Alternative titles; symbols
HGNC Approved Gene Symbol: CRYAA
Cytogenetic location: 21q22.3 Genomic coordinates (GRCh38): 21:43,169,008-43,172,810 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 21q22.3 | Cataract 9, multiple types | 604219 | Autosomal dominant; Autosomal recessive | 3 |
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-, beta- (see 123610), and gamma- (see 123660) crystallins, the major protein components of the vertebrate eye lens. Alpha-crystallin is composed of 2 primary gene products--alpha-A and alpha-B (123590) (summary by Moormann et al., 1982).
Quax-Jeuken et al. (1985) isolated bovine cDNA clones for the alpha-A and alpha-B subunits of crystallin.
Wistow (1985) stated that the CRYAA gene encodes a deduced 173-amino acid protein that is highly stable and evolutionarily conserved.
The CRYAA gene contains 3 exons (Wistow, 1985).
Jaworski and Piatigorsky (1989) discovered what they termed a pseudo-exon within the active single-copy human gene CRYA1. The pseudo-exon appeared to be in the early stages of extinction, perhaps the result of a failed experiment in the evolution of this specialized, lens-specific protein.
Using a cDNA clone for Southern analysis of DNA from human-rodent hybrids, Quax-Jeuken et al. (1985) assigned the gene for alpha-A crystallin (CRYA1) to chromosome 21. The authors suggested that juvenile cataract of Down syndrome may be related to trisomy of the CRYA1 gene. Hawkins et al. (1987) confirmed the assignment to chromosome 21 by probing of somatic cell hybrids and regionalized the gene to 21q22.3 by in situ hybridization and use of parent cells containing various parts of chromosome 21 in creation of the hybrid cells. By linkage studies with RFLPs, Petersen et al. (1991) confirmed the assignment to 21q22.3 and indicated the position of the CRYA1 gene in relation to 15 other genes and DNA markers in that band.
In the mouse, Skow and Donner (1985) found that alpha-A-crystallin (symbolized Acry-1) is linked to H2 on mouse chromosome 17 and is located between glyoxalase and H-2K, very close to the latter. Skow et al. (1985) demonstrated that the corresponding locus in the rat is linked to the major histocompatibility locus. Kaye et al. (1990) mapped the Crya-1 gene to mouse chromosome 17 by means of Southern analysis of mouse/Chinese hamster somatic cell hybrids and regionalized the assignment by in situ hybridization. They found that the gene is located in an area that shows conservation with human chromosome 6 rather than human chromosome 21. Thus, this may be an example of failure of homology of synteny.
The alpha-crystallins show homology with the small heat-shock proteins of Drosophila and soybean (Schoffl et al., 1984.) Heat-shock proteins (see 140550) form aggregates, as do alpha-crystallins, and are thought to protect cellular components under conditions of stress. Perhaps alpha-crystallin exerts a similar, as yet unknown stabilizing or protective effect in the lens fiber cells, which have to maintain a life-long resistance against deleterious influences. On the other hand, the superfamily of the beta- and gamma-crystallins shows structural similarities with a bacterial spore coat protein (Wistow, 1985).
The importance of alpha-crystallins in the maintenance of lens transparency was demonstrated by the work of Brady et al. (1997), who showed that mice homozygous for a targeted disruption of the alpha-A-crystallin gene developed cataracts and had cytoplasmic inclusion bodies containing the small heat-shock protein alpha-B-crystallin (123590). Litt et al. (1998) speculated that the cataracts in the family they studied may result from partial loss of the chaperone function of alpha-A-crystallin and/or from an increased tendency of the mutant polypeptide to aggregate because of its decreased positive charge and its gain of a sulfhydryl group. The presence of congenital microphthalmia in their family indicated that alpha-A-crystallin, similarly to gamma-E-crystallin in the Elo mutant mouse (Cartier et al., 1992), plays an important role in the normal embryologic development of the anterior segment of the eye. In the Elo mouse, a 1-bp deletion in the gamma-E-crystallin gene causes autosomal dominant cataract and microphthalmia (Cartier et al., 1992).
The alpha-crystallin subunits alpha-A and alpha-B can each 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.
Fu and Liang (2003) studied the effect of crystallin gene mutations that result in congenital cataract on protein-protein interactions. Interactions between mutated crystallins alpha-A (R116C; 123580.0001), alpha-B (R120G; 123590.0001), and gamma-C (T5P; 123680.0001) and the corresponding wildtype proteins, as well as with wildtype beta-B2-crystallin (123620) and HSP27, were analyzed in a mammalian cell 2-hybrid system. For mutated alpha-A-crystallin, interactions with wildtype beta-B2- and gamma-C-crystallin decreased and those with wildtype alpha-B-crystallin and HSP27 increased. For mutated alpha-B-crystallin, interactions with wildtype alpha-A- and alpha-B-crystallin decreased, but those with wildtype beta-B2- and gamma-C-crystallin increased slightly. For mutated gamma-C-crystallin, most of the interactions were decreased. The results indicated that crystallin mutations involved in congenital cataracts altered protein-protein interactions, which might contribute to decreased protein solubility and formation of cataract.
By proteomic analysis of complexes isolated from transgenic mouse lens expressing human alpha-A crystallin, Barton et al. (2009) identified Grifin (619187) as a binding partner of alpha-crystallin. Grifin also copurified with alpha-crystallin complexes from nontransgenic mouse lens.
Kourtis et al. (2012) demonstrated that preconditioning of C. elegans at a mildly elevated temperature strongly protected from heat-induced necrosis. The heat-shock transcription factor HSF1 (140580) and the small heat-shock protein HSP-16.1 mediate cytoprotection by preconditioning. HSP-16.1 localizes to the Golgi, where it functions with the calcium- and magnesium-transporting ATPase PMR1 (604384) to maintain calcium homeostasis under heat stroke. In mouse cortical neurons and striatal cells, Kourtis et al. (2012) found that overexpression of crystallin alpha-A, which colocalizes with the Golgi marker alpha-mannosidase-2 (154582) and the PMR1 ATPase, was sufficient to protect mammalian neurons from heat stroke-induced death, even in the absence of preconditioning. Heat stroke caused massive necrotic death and axonal degeneration in neurons expressing short hairpin RNAs against Pmr1, even after preconditioning.
Cataract 9, Multiple Types, With or Without Microcornea
In affected members of a family segregating autosomal dominant congenital cataracts mapping to chromosome 21q22.3 (CTRCT9; 604219), Litt et al. (1998) sequenced the coding region of the CRYAA gene and identified a missense mutation (R116C; 123580.0001) that segregated with the disorder.
Pras et al. (2000) identified homozygosity for a nonsense mutation in the CRYAA gene (123580.0002) in 3 sibs from an inbred Jewish Persian family with autosomal recessive congenital cataract. The patients underwent cataract extraction in the first 3 months of life, and no details of the pathologic findings in the lens were available.
Mackay et al. (2003) described a 4-generation Caucasian family segregating an autosomal dominant form of 'nuclear' cataract presenting at birth or during infancy and confined to the central zone or fetal nucleus of the lens. Haplotype analysis indicated that the disease gene lay in the physical interval between 2 markers flanking the CRYAA gene. Sequence analysis identified an arg49-to-cys change in the CRYAA gene (R49C; 123580.0003) in affected individuals.
In a 4-generation family of Indian origin segregating autosomal dominant fan-shaped cataract and microcornea, Vanita et al. (2006) identified heterozygosity for the CRYAA R116C missense mutation, previously detected in a North American family with a zonular type of congenital cataract by Litt et al. (1998). Based on the tight association of cataract and microcornea in the Indian family and because expression of CRYAA has been demonstrated in the anterior eye segment as well the lens, Vanita et al. (2006) suggested that apart from the lens, alpha-A-crystallins might play a role in development of the anterior segment of the eye.
In a sister and brother and their mother with progressive presenile total cataract, Santhiya et al. (2006) analyzed functional candidate genes and identified heterozygosity for a missense mutation in the CRYAA gene (G98R; 123580.0005). The mutation was not found in the unaffected father or sister, in 30 random DNA samples of Indian origin, or in 96 healthy German controls.
In 12 affected and 4 unaffected members of a 4-generation French family with autosomal dominant cataract and iris coloboma, Beby et al. (2007) analyzed microsatellites for 15 known cataract loci and found suggestive linkage at the CRYAA locus on chromosome 21, as well as a specific haplotype segregating with the disease. Sequence analysis of the CRYAA gene revealed that all affected family members were heterozygous for the R116C mutation; the mutation was not found in unaffected individuals. Two affected individuals also had congenital microphthalmia; the authors noted that Cryaa -/- mice have been found to have both microphthalmia and cataract (Brady et al., 1997).
In 3 affected sibs from a consanguineous Saudi Arabian family with congenital total white cataract and microcornea mapping to 21q22.3, Khan et al. (2007) sequenced the candidate gene CRYAA and identified homozygosity for a missense mutation (R54C; 123580.0006). Their asymptomatic parents and 1 sib were found to be heterozygous for the mutation; on slit-lamp examination, all 3 heterozygotes had similar discernible but clinically insignificant bilateral punctate lenticular opacities that were not present in the other asymptomatic family members.
In 3 unrelated Danish families segregating autosomal dominant congenital cataract and microcornea, Hansen et al. (2007) identified 3 different heterozygous missense mutations in the CRYAA gene (123580.0007-123580.0009).
Richter et al. (2008) studied 14 affected and 14 unaffected members of a large 4-generation Chilean family, previously reported by Shafie et al. (2006) as 'family ADC54,' segregating autosomal dominant cataract, microcornea, and/or corneal opacity. Richter et al. (2008) found linkage to chromosome 21 with a maximum lod score of 4.89 at D21S171, and identified a heterozygous missense mutation in the CRYAA gene (R116H; 123580.0004) in affected members of the family. There was significant asymmetry of density, morphology, and color of the cataracts within and between affected individuals; the variable morphology included anterior polar, cortical, embryonal, fan-shaped, and anterior subcapsular cataracts. Richter et al. (2008) stated that, with the exception of iris coloboma, the clinical features of all 6 previously reported families with mutations in the CRYAA gene were found in this Chilean family.
In affected members of a 3-generation South Australian family segregating autosomal dominant lamellar cataract of variable severity, Laurie et al. (2013) identified heterozygosity for a CRYAA missense mutation (R21Q; 123580.0010).
Associations Pending Confirmation
For discussion of a possible association between variation in the CRYAA gene and aniridia, microcornea, and spontaneously resorbed cataract, see 106230.
Hsu et al. (2006) characterized lenses from transgenic mice designed to express mutant (R116C) and wildtype alpha-A-crystallin subunits. Expression of R116C alpha-A-crystallin subunits resulted in posterior cortical cataracts and abnormalities associated with the posterior suture. The severity of lens abnormalities did not increase between the ages of 9 and 30 weeks. With respect to opacities and morphologic abnormalities, lenses from transgenic mice that expressed wildtype human alpha-A-crystallin subunits were indistinguishable from age-matched nontransgenic control mice. Similar phenotypes were observed in different independent lines of R116C transgenic mice that differed by at least 2 orders of magnitude in the expression level of the mutant transgenic protein. Low levels of R116C alpha-A-crystallin subunits were sufficient to induce lens opacities and sutural defects.
In affected members of a family with autosomal dominant congenital cataract (CTRCT9; 604219), described as congenital zonular central nuclear opacities, Litt et al. (1998) identified heterozygosity for a 413G-A transition in exon 3 of the CRYAA gene, resulting in an arg116-to-cys (R116C) substitution at a highly conserved residue. Five of the 13 affected individuals also had microphthalmia and microcornea. The mutation was not found in 14 unaffected family members or 111 unrelated controls.
Cobb and Petrash (2000) examined the quaternary stability of the R116C CRYA mutant. Homocomplexes of mutant subunits become highly polydisperse at body temperature. Compared to the wildtype protein, they have reduced chaperone-like activity and ability to exchange subunits, but increased membrane-binding capacity.
Fu and Liang (2003) observed that alpha-A-crystallin carrying the R116C mutation had decreased interaction with wildtype crystallins beta-B2 (123620) and gamma-C (123680) but increased interaction with alpha-B-crystallin (123590) and HSP27 (602195).
In 12 affected members of a 4-generation French family with autosomal dominant nuclear cataract and iris coloboma, Beby et al. (2007) identified heterozygosity for the R116C mutation in the CRYAA gene. The mutation was not found in unaffected family members.
In a 4-generation family of Indian origin segregating autosomal dominant fan-shaped cataract and microcornea, Vanita et al. (2006) identified heterozygosity for the CRYAA R116C missense mutation, which segregated with disease in the family and was not found in 100 controls. No other ocular anomalies were detected in affected members of this family.
In 3 affected sibs from an inbred Jewish Persian family with autosomal recessive congenital cataract, Pras et al. (2000) identified homozygosity for a G-to-A transition at nucleotide 27 of the CRYAA gene, resulting in a trp9-to-ter (W9X) substitution. The parents and an unaffected sib were heterozygous for the mutation.
In a 4-generation Caucasian family segregating an autosomal dominant form of 'nuclear' cataract (CTRCT9; 604219), Mackay et al. (2003) identified heterozygosity for a C-to-T transition in exon 1 of the CRYAA gene, resulting in an arg49-to-cys (R49C) change. Transfection studies of lens epithelial cells revealed that, unlike wildtype CRYAA, the mutant protein was abnormally localized to the nucleus and failed to protect from staurosporine-induced apoptotic cell death. This was the first dominant cataract-causing mutation in CRYAA located outside the phylogenetically conserved 'alpha-crystallin core domain' of the small heat-shock protein family.
Using a thermal stability assay, Makley et al. (2015) identified a class of molecules that bind alpha-crystallins (cryAA and cryAB) and reversed their aggregation in vitro. The most promising compound improved lens transparency in mouse models of R49C cryAA and R120G cryAB (123590.0001) hereditary cataract. It also partially restored protein solubility in the lenses of aged mice in vivo and in human lenses ex vivo. These findings suggest an approach to treating cataracts by stabilizing alpha-crystallins.
In 14 affected members of a large 4-generation Chilean family, previously reported by Shafie et al. (2006) as 'family ADC54,' segregating autosomal dominant cataract, microcornea, and/or corneal opacity (CTRCT9; 604219), Richter et al. (2008) identified a 414G-A transition in exon 3 of the CRYAA gene, resulting in an arg116-to-his (R116H) substitution that changes a positively charged residue to a slightly negatively charged residue in a highly conserved region. The mutation was not found in 12 controls. There was significant asymmetry of density, morphology, and color of the cataracts within and between affected individuals; the variable morphology included anterior polar, cortical, embryonal, fan-shaped, and anterior subcapsular cataracts. Microcornea was evident in 3 affected individuals. Richter et al. (2008) noted that other affected individuals with nystagmus might also have mild microcornea, which could only be measured under anesthesia.
In 3 affected members over 2 generations of an Indian family with total cataract (CTRCT9; 604219), Santhiya et al. (2006) identified heterozygosity for a 291G-A transition in exon 2 of the CRYAA gene, resulting in a gly98-to-arg (G98R) substitution at a highly conserved residue within the core domain. The mutation was not found in 2 unaffected family members, in 30 random DNA samples of Indian origin, or in 96 healthy German controls. Cataract in this family began as a peripheral ring-like cortical opacity in the second decade of life, progressing to total cataract in the third decade; the affected family members had no other ocular defects. (The authors stated the nucleotide change as 292G-A and as 291G-A in the rest of their article.)
In 3 affected sibs from a consanguineous Saudi Arabian family with congenital total white cataract with microcornea (CTRCT9; 604219), Khan et al. (2007) identified homozygosity for a c.160C-T transition in exon 1 of the CRYAA gene, resulting in an arg54-to-cys (R54C) substitution. Their asymptomatic parents and 1 sib were found to be heterozygous for the mutation; on slit-lamp examination, all 3 heterozygotes had similar discernible but clinically insignificant bilateral punctate lenticular opacities that were not present in the other asymptomatic family members. The mutation was not found in 60 healthy Saudi individuals.
In 7 affected members over 3 generations of a Danish family segregating autosomal dominant congenital nuclear cataract with microcornea (CTRCT9; 604219), Hansen et al. (2007) identified heterozygosity for a c.337G-A transition in the CRYAA gene, resulting in an arg116-to-his (R116H) substitution at 1 of the most highly conserved residues in the alpha-crystallin domain. The mutation was not found in 6 unaffected family members or 170 ethnically matched controls. Examination of affected family members revealed nuclear cataracts with polar and/or equatorial ramification; corneas were 8 to 10 mm in diameter.
In a Danish mother and son with posterior polar cataract with microcornea (CTRCT9; 604219), Hansen et al. (2007) identified heterozygosity for a c.34C-T transition in exon 1 of the CRYAA gene, resulting in an arg12-to-cys (R12C) substitution at a highly conserved residue in the N-terminal region. The mutation was not found in 170 ethnically matched controls. Examination of 1 affected family member showed posterior polar cataracts, progressing to dense nuclear and laminar cataracts, with involvement of the anterior and posterior poles; the cornea was 9.5 mm in diameter. The authors noted that the phenotypes associated with this mutation and R21W (123580.0009) are similar; both consist of a central, zonular cataract with varying involvement of the anterior and posterior poles.
In a Caucasian Canadian family in which 3 members had bilateral congenital cataract, microcornea, and macrocephaly, Reis et al. (2013) identified heterozygosity for the R12C mutation in the CRYAA gene. The mutation, which segregated with disease in the family, was not found in 12,961 control alleles from the Exome Variant Server database. Variable features present in the affected individuals included coloboma and glaucoma.
In 4 affected members over 3 generations of a Danish family segregating autosomal dominant central laminar cataract with microcornea (CTRCT9; 604219), Hansen et al. (2007) identified heterozygosity for a c.61C-T transition in exon 1 of the CRYAA gene, resulting in an arg21-to-trp (R21W) substitution at a highly conserved residue in the N-terminal region. The mutation was not found in 170 ethnically matched controls. Examination of the 4 affected family members showed central and laminar cataracts, with variable opacification of the anterior and posterior poles; corneas were 8 to 10 mm in diameter. The authors noted that the phenotypes associated with this mutation and R12C (123580.0008) are similar; both consist of a central, zonular cataract with varying involvement of the anterior and posterior poles.
In 5 affected individuals over 3 generations of a South Australian family with lamellar cataract of variable severity (CTRCT9; 604219), Laurie et al. (2013) identified heterozygosity for a c.62G-A transition in the CRYAA gene, resulting in an arg21-to-gln (R21Q) substitution at a highly conserved residue in the N-terminal region. The proband had moderate fetal nuclear lamellar cataract diagnosed at age 2 years, and his brother was diagnosed with dense white nuclear cataract at age 4.5 years. The mutation was not found in 4 unaffected family members or in 95 South Australian controls, but was detected in the asymptomatic mother, maternal uncle, and maternal grandfather, all of whom displayed mild lamellar opacity on examination in adulthood following the children's diagnosis. Western blotting of proteins freshly extracted from cataractous lens material of the proband demonstrated a marked reduction in the amount of high molecular weight oligomers compared to lens material from an unaffected individual.
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