggested a deleterious impact of recently derived pseudogenes involved in gene conversion in gamma-crystallin gene cluster.
McManus et al. (2007) found that CRYGD proteins with cataract-associated mutations of pro23 became less soluble as temperature increased, in dramatic contrast to the native protein. As a result, the mutant proteins had much lower solubilities at body temperature than the native protein.
In affected members of a Danish family segregating autosomal dominant congenital cataract and microcornea, Hansen et al. (2007) identified a heterozygous nonsense mutation in the CRYGD gene (Y134X; 123690.0008).
Nomenclature of Allelic Variants
Hansen et al. (2007) noted that until September 2007 the systematic name for all CRYGD mutations (except the E107A mutation) used the N-terminal processed CRYGD protein, which starts with glycine at position 2 in the translated mRNA. Based on the numbering system established by den Dunnen and Antonarakis (2001), however, the first methionine in the coding sequence should be assigned position 1, and the adenosine in the corresponding start ATG codon should be assigned position +1. This change in numbering is reflected in the relevant allelic variants included below.
In an ongoing program to identify new mouse models of hereditary eye disease, Smith et al. (2000) identified a semidominant form of cataract consisting of an irregular opacity of the nuclear lens thought to be similar to the human Coppock cataract (see 604307). The cataract phenotype mapped to mouse chromosome 1 in the vicinity of the gamma-crystallin gene cluster. Using a systemic candidate gene approach to analyze the entire Cryg cluster, a G-to-A transition was found in exon 3 of Crygd associated with the Lop12 mutation. The mutation led to the formation of an in-frame stop codon that produced a truncated protein of 156 amino acids. It was predicted that the defective gene product would alter protein folding of the gamma-crystallins and result in lens opacity.
Based on a new numbering system, this variant has been changed from ARG14CYS to ARG15CYS; see Hansen et al. (2007).
Stephan et al. (1999) found an arg14-to-cys (R14C) missense mutation in the CRYGD gene in affected members of a family with autosomal dominant punctate cataract of early postnatal onset and progressive nature (CTRCT4; 115700).
To gain understanding of how the R14C mutation leads to cataract, Pande et al. (2000) expressed recombinant wildtype human gamma-D crystallin and its R14C mutant form in Escherichia coli and showed that R14C forms disulfide-linked oligomers, which markedly raised the phase separation temperature of the protein solution. Eventually, R14C precipitated. In contrast, the wildtype version slowly formed only disulfide-linked dimers and no oligomers. These data strongly suggested that the observed cataract is triggered by the thiol-mediated aggregation of R14C. The aggregation profiles of the wildtype and mutant forms were consistent with homology modeling studies that revealed that R14C contains 2 exposed cysteine residues, whereas wildtype has only 1. Studies showed that the wildtype and R14C mutant forms had nearly identical secondary and tertiary structures and stabilities. Thus, contrary to commonly held views at the time, Pande et al. (2000) concluded that unfolding or destabilization of the protein was not necessary for cataractogenesis.
Based on a new numbering system, this variant has been changed from ARG58HIS to ARG59HIS; see Hansen et al. (2007).
Heon et al. (1999) found that a G-to-A transition at nucleotide 411 of the CRYGD gene, resulting in an arg58-to-his substitution, segregated with the phenotype of aculeiform cataract (CTRCT4; 115700) in 3 affected families.
Based on a new numbering system, this variant has been changed from ARG36SER to ARG37SER; see Hansen et al. (2007).
Kmoch et al. (2000) described a 5-year-old boy with a juvenile-onset crystalline cataract (CTRCT4; 115700) caused by deposition of numerous birefringent, pleochroic, and macroscopically prismatic crystals. Protein analysis identified the material as gamma-D-crystallin, and sequencing of the CRYGD gene revealed heterozygosity for a C-to-A transversion at position 109 of the inferred cDNA, resulting in an arg36-to-ser substitution.
Based on a new numbering system, this variant has been changed from PRO23THR to PRO24THR; see Hansen et al. (2007).
In a father and daughter with congenital lamellar cataracts (CTRCT4; 115700), Santhiya et al. (2002) identified heterozygosity for a 70C-A transversion in exon 2 of the CRYGD gene, predicted to lead to a pro23-to-thr (P23T) substitution.
In a 4-generation Moroccan family with congenital cerulean cataract, Nandrot et al. (2003) found that a C-to-A transversion in exon 2 of the CRYGD gene, resulting in a P23T substitution, segregated with the phenotype. The authors indicated the nucleotide change as 305C-A but noted that this was the same mutation as that found by Santhiya et al. (2002).
Based on a new numbering system, this variant has been changed from TRP156TER to TRP157TER; see Hansen et al. (2007).
In a father and daughter with congenital central nuclear cataract (CTRCT4; 115700), Santhiya et al. (2002) found heterozygosity for a nonsense mutation in the CRYGD gene: a 470G-A transition leading to a premature stop at codon 156 (W156X).
Based on a new numbering system, this variant has been changed from PRO23SER to PRO24SER; see Hansen et al. (2007).
In a large kindred of mixed white and Mongolian origin with polymorphic congenital cataract (CTRCT4; 115700), Plotnikova et al. (2007) found a 70C-T transition in exon 2 of the CRYGD gene that resulted in a pro23-to-ser (P23S) substitution.
In affected members of a Danish family segregating autosomal dominant congenital cataract and microcornea (CTRCT4; 115700), Hansen et al. (2007) identified heterozygosity for a c.418C-A transversion in exon 3 of the CRYGD gene, resulting in a tyr134-to-ter (Y134X) substitution. The mutation was not found in 170 ethnically matched controls.
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Plotnikova, O. V., Kondrashov, F. A., Vlasov, P. K., Grigorenko, A. P., Ginter, E. K., Rogaev, E. I. Conversion and compensatory evolution of the gamma-crystallin genes and identification of a cataractogenic mutation that reverses the sequence of the human CRYGD gene to an ancestral state. Am. J. Hum. Genet. 81: 32-43, 2007. [PubMed: 17564961] [Full Text: https://doi.org/10.1086/518616]
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