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Characterization of a New, Dominant V124E Mutation in the Mouse A-Crystallin–Encoding Gene

¹ From the National Research Center for Environment and Health (GSF), Institute of Mammalian Genetics and the ² Institute of Experimental Genetics, Neuherberg, Germany; the ³ Institute of Molecular Genetics, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany; and ⁵ Lehrstuhl für Molekulare Tierzucht und Biotechnologie, Ludwig-Maximilians-Universität, Munich, Germany.

PURPOSE. During an ethylnitrosourea (ENU) mutagenesis screening, mice were tested for the occurrence of dominant cataracts. The purpose of the study was morphologic description, mapping of the mutant gene, and characterization of the underlying molecular lesion in a particular mutant, Aey7.

METHODS. Isolated lenses were photographed and histologic sections of the eye were analyzed according to standard procedures. Linkage analysis was performed with a set of microsatellite markers covering all autosomal chromosomes. cDNA was amplified after reverse transcription of lens mRNA. For PCR, cDNA or genomic DNA was used as a template.

RESULTS. Nuclear opacity and posterior suture anomaly were visible at eye opening and progressed to a nuclear and zonular cataract at 2 months of age. The opacity as well as the microphthalmia was more pronounced in the homozygotes than in the heterozygotes. The mutation was mapped to chromosome 17 between the markers D17Mit133 and D17Mit180. This position made the A-crystallin–encoding gene (Cryaa) an excellent candidate gene. Sequence analysis revealed a mutation of a T to an A at position 371 in the Cryaa cDNA. The mutation was confirmed by an additional MnlI restriction site in the genomic DNA of homozygous mutants leading to replacement of Val with Glu at codon 124 affecting the C-terminal region of the A-crystallin.

CONCLUSIONS. The Aey7 mutant represents the first dominant mouse cataract mutation affecting the Cryaa gene. The mutation leads to progressive opacification of the lens. Compared with the ß- and -crystallin–encoding genes, mutations in the -crystallin–encoding genes are rare.

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