The clinical and genetic heterogeneity of autosomal dominant cataract

Abstract

Aims-To determine the diVerent morphologies of autosomal dominant cataract (ADC), assess the intra-and interfamilial variation in cataract morphology, and undertake a genetic linkage study to identify loci for genes causing ADC and detect the underlying mutation. Methods-Patients were recruited from the ocular genetic database at Moorfields Eye Hospital. All individuals underwent an eye examination with particular attention to the lens including anterior segment photography where possible. Blood samples were taken for DNA extraction and genetic linkage analysis was carried out using polymorphic microsatellite markers. Results-292 individuals from 16 large pedigrees with ADC were examined, of whom 161 were found to be aVected. The cataract phenotypes could all be described as one of the eight following morphologies-anterior polar, posterior polar, nuclear, lamellar, coralliform, blue dot (cerulean), cortical, and pulverulent. The phenotypes varied in severity but the morphology was consistent within each pedigree, except in those aVected by the pulverulent cataract, which showed considerable intrafamilial variation. Positive linkage was obtained in five families; in two families linkage was demonstrated to new loci and in three families linkage was demonstrated to previously described loci. In one of the families the underlying mutation was isolated. Exclusion data were obtained on five families. Conclusions-Although there is considerable clinical heterogeneity in ADC, the phenotype is usually consistent within families. There is extensive genetic heterogeneity and specific cataract phenotypes appear to be associated with mutations at more than one chromosome locus. In cases where the genetic mutation has been identified the molecular biology and clinical phenotype are closely associated. (Br J Ophthalmol 1999;83:802-808)

A novel missense mutation in HSF4 causes autosomal-dominant congenital lamellar cataract in a British family

“…The phenotypic classification of the cataract depends on the position and type of the lens opacity such as: anterior polar, posterior polar, nuclear, lamellar, coralliform, blue-dot (cerulean), cortical, pulverulent, polymorphic, complete cataract and posterior nuclear cataract 5,6 . Significant progress has been made in identifying the molecular genetic basis of human cataract.…”

Fine localization of a new cataract locus, Kec, on mouse chromosome 14 and exclusion of candidate genes as the gene that causes cataract in the Kec mouse

“…The cataract phenotype in Kec mice is similar to zonular pulverulent cataracts, which display a powdery, snowflake appearance for the opacification (17). Autosomal dominant zonular pulverulent cataracts have been described in association with mutations in the gap-junction protein genes alpha 3 (GJA3) (3,18) and alpha 8 (GJA8) (19)(20)(21) and the crystalline gene, gamma C (CRYGC) (18).…”

A CRYGC gene mutation associated with autosomal dominant pulverulent cataract

“…Disruption of the crystallin structure results in the formation of congenital cataract (Ionides et al, 1999;Lambert and Drack, 1996). Congenital cataract represents 10% of the cases of childhood blindness (Gilbert et al, 1993;Ionides et al, 1999;Reddy et al, 2004). This disorder is visible within the first year of life; nevertheless, the age of onset is not necessarily related to the cause of cataract (Francois, 1982;Merin and Crawford, 1971).…”

“…The lens is responsible for the variable refractive power of focusing and one-third of the stationary refractive power. Disruption of the crystallin structure results in the formation of congenital cataract (Ionides et al, 1999;Lambert and Drack, 1996). Congenital cataract represents 10% of the cases of childhood blindness (Gilbert et al, 1993;Ionides et al, 1999;Reddy et al, 2004).…”