Cataract 3, Multiple Types

A number sign (#) is used with this entry because multiple types of cataract (CTRCT3) are caused by heterozygous mutation in the beta-B2-crystallin gene (CRYBB2; 123620) on chromosome 22q11.

Description

Mutations in the CRYBB2 gene have been found to cause several types of cataract, which have been described as congenital cerulean, 'blue dot,' Coppock-like, sutural with punctate and cerulean opacities, pulverulent embryonal, pulverulent with cortical opacities, dense posterior star-shaped subcapsular with pulverulent opacities in the cortical and embryonal regions, and dense embryonal.

Before it was known that mutations in the CRYBB2 gene cause several types of cataract, the preferred title of this entry was 'Cataract, Congenital, Cerulean Type 2,' with the symbol CCA2.

Clinical Features

Bodker et al. (1990) reported a kindred in which autosomal dominant cataract was known to have occurred in at least 6 generations. Of a total of 159 relatives, 17 affected persons were evaluated. 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 and dense congenital cataracts. Bodker et al. (1990) suggested that this represented the homozygous state. There were no extraocular abnormalities; specifically, the patient was of normal intelligence. Linkage at short distances could be excluded for all 18 markers that were informative.

Kramer et al. (1996) reported studies on a family that included 24 individuals affected with the cerulean blue form of autosomal dominant congenital cataract. This family represents a branch of a family originally reported by Bodker et al. (1990). In younger affected family members the cataracts were characterized by numerous peripheral blue flakes and occasional spoke-like central opacifications. Kramer et al. (1996) reported that most affected individuals experienced only mild reduction of visual acuity during childhood and adolescence. Cataract extraction became necessary in most affected individuals between 20 and 40 years of age. One affected family member, who is the daughter of affected first cousins, exhibited bilateral microphthalmia and microcornea at birth.

Gill et al. (2000) studied a 4-generation Swiss family with autosomal dominant Coppock-like cataract in which the locus on chromosome 2 (see 604307) was excluded. The cataracts were bilateral, symmetrical, and characterized by a pulverulent opacification of the embryonal nucleus, giving a gray disc appearance associated with zonular opacities to a variable degree. Although the progressive nature of this cataract was not clearly documented, a steady decrease in the visual acuity starting in the teens and premature nuclear sclerosis were observed. Visual impairment was usually first noticed in the teenage years, and most affected individuals required cataract surgery in their forties.

Vanita et al. (2001) reported a 5-generation Indian family with sutural cataract with punctate and cerulean opacities. Slit-lamp examination showed prominent, dense, white opacification around the anterior and posterior Y sutures. The posterior Y sutures and the posterior pole of the lens were more severely affected than the anterior pole. It also showed grayish and bluish, sharply defined, elongated, spindle shaped, and oval punctate and cerulean opacities of various sizes arranged in lamellar form. The spots were bigger and more concentrated towards the peripheral layers. These did not delineate the embryonal or fetal nucleus. No pulverulent disc-like opacity was observed in the nuclear region. The sutural opacities appeared denser and whiter compared to the punctate and cerulean spots and were also more elongated and larger in size. Phenotypic variation with respect to the size and density of the sutural opacities as well as the number and position of punctate and cerulean spots was observed among the affected members. Some subjects showed severely affected sutures with dense white opacifications spreading along the secondary divisions of the Y sutures. In some affected subjects the spots were present only as a single layer in the cortex while in the others the spots occurred in concentric layers involving the whole cortex. Vanita et al. (2001) stated that the phenotype of this family differed from all other forms of cataract reported to that time.

Bateman et al. (2007) reported a 4-generation Chilean family segregating autosomal dominant cataract with variable location, morphology, color, and density of the opacities among affected family members. 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.

Mapping

In a family with the cerulean blue form of cataract, Kramer et al. (1996) found linkage of the disorder to chromosome 22 and maximum multipoint location scores occurred at D22S258 (lod = 7.59) and CYBB2 (lod = 7.53) in the beta-crystallin gene cluster (see 600929). Haplotype analysis in this family indicated that the disease locus is located in a 7-cM region between TOP1P2 and D22S351. The beta-crystallin genes CRYBB2 (123620), CRYBB3 (123630), and CRYBB2P1 lie within this region and were therefore candidate genes. The severely affected female who presented at birth with microphthalmia and microcornea was homozygous for the disease-bearing chromosome. Kramer et al. (1996) noted that an individual who carried the disease chromosome was unaffected.

In a 4-generation Swiss family with autosomal dominant Coppock-like cataract in which the locus on chromosome 2 was excluded, Gill et al. (2000) mapped the phenotype to 22q11.2-q13.1 by linkage analysis.

In an Indian family with sutural cataract with punctate and cerulean opacities, Vanita et al. (2001) mapped the phenotype to chromosome 22 by linkage analysis.

Molecular Genetics

In affected members of a family with cerulean cataract reported by Kramer et al. (1996), Litt et al. (1997) identified heterozygosity for a nonsense mutation in the CRYBB2 gene (Q155X; 123620.0001). A severely affected female family member, who was born of first-cousin affected parents and exhibited microphthalmia and microcornea in addition to cataract, was homozygous for the mutation.

In affected members of a 4-generation Swiss family with autosomal dominant Coppock-like cataract mapping to chromosome 22q11.2-q13.1, Gill et al. (2000) identified a premature termination mutation in the CRYBB2 gene (123620.0001).

Hejtmancik (1998) presented a table of 9 loci, including this one, that had been implicated in nonsyndromal cataract and mapped to specific chromosomal sites. Eight animal models of cataract in which molecular defects had been identified were also tabulated.

In an Indian family with sutural cataract with punctate and cerulean opacities, Vanita et al. (2001) detected 2 sequence changes in the CRYBB2 gene (123620) cosegregating with the phenotype. The first was the previously described Q144X mutation. The second mutation (c.483C-T; 123620.0002) was a silent polymorphism found exclusively in patients. The authors ascribed this mutation to gene conversion between the CRYBB2 gene and its pseudogene, CRYBB2P1.

In a 4-generation Chilean family segregating multiple types of autosomal dominant cataract, Bateman et al. (2007) identified the Q155X mutation and the previously reported 483C-T silent polymorphism. No mutations were found in the CRYBB1 gene.