Cataract 2, Multiple Types

A number sign (#) is used with this entry because multiple types of cataract (CTRCT2) are caused by heterozygous mutation in the CRYGC gene (123680) on chromosome 2q33.

Description

Mutations in the CRYGC gene have been found to cause several types of cataract, which have been described as Coppock-like; embryonic, fetal, infantile nuclear; zonular pulverulent; and lamellar. Some patients also exhibit microcornea.

Before it was known that mutations in the CRYGC gene cause several types of cataract, this entry was titled 'Cataract, Coppock-like,' with the symbol CCL.

Clinical Features

Nettleship and Ogilvie (1906) described 18 cases of embryonic nuclear cataract in 4 generations of a family named Coppock.

Harman (1910) described a 4-generation family (family 'F--n') segregating autosomal dominant congenital cataract, described as 'discoid and mixed form.' Lubsen et al. (1987) studied descendants of the 'F--n' family and stated that the cataracts, which they designated as 'Coppock-like,' were present at birth, affected primarily the embryonic nucleus of the lens, and were nonprogressive.

Ren et al. (2000) reported a family with autosomal dominant variable zonular pulverulent cataract. The range of severity of cataract varied from a subtle unilateral zonular pulverulent cataract not impairing visual function to dense bilateral nuclear cataracts resulting in blindness. Detailed clinical findings of affected individuals were previously reported by Scott et al. (1994).

Santhiya et al. (2002) reported an Indian mother and 2 children with congenital lamellar cataract.

Gonzalez-Huerta et al. (2007) described a Mexican family in which 9 members over 4 generations had congenital nuclear cataract. The proband was a 3-year-old boy who developed nystagmus and photophobia at 9 months of age. Examination revealed nystagmus, peripupillary iris atrophy, and cataract, with focal opacities in the nuclear and perinuclear areas bilaterally. His 11-year-old brother had undergone cataract surgery; clinical records designated his lens opacities as 'nuclear congenital cataract.' Neither brother had other eye findings, and the remainder of the physical examination was normal in both.

Zhang et al. (2009) studied a Chinese family in which 6 members over 4 generations were affected with nuclear cataracts and microcornea. Autosomal dominant inheritance was supported by the presence of affected individuals in each generation, with male-to-male transmission. Affected individuals presented with bilateral congenital nuclear cataracts that consisted of a central nuclear opacity affecting the embryonic, fetal, and infantile nucleus of the lens, as well as congenitally small eyeballs, with corneas measuring approximately 9 to 10 mm in diameter. All affected individuals had only hand-movement visual acuity, and they also had nystagmus and amblyopia. Zhang et al. (2009) noted that although congenital cataract with microcornea (CCMC) had been considered to be a rare phenotype, the frequency might be underestimated because the focus was often on the sight-threatening cataract, with corneal diameters going unnoticed.

Guo et al. (2012) reported a Chinese family in which 6 members over 4 generations had nuclear cataracts and microcornea. The nuclear opacities were located in the embryonic, fetal, and infantile nuclei. Bilateral cataracts and microcornea with an approximately 9-mm diameter were consistent in all of the affected family members. In addition, nystagmus and amblyopia were observed in all patients. Guo et al. (2012) noted that microcornea is one of the most common abnormalities associated with congenital cataract, emphasizing the interdependence of the lens and cornea in development and metabolism.

Li et al. (2012) described an 8-year-old Chinese girl who was born with bilateral cataracts involving the central nuclear region of both lenses. Her mother and her maternal grandfather also had congenital nuclear cataracts. There was no history of other ocular or systemic abnormalities in the family.

Mapping

In the descendants of a family that was originally reported by Harman (1910) (family 'F--n'), segregating autosomal dominant congenital cataract, Lubsen et al. (1987) used RFLP haplotypes at the CRYG cluster (see 123660) to detect linkage with what they designated as a 'Coppock-like' cataract of the embryonic lens nucleus. Lubsen et al. (1987) used RFLP haplotypes at the CRYG cluster (see 123660) to detect linkage with a hereditary Coppock-like cataract of the embryonic lens nucleus. Haplotype P was found only in family members who suffered from cataract, and all family members who suffered from cataract had haplotype P. The absolute correlation, giving a lod score of 7.58, suggested that the primary cause of cataract in these individuals was a lesion in a gamma-crystallin gene on chromosome 2q33. Renwick (1987) stated that the 'Coppock-like' pedigree was selected for study because the cataract involved the embryonic nucleus, which is known to be the part where gamma-crystallin predominates. The Coppock-like cataract is about 2 mm in diameter. The CAE cataract (116200), which is linked to Duffy, affects both the embryonic and the fetal nuclei; it is about 4 mm in diameter.

In affected members from a 4-generation Mexican family segregating autosomal dominant nuclear cataract, Gonzalez-Huerta et al. (2007) found haplotype sharing with the markers D2S235 and D2S2382 in the region of the CRYG gene cluster.

By exclusion of large chromosomal regions in a 4-generation Chinese family segregating autosomal dominant nuclear cataract and microcornea, Zhang et al. (2009) obtained suggestive evidence of linkage for marker D2S22321 at 2q33.3, with a positive lod score (theta = 0). A maximum 2-point lod score of 2.29 was obtained at marker D2S235 (theta = 0), with adjacent markers also showing lod scores greater than 1.0. Haplotype analysis revealed recombination events that defined a 19.04-cM critical region, bounded by D2S117 and D2S2382 at chromosome 2q32.3-q35. Zhang et al. (2009) noted that penetrance appeared to be complete because all affected individuals had an affected parent and none of the unaffected family members carried the disease-associated haplotype.

Molecular Genetics

Heon et al. (1999) identified a heterozygous mutation in the CRYGC gene (T5P; 123680.0001) in the family with Coppock-like cataract originally reported by Harman (1910) and restudied by Lubsen et al. (1987).

In affected members of a family with autosomal dominant variable zonular pulverulent cataract, Ren et al. (2000) identified a heterozygous 5-bp duplication in exon 2 of the CRYGC gene (123680.0002).

In an Indian mother and 2 children with congenital lamellar cataract, Santhiya et al. (2002) identified a heterozygous missense mutation in the CRYGC gene (R168W; 123680.0003).

In 6 affected individuals from a 4-generation Mexican family segregating autosomal dominant nuclear cataract, Gonzalez-Huerta et al. (2007) sequenced the candidate CRYG gene cluster and identified heterozygosity for the R168W CRYGC mutation that had previously been found in an Indian family with lamellar cataracts (Santhiya et al., 2002). The mutation was not detected in unaffected family members or 170 controls.

In a 4-generation Chinese family with autosomal dominant nuclear cataract and microcornea mapping to 2q32.3-q35, Zhang et al. (2009) analyzed the candidate CRYGA-CRYGD gene cluster and identified a heterozygous nonsense mutation in the CRYGC gene (W157X; 123680.0004) that segregated fully with disease in the family and was not found in 100 controls. Zhang et al. (2009) stated that the association between microcornea and congenital cataracts in all affected individuals indicated that mutations disrupting lens biochemistry and physiology early in development can result in microphakia and subsequent microcornea as a secondary effect of damage to the lens.

In a 4-generation Chinese family segregating autosomal dominant nuclear cataract and microcornea, Guo et al. (2012) sequenced 9 candidate genes and identified heterozygosity for a CRYGC W157X mutation (123680.0005) in affected family members. This substitution was caused by a different nucleotide change from that identified by Zhang et al. (2009), which resulted in the same amino acid change.

In an 8-year-old Chinese girl with congenital nuclear cataract, Li et al. (2012) identified heterozygosity for a missense mutation in the CRYGC gene (G129C; 123680.0006). The mutation was present in her affected mother and maternal grandfather, but was not found in unaffected family members or 50 controls. In a zebrafish model, the G129C mutant recapitulated the human cataract phenotype.

History

The Coppock-like cataract was mapped to chromosome 2 by demonstration of close linkage to a particular combination of polymorphic TaqI sites (haplotype) within the gamma-crystallin gene cluster. Mapping of these sites showed that they define a 15-kb region encompassing the gamma-D (123690) and psi-gamma-E (CRYGE or CRYG5; 123660) genes. Cloning of these 2 genes from the CCL chromosome demonstrated that the gamma-D gene was functionally equivalent to its allele cloned from a wildtype chromosome. On the other hand, the CCL psi-gamma-E gene contained a cluster of sequence changes within and around its TATA box. Together these resulted in a 10-fold increase in the activity of the psi-gamma-E promoter, raising the level of expression of this gene to 30% of that of the gamma-D gene. The predicted protein product of the CRYG5 pseudogene is a 6-kD N-terminal gamma-crystallin fragment. Brakenhoff et al. (1994) suggested that reactivation of this gene and concomitant overexpression of the gamma-crystallin fragment may be the cause of Coppock-like cataract. This, if true, represents a unique mutational mechanism for the pathogenesis of a disorder. Heon et al. (1999) suggested that the changes in the CRYGE promoter region are not causally related to a cataract phenotype.