Resolution of a mispaired secondary structure intermediate could account for a novel micro-insertion/deletion (387 insA/del 8 bp) in the PYGM gene causing McArdle's disease

We report two siblings with McArdle's disease who are both compound heteroz ygotes for two non-identical frameshift mutations in the PYGM gene; a previ ously reported 753 delA in exon 18 and a novel 387 insA/del 8 bp in exon 10 . The novel mutation is predicted to result in premature termination of tra nslation 33 amino acids downstream of the site of mutation, potentially enc oding a severely truncated protein of 419 amino acids instead of 841 amino acids. The complete lack of myophosphorylase activity observed in muscle de rived from one sibling suggests that this mutation has deleterious function al consequences. The underlying mechanism of mutagenesis ma!: have been sli pped mispairing mediated by the formation of a Moebius loop-like secondary intermediate.