DIFFERENTIAL EXPRESSION OF DYSTROPHIN ISOFORMS IN STRAINS OF MDX MICEWITH DIFFERENT MUTATIONS

Mutations in the dystrophin gene are responsible for Duchenne and Beck er muscular dystrophy (DMD/BMD), Studies of dystrophin expression and function have benefited from use of the mdx mouse, an animal model for DMD/BMD. Here we characterized mutations in three additional strains of mdx mice, the mdx(2cv), mdx(4cv) and mdx(5cv) alleles, The mutation in the mdx(2cv) mouse was found to be a single base change in the spl ice acceptor sequence of dystrophin intron 42, This mutation leads to a complex pattern of aberrant splicing that generates multiple transcr ipts, none of which preserve the normal open reading frame, In the mdx (5cv) allele, the dystrophin mRNA contains a 53 bp deletion of sequenc es from exon 10, Analysis of the genomic DNA uncovered a single A to T transversion in exon 10, Although this base change does not alter the encoded amino acid, a new splice donor was created (GTGAG) that gener ates a frameshifting deletion in the processed mRNA, In the mdx(4cv) a llele, direct sequencing revealed a C to T transition in exon 53, crea ting an ochre codon (CAA to TAA), The differential location of these m utations relative to the seven known dystrophin promoters results in a series of mdx mouse mutants that differ in their repertoire of isofor m expression, such that these mice should be useful for studies of dys trophin expression and function. The mdx(4cv) and mdx(5cv) strains may be of additional use in gene transfer studies due to their low freque ncy of mutation reversion.