title: Cell death triggered by a novel mutation in the alphaA-crystallin gene underlies autosomal dominant cataract linked to chromosome 21q.
abstract: Hereditary cataract is a clinically and genetically heterogeneous lens disease that accounts for a significant proportion of visual impairment and blindness in childhood. The alphaA-crystallin (CRYAA) gene (CRYAA) encodes a member of the small-heat-shock protein (sHSP) family of molecular chaperones and is primarily and abundantly expressed in the ocular lens. Here, we have used linkage analysis to identify a novel missense mutation in CRYAA that underlies an autosomal dominant form of 'nuclear' cataract segregating in a four-generation Caucasian family. A maximum two-point LOD score (Z(max)) of 2.19 (maximum recombination fraction, theta(max)=0) and multipoint Z(max) of 3.3 (theta(max)=0) was obtained at marker D21S1885. Haplotype analysis indicated that the disease gene lay in the approximately 2.7 Mb physical interval between D21S1912 and D21S1260 flanking CRYAA on 21q22.3. Sequence analysis identified a C --> T transition in exon 1 of CRYAA from affected individuals that was predicted to result in the nonconservative substitution of cysteine for arginine at codon 49 (R49C). Transfection studies of lens epithelial cells revealed that, unlike wild-type CRYAA, the R49C mutant protein was abnormally localized to the nucleus and failed to protect from staurosporine-induced apoptotic cell death. This study has identified the first dominant cataract mutation in CRYAA located outside the phylogenetically conserved 'alpha-crystallin core domain' of the sHSP family.
mesh_terms: D000483:Alleles; D017209:Apoptosis; D016923:Cell Death; D002467:Cell Nucleus / Q000378:metabolism; D002469:Cell Separation; D002478:Cells, Cultured; D002891:Chromosomes, Human, Pair 21; D020285:Cryoelectron Microscopy; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000378:metabolism; D005091:Exons; D005260:Female; D005434:Flow Cytometry; D005799:Genes, Dominant; D008040:Genetic Linkage; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015151:Immunoblotting; D007438:Introns; D008126:Lod Score; D008297:Male; D008856:Microscopy, Fluorescence; D016253:Microscopy, Immunoelectron; D008957:Models, Genetic; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D017434:Protein Structure, Tertiary; D019311:Staurosporine / Q000494:pharmacology; D014162:Transfection; D038202:alpha-Crystallin A Chain / Q000235:genetics*
chemical_list: D017931:DNA Primers; D018076:DNA, Complementary; D038202:alpha-Crystallin A Chain; D019311:Staurosporine