MUTATIONS IN THE LIVER-GLYCOGEN PHOSPHORYLASE GENE (PYGL) UNDERLYING GLYCOGENOSIS TYPE-VI (HERS-DISEASE)

Deficiency of glycogen phosphorylase in the liver gives rise to glycog en-storage disease type VI (Hers disease; MIM 232700). We report the i dentification of the first mutations in PYGL, the gene encoding the li ver isoform of glycogen phosphorylase, in three patients with Hers dis ease. These are two splice-site mutations and two missense mutations. A mutation of the 5' splice-site consensus of intron 14 causes the ret ention of intron 14 and the utilization of two illegitimate 5' splice sites, whereas a mutation of the 3' splice-site consensus of intron 4 causes the skipping of exon 5. Two missense mutations, N338S and N376K , both cause nonconservative replacements of amino acids that are abso lutely conserved even in yeast and bacterial phosphorylases. We also r eport corrections of the PYGL coding sequence, sequence polymorphisms, and a partial PYGL gene structure with introns in the same positions as in PYGM, the gene of the muscle isoform of phosphorylase. Our findi ngs demonstrate that PYGL mutations cause Hers disease, and they may i mprove laboratory diagnosis of deficiencies of the liver phosphorylase system.