Cataract 1, Multiple Types

A number sign (#) is used with this entry because multiple types of cataract (CTRCT1) are caused by heterozygous mutation in the gene encoding the alpha-8 subunit of the gap junction protein (GJA8; 600897) on chromosome 1q21.

Description

Mutations in the GJA8 gene have been found to cause several types of autosomal dominant cataract, which have been described as congenital, zonular pulverulent, nuclear progressive, nuclear pulverulent, stellate nuclear, nuclear total, total, and posterior subcapsular. Cataract associated with microcornea, sometimes called the cataract-microcornea syndrome, is also caused by mutation in the GJA8 gene.

Before it was known that mutation in the GJB8 gene caused multiple types of cataract, this entry was titled 'Cataract, zonular pulverulent, 1,' with the symbols CZP1, CZP, and CAE1.

Clinical Features

Renwick and Lawler (1963) studied the 'Ev.' kindred with zonular pulverulent cataract that had been described earlier by Nettleship (1909). Renwick and Lawler (1963) referred to the disorder as congenital zonular cataract; Renwick (1970) described it as total nuclear cataract. Renwick (1987) stated that the Duffy-linked ('Ev.') type of cataract (see MAPPING) is zonular with a pulverulent center, affecting both the embryonic nucleus and the fetal nucleus, i.e., is 'total nuclear.' It is larger (about 4 mm) than the Coppock-like cataract (see 604307) (about 2 mm), which is limited to the embryonic nucleus.

Conneally et al. (1978) reported a family with lenticular opacities located in the fetal nucleus with scattered, fine, diffuse cortical opacities and incomplete cortical 'riders' similar to those described by Nettleship (1909).

Crews and Bundey (1982) reported a 4-generation family in which congenital cataract segregated as an autosomal dominant, with 9 affected males and 1 affected female, as well as 1 female who was clinically unaffected but did have cataract upon ophthalmologic examination; father-to-son transmission was evident in 1 branch of the family.

Stefaniak et al. (1995) reported a family in which 14 members had cataract with microcornea. Transmission was probably autosomal dominant, although the proportion of affected members was so high that Stefaniak et al. (1995) were tempted to suspect preferential transmission of the chromosome carrying the mutant gene. In this 4-generation family, all 7 members of the third generation were affected and almost all members of the fourth generation as well.

Berry et al. (1999) examined affected members of a family of Pakistani origin segregating autosomal dominant congenital nonprogressive zonular nuclear pulverulent cataract. All 10 affected individuals displayed the same pulverulent phenotype, but unlike the cataracts previously described by Shiels et al. (1998) in 2 distantly related branches of the English kindred originally reported by Renwick and Lawler (1963), this family had fine dust-like opacities that were most dense throughout the nucleus, as well as several cortical 'riders' present in the zonular region.

Polyakov et al. (2001) described a mother and son from a 3-generation Russian family segregating autosomal dominant zonular pulverulent cataract. The boy had onset of disease at 3 years of age; examination revealed bilateral nonhomogeneous pulverulent cataracts consisting of opaque particles of different sizes, most of them very small, unevenly distributed in a 5-mm disc in the center of the lens, as well as a slightly cloudy nonhomogeneous 2-mm area in the posterior pole region. Progression of the disease was symmetrical in both eyes. His mother had a similar phenotype.

Willoughby et al. (2003) reported a 4-generation Iranian family segregating autosomal dominant progressive congenital nuclear cataract. Affected family members had bilateral congenital cataracts that progressed and required surgery in the second and third decades due to dense fetal/embryonal nuclear cataract. No other systemic or ocular defects were present, including microcornea or microphthalmia.

Mapping

In a kindred known as 'Ev.' with zonular pulverulent cataract, previously described by Nettleship (1909), Renwick and Lawler (1963) demonstrated linkage with the Duffy blood group, which was later mapped to chromosome 1q21-q22 (see 110700). Renwick (1970) discussed the possibility that some other forms of dominant cataract might be linked with Duffy. A morphologically identical cataract was described by Hammerstein and Scholt (1973) who in their kindred found no linkage with Duffy.

In a family with zonular pulverulent cataract with fine, diffuse cortical opacities and incomplete cortical 'riders' similar to those described by Nettleship (1909), Conneally et al. (1978) found linkage to 1qh (lod of 2.7 at a recombination fraction of 0.0); no linkage to 1q was found in several other families with cataract.

Inheritance

Renwick and Lawler (1963) demonstrated that the locus for cataract in the English family originally reported by Nettleship (1909) cosegregated in an autosomal dominant manner with the Duffy blood group locus.

Molecular Genetics

In 2 distantly related branches of an 8-generation English kindred known as 'Ev.' with zonular pulverulent cataract, in which Renwick and Lawler (1963) demonstrated linkage to the Duffy blood group, Shiels et al. (1997) and Shiels et al. (1998) found evidence of linkage to the region of chromosome 1q where the GJA8 gene (600897) is located. Sequencing of the entire protein coding region of the GJA8 gene demonstrated a C-to-T transition (600897.0001) that created a novel MnlI restriction enzyme site. Restriction analysis confirmed that this change was present only in affected members of the pedigree and was not detectable in 50 unrelated normal chromosomes.

Hejtmancik (1998) presented a table of 9 loci, including this one, which 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.

Berry et al. (1999) studied 10 affected and 5 unaffected members of a family of Pakistani origin segregating autosomal dominant congenital nonprogressive zonular nuclear pulverulent cataract and found linkage to the CZP locus; analysis of the GJA8 gene revealed heterozygosity for a missense mutation (E48K; 600897.0002) in affected individuals that was not found in 100 ethnically matched control chromosomes.

In a mother and son from a 3-generation Russian family with zonular pulverulent cataract, Polyakov et al. (2001) identified heterozygosity for a missense mutation in the GJA8 gene (I247M; 600897.0003) that was not found in unaffected family members or 25 unrelated controls.

In a 4-generation Iranian family segregating autosomal dominant progressive congenital nuclear cataract, Willoughby et al. (2003) identified heterozygosity for a missense mutation in the GJA8 gene (R23T; 600897.0004).

Devi and Vijayalakshmi (2006) analyzed the GJA8 gene in 60 unrelated Indian patients with congenital or early childhood cataract, and identified 2 different missense mutations (600897.0005 and 600897.0006, respectively) in 2 probands from families with cataract and microcornea, variably associated with myopia. One proband had a total cataract and the other had a posterior subcapsular cataract.

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 most cataracts had a clear peripheral zone. In some patients, cataract progression during the first years of life was noted. In the family with the GJA8 mutation, the cataract was described as a star-shaped nuclear opacity with a whitish central core.

Arora et al. (2008) sequenced the GJA8 gene in 150 families with inherited cataract and identified heterozygosity for a missense mutation (600897.0007) in a 2-generation Caucasian family segregating autosomal dominant congenital nuclear pulverulent cataract. He et al. (2011) identified the same mutation in affected members of a 6-generation Chinese family segregating nuclear cataract as well as in 1 unaffected member of the family, suggesting incomplete penetrance.

Animal Model

Chung et al. (2007) demonstrated that transgenic expression of Cx50 in mice led to cataracts associated with formation of cytoplasmic vesicles containing Cx50 and decreased or slowed epithelial differentiation without major alterations in the distribution of other integral membrane or membrane-associated proteins or the integrity/solubility of crystallins.

History

Pulverulent cataract was the first inherited disease to be linked to a human autosome: the linkage to Duffy was demonstrated by Renwick and Lawler (1963) and the location of the Duffy locus (110700) on 1q was established by Donahue et al. (1968).

Harman (1909) described a 5-generation nonconsanguineous family in which 19 members had isolated congenital cataract. The author noted that in many cases the opacities were quite small, close to the nuclear region, and had a shape suggesting a disturbance in the union of the anterior ends of the lens fibers as they grew forward. Harman (1910) reported a series of 8 nonconsanguineous pedigrees with various forms of congenital cataract (lamellar, coralliform, discoid).

Smith (1910) reported 26 cases of cataract in 4 generations.

Vogt (1931) and Weber (1940) documented autosomal dominant inheritance of nuclear diffuse nonprogressive cataract.

Meissner (1933) reported 22 cases of congenital cataract in 6 generations of 1 family and 13 cases in 5 generations in a second. Three generations were affected in the family reported by Jahns (1938).

Gruber (1945) described 6 cases of membranous cataract in 4 generations. This should be considered a total cataract that has undergone regression or resorption.

Lee and Benedict (1950) described 63 cases of cataract in 6 generations.

Brown (1924) and Parrow (1955) reported pedigrees with autosomal dominant inheritance of nuclear total cataract.

Transmission of floriform cataract was recorded through 4 generations by Doggart (1957) and through 5 generations by Tosch (1958).