Production of animal models for Duchenne muscular dystrophy (DMD) using chromosomal manipulation and recombination

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Duchenne muscular dystrophy (DMD) is caused by mutation in the 2.4-Mb dystrophin (DMD) gene. This gene encodes a number of tissue-specific isoforms of dystrophin generated by transcription from at least seven promoters and also by alternative splicing. We deleted entire genomic region of the DMD gene on mouse chromosome X using a Cre-loxP recombination system. The DMD-null mice were viable but displayed severe muscular hypertrophy and dystrophy. Production of multiple dystrophin isoforms due to alternative splicing or exon skipping was totally prevented in the DMD-null mouse. In addition, we introduced an artificial chromosome which contained the human dystrophin gene (HAC-DMD) into the DMD-null ES cells and subsequently produced chimeric mice using the ES cells. The mouse thus produced possesses the human DMD gene instead of mouse DMD gene. These new mutants will provide an improved model system for functional studies of human dystrophin and its isoforms.