Parental Source Effect on Inherited Mutations in the Dystrophin Gene of Mice and Humans

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Skewed X inactivation has been suspected as the genetic cause for some female carriers of Duchenne/Becker muscular dystrophy (DMD/BMD) presenting symptoms [1], as well as in manifesting females in other X-linked recessive diseases. No clear “parental source effect” – a difference in phenotype depending upon transmission of the mutated allele by either the father or the mother – has been observed [Cremer]. To date, most studies in this field have analysed the methylation status of flanking polymorphic sites (a measure of the maintenance of X inactivation and imprinting), not the expression of the causal gene itself.

To test the parental source effect on the protein expression of the dystrophin gene, we have set up crosses of mdx/mdx and mdx/y mice – the well-known DMD animal model [2] with the respective wild-type mice of the same strain (Table 1). The obligate heterozygous F₁ females show a mosaic expression of dystrophin in skeletal and cardiac muscle upon immunehistological staining. Because the source of the mutation in the litters is well defined, the mosaic pattern should reflect a parental source effect, if any. Such an effect should also change the level of muscle enzymes in serum and may thus be easily testable in humans, too. Since DMD is genetically lethal in humans, one can test the hypothesis of a parental source effect in BMD families only.