title: CRYBA4, a novel human cataract gene, is also involved in microphthalmia.
abstract: Genetic analysis of a large Indian family with an autosomal dominant cataract phenotype allowed us to identify a novel cataract gene, CRYBA4. After a genomewide screen, linkage analysis identified a maximum LOD score of 3.20 (recombination fraction [theta] 0.001) with marker D22S1167 of the beta -crystallin gene cluster on chromosome 22. To date, CRYBA4 was the only gene in this cluster not associated with either human or murine cataracts. A pathogenic mutation was identified in exon 4 that segregated with the disease status. The c.317T-->C sequence change is predicted to replace the highly conserved hydrophobic amino acid phenylalanine94 with the hydrophilic amino acid serine. Modeling suggests that this substitution would significantly reduce the intrinsic stability of the crystalline monomer, which would impair its ability to form the association modes critical for lens transparency. Considering that CRYBA4 associates with CRYBB2 and that the latter protein has been implicated in microphthalmia, mutational analysis of CRYBA4 was performed in 32 patients affected with microphthalmia (small eye). We identified a c.242T-->C (Leu69Pro) sequence change in exon 4 in one patient, which is predicted here to disrupt the beta -sheet structure in CRYBA4. Protein folding would consequently be impaired, most probably leading to a structure with reduced stability in the mutant. This is the first report linking mutations in CRYBA4 to cataractogenesis and microphthalmia.
authors.affiliation: Program of Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada.
authors.forename: Gail
authors.initials: G
authors.lastname: Billingsley
authors.forename: Sathiyavedu T
authors.initials: ST
authors.lastname: Santhiya
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Paterson
authors.forename: Koji
authors.initials: K
authors.lastname: Ogata
authors.forename: Shoshana
authors.initials: S
authors.lastname: Wodak
authors.forename: S Mohsen
authors.initials: SM
authors.lastname: Hosseini
authors.forename: Shyam Manohar
authors.initials: SM
authors.lastname: Manisastry
authors.forename: Perumalsamy
authors.initials: P
authors.lastname: Vijayalakshmi
authors.forename: Pudhiya Mundyat
authors.initials: PM
authors.lastname: Gopinath
authors.forename: Jochen
authors.initials: J
authors.lastname: Graw
authors.forename: Elise
authors.initials: E
authors.lastname: Héon
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002386:Cataract / Q000235:genetics*; D005091:Exons; D005190:Family; D005260:Female; D005799:Genes, Dominant; D015894:Genome, Human; D006801:Humans; D008126:Lod Score; D008297:Male; D008850:Microphthalmos / Q000235:genetics*; D018895:Microsatellite Repeats; D008958:Models, Molecular; D010375:Pedigree; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D038205:beta-Crystallin A Chain / Q000737:chemistry / Q000235:genetics*
chemical_list: C103907:CRYBA4 protein, human; D038205:beta-Crystallin A Chain