TY - JOUR
T1 - Missense mutations have unexpected consequences: The McArdle disease paradigm
AU - García-Consuegra, Inés
AU - Asensio-Peña, Sara
AU - Ballester-Lopez, Alfonsina
AU - Francisco-Velilla, Rosario
AU - Pinos, Tomás
AU - Pintos-Morell, Guillem
AU - Coll-Cantí, Jaume
AU - González-Quintana, Adrián
AU - Andreu, Antoni L.
AU - Arenas, Joaquín
AU - Lucia, Alejandro
AU - Nogales-Gadea, Gisela
AU - Martín, Miguel A.
PY - 2018/10/1
Y1 - 2018/10/1
N2 - © 2018 Wiley Periodicals, Inc. McArdle disease is a disorder of muscle glycogen metabolism caused by mutations in the PYGM gene, encoding for the muscle-specific isoform of glycogen phosphorylase (M-GP). The activity of this enzyme is completely lost in patients’ muscle biopsies, when measured with a standard biochemical test which, does not allow to determine M-GP protein levels. We aimed to determine M-GP protein levels in the muscle of McArdle patients, by studying biopsies of 40 patients harboring a broad spectrum of PYGM mutations and 22 controls. Lack of M-GP protein was found in muscle in the vast majority (95%) of patients, irrespective of the PYGM genotype, including those carrying missense mutations, with few exceptions. M-GP protein biosynthesis is not being produced by PYGM mutations inducing premature termination codons (PTC), neither by most PYGM missense mutations. These findings explain the lack of PYGM genotype–phenotype correlation and have important implications for the design of molecular-based therapeutic approaches.
AB - © 2018 Wiley Periodicals, Inc. McArdle disease is a disorder of muscle glycogen metabolism caused by mutations in the PYGM gene, encoding for the muscle-specific isoform of glycogen phosphorylase (M-GP). The activity of this enzyme is completely lost in patients’ muscle biopsies, when measured with a standard biochemical test which, does not allow to determine M-GP protein levels. We aimed to determine M-GP protein levels in the muscle of McArdle patients, by studying biopsies of 40 patients harboring a broad spectrum of PYGM mutations and 22 controls. Lack of M-GP protein was found in muscle in the vast majority (95%) of patients, irrespective of the PYGM genotype, including those carrying missense mutations, with few exceptions. M-GP protein biosynthesis is not being produced by PYGM mutations inducing premature termination codons (PTC), neither by most PYGM missense mutations. These findings explain the lack of PYGM genotype–phenotype correlation and have important implications for the design of molecular-based therapeutic approaches.
KW - genotype–phenotype correlation
KW - McArdle disease
KW - missense mutations
KW - muscle glycogen phosphorylase
U2 - 10.1002/humu.23591
DO - 10.1002/humu.23591
M3 - Article
C2 - 30011114
VL - 39
SP - 1338
EP - 1343
ER -