Cataract 4, Multiple Types

A number sign (#) is used with this entry because multiple types of cataract (CTRCT4) are caused by heterozygous mutation in the gamma-D-crystallin gene (CRYGD; 123690) on chromosome 2q33.

Description

Mutations in the CRYGD gene have been found to cause multiple types of cataract, which have been described as aculeiform, crystalline aculeiform, crystalline, crystal, frosted, needle-shaped, fasciculiform, congenital cerulean, nonnuclear polymorphic congenital, central nuclear, lamellar, and punctate. Some patients also exhibit microcornea.

Because multiple types of cataract are caused by mutation in the CRYGD gene, some of which display intrafamilial variability, several earlier distinct cataract entries in OMIM have been included here.

Clinical Features

Rogaev et al. (1996) reported a large pedigree in which 103 of 254 members had autosomal dominant nonnuclear polymorphic congenital cataract. The disorder showed great variability in location, color, and number of opacities in this pedigree. Rogaev et al. (1996) differentiated the phenotype of nonnuclear cataract from that of Coppock-like cataract (see 604307). In the nonnuclear form, the fetal nucleus is normal and opacities are located between the fetal nucleus and the cortex of the lens, whereas the opacity in Coppock-like cataract is limited to the fetal nucleus of the lens.

Plotnikova et al. (2007) noted that the family reported by Rogaev et al. (1996), part of a central Asian population of mixed white and Mongolian origin, was characterized by tribe ancestry, high endogamy, and complex ethnic genesis. They summarized the clinical findings. The PCC type of cataract is characterized by a nonprogressive phenotype and partial opacity that has a variable location on the periphery between the fetal nucleus of the lens and the equator. The opacities are irregular and look similar to a bunch of grapes or a lump of cotton balls and may be present simultaneously in different lens layers.

Heon et al. (1998) reported 3 unrelated families, 1 originating from Macedonia and 2 from the Neuchatel area of Switzerland, with classic aculeiform cataract, a form of congenital crystalline cataract that was originally described by Vogt (1922). The phenotype is characterized by fiberglass-like or needle-like crystals projecting in different directions, through or close to the axial region of the lens. Some crystals may be more than 1 mm in length. The opacity does not appear to respect the sutures or the direction of the lens fibers and appears to originate from the fetal and postnatal nuclei, suggesting a congenital origin with some postnatal progression. The opacity causes a variable degree of vision loss; in some cases surgery is required to restore visual function. Although usually bilateral, unilateral cases of aculeiform cataract have been described.

Stephan et al. (1999) identified a 3-generation family with hereditary progressive cataracts transmitted as a fully penetrant autosomal dominant trait. The lenses of affected individuals appeared clear at birth, but with time focal opacities developed, which suggested some progressive alteration in protein structure or interaction. The cataract was always detectable by age 2.5 years and consisted of grayish-white punctate opacities in the nucleus and surrounding deep cortex, with intervening and peripheral clear lens. The cataracts were 5 to 6 mm in diameter, and the opacities became more dense over time such that lens extraction was ultimately required because of decreased vision. Once the opaque lens was removed and a synthetic lens inserted, vision returned to 20/20 and the eye functioned normally.

Kmoch et al. (2000) described a 5-year-old boy with a juvenile-onset 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. 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.

Hilal et al. (2002) described a 4-generation Moroccan family with autosomal dominant congenital cerulean cataract. Lens opacities could be observed in all affected individuals at birth by direct visual observation; the diagnosis was consistently established at birth by unaffected family members. Some patients had extremely decreased or nondetectable visual acuity at birth, while others retained very low but detectable vision. Nystagmus was not unusual during the first months of life in some severely affected patients. Some severely affected children underwent lens extraction before the age of 5 years. It appeared that progression of cerulean cataract in this family followed a faster time course than that reported in other families with cerulean cataract.

Mapping

Rogaev et al. (1996) performed linkage analysis in a large pedigree with autosomal dominant nonnuclear polymorphic congenital cataract. Evidence for linkage was found to chromosome 2q33-q35. A trinucleotide microsatellite marker for gamma-crystallin-1 (CRYG1; 123660) was found to cosegregate with the disorder (maximum lod = 10.62 at theta = 0). Rogaev et al. (1996) noted that nuclear Coppock-like cataract (see 604307) has also been linked to gamma-crystallin, but they considered the phenotypes of the 2 forms of cataract to be different.

In 3 unrelated families, 1 originating from Macedonia and 2 from the Neuchatel area of Switzerland, segregating the classic aculeiform cataract phenotype, Heon et al. (1998) demonstrated linkage to short tandem repeat (STR) polymorphic markers in the 2q33-q35 region, where the gamma-crystallin gene cluster is located. The combined maximum lod score was 6.27 at a recombination fraction of 0.0, with marker D2S2208. The lod score results for the Macedonian family alone exceeded 3.0 for at least 6 neighboring markers. Heon et al. (1998) noted the polymorphic congenital cataract linked by Rogaev et al. (1996) to 2q33-q35 and the report of a Coppock-like cataract that shows linkage to the gamma-crystallin cluster of genes. Whether these were allelic to aculeiform cataract was uncertain, but Heon et al. (1998) noted that they are clinically distinct.

To find the trait locus in a 3-generation family with hereditary progressive cataracts, Stephan et al. (1999) performed a genomewide search and obtained evidence for linkage at chromosome 2q33-q35.

In a Moroccan family with autosomal dominant congenital cerulean cataract, Hilal et al. (2002) excluded linkage to previously identified loci on 17q24 (see 115660) and 22q11.2-q12.2 (see 601547). Nandrot et al. (2003) obtained linkage of the disorder in this family to chromosome 2q33-q35, with a maximum lod score (7.19 at recombination fraction theta = 0) for marker D2S2208 near the gamma-crystallin gene cluster.

Inheritance

Rogaev et al. (1996) reported a large pedigree in which 103 of 254 members had autosomal dominant nonnuclear polymorphic congenital cataract.

Although recessive inheritance is suggested by some reports, dominant inheritance is clear from studies such as those of Romer (1926) and of Gifford and Puntenney (1937). Autosomal dominant inheritance with complete penetrance and minimal variable expressivity of aculeiform cataract has been reported, with no sex predilection (Heon et al., 1998).

Molecular Genetics

In affected members of a 3-generation family segregating juvenile-onset progressive punctate cataracts, Stephan et al. (1999) identified a heterozygous missense mutation in the CRYGD gene (R14C; 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 a heterozygous missense mutation in the CRYGD gene (123690.0002).

By sequencing of the CRYGD gene in a 5-year-old boy with juvenile-onset cataract caused by deposition of numerous birefringent, pleochroic, and macroscopically prismatic crystals, Kmoch et al. (2000) identified a heterozygous missense mutation (R36S; 123690.0003).

In a father and daughter with congenital central nuclear cataract, Santhiya et al. (2002) found heterozygosity for a nonsense mutation in the CRYGD gene (W156X; 123690.0005).

Nandrot et al. (2003) examined genes within the gamma-crystallin gene cluster on chromosome 2q33-q35 for disease-causing mutations in the Moroccan family with cerulean cataract identified by Hilal et al. (2002). Sequence analysis of the CRYGA (123660), CRYGB (123670), and CRYGC (123680) genes identified no mutations. The authors found a heterozygous C-to-A transversion in exon 2 of the CRYGD gene (123690.0004) in all affected family members. This mutation resulted in a pro23-to-thr substitution in the first of the 4 Greek key motifs that characterize this protein. 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 suggested strongly that the P23T mutation might alter the protein folding or decrease the thermodynamic stability or solubility of the protein. The authors concluded that theirs was the first report of a mutation in the CRYGD gene resulting in autosomal dominant congenital cerulean cataracts. The same P23T mutation in the CRYGD gene had previously been identified in a father and daughter with congenital lamellar cataract by Santhiya et al. (2002).

Plotnikova et al. (2007) screened the pedigree with polymorphic congenital cataract reported by Rogaev et al. (1996) for mutations in the CRYGA-CRYGD genes and performed an evolutionary and structural analysis of the mutation and the gamma-crystallin gene family. They identified a mutation in the CRYGD gene (P23S; 123690.0007). Autosomal dominant polymorphic cataract had a frequency of approximately 0.3% in the population studied.

In 10 Danish families segregating autosomal dominant developmental cataract and microcornea, Hansen et al. (2007) analyzed 9 candidate genes and identified 5 families with heterozygous mutations, 3 of which were in the CRYAA gene (123580.0007-123580.0009), 1 in the GJA8 gene (600897.0008), and 1 in the CRYGD gene (123690.0008). Corneal diameters varied between 8 and 10 mm. Nystagmus was present in some families and absent in others, depending primarily on the degree of visual impairment during the first months of life. Cataract phenotypes varied, but often involved the nuclei, with cortical laminar elements and anterior and posterior polar opacities to a variable extent; most cataracts had a clear peripheral zone. In some patients, cataract progression during the first years of life was noted. Hansen et al. (2007) stated that this was the first CRYGD mutation to be associated with microcornea.