title: Clinical variability of autosomal dominant cataract, microcornea and corneal opacity and novel mutation in the alpha A crystallin gene (CRYAA).
abstract: We studied 28 individuals from a four-generation Chilean family (ADC54) including 13 affected individuals with cataracts, microcornea and/or corneal opacity. All individuals underwent a complete ophthalmologic exam. We screened with a panel of polymorphic DNA markers for known loci that cause autosomal dominant cataracts, if mutated, and refined the locus using the ABI Prism Linkage Mapping Set Version 2.5, and calculated two-point lod scores. Novel PCR primers were designed for the three coding exons, including intron-exon borders, of the candidate gene alpha A crystallin (CRYAA). Clinically, affected individuals had diverse and novel cataracts with variable morphology (anterior polar, cortical, embryonal, fan-shaped, anterior subcapsular). Microcornea and corneal opacity was evident in some. Marker D21S171 gave a lod score of 4.89 (theta(m) = theta(f) = 0). CRYAA had a G414A transition that segregated with the disease and resulted in an amino acid alteration (R116H). The phenotypic variability within this family was significant with novel features of the cataracts and a corneal opacity. With the exception of iris coloboma, the clinical features in all six previously reported families with mutations in the CRYAA gene were found in this family. We identified a novel G414A transition in exon 3 of CRYAA that co-segregated with an autosomal dominant phenotype. The resulting amino acid change R116H is in a highly conserved region and represents a change in charge. The genotype-phenotype correlation of this previously unreported mutation provides evidence that other factors, genetic and/or environmental, may influence the development of cataract as a result of this alteration.
authors.affiliation: Department of Ophthalmology, Rocky Mountain Lions Eye Institute, Aurora, Colorado 80045, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Richter
authors.forename: Pamela
authors.initials: P
authors.lastname: Flodman
authors.forename: Fernando
authors.initials: F
authors.lastname: Barria von-Bischhoffshausen
authors.forename: Douglas
authors.initials: D
authors.lastname: Burch
authors.forename: Sandra
authors.initials: S
authors.lastname: Brown
authors.forename: Linda
authors.initials: L
authors.lastname: Nguyen
authors.forename: Julia
authors.initials: J
authors.lastname: Turner
authors.forename: M Anne
authors.initials: MA
authors.lastname: Spence
authors.forename: J Bronwyn
authors.initials: JB
authors.lastname: Bateman
mesh_terms: D000328:Adult; D001483:Base Sequence; D002386:Cataract / Q000235:genetics*; D002648:Child; D002891:Chromosomes, Human, Pair 21; D003315:Cornea / Q000002:abnormalities*; D003318:Corneal Opacity / Q000235:genetics*; D003459:Crystallins / Q000235:genetics*; D017931:DNA Primers; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype
chemical_list: D003459:Crystallins; D017931:DNA Primers