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Missense mutations have unexpected consequences: The McArdle disease paradigm
Author(s) -
GarcíaConsuegra Inés,
AsensioPeña Sara,
BallesterLopez Alfonsina,
FranciscoVelilla Rosario,
Pinos Tomás,
PintosMorell Guillem,
CollCantí Jaume,
GonzálezQuintana Adrián,
Andreu Antoni L.,
Arenas Joaquín,
Lucia Alejandro,
NogalesGadea Gisela,
Martín Miguel A.
Publication year - 2018
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23591
Subject(s) - missense mutation , biology , glycogen phosphorylase , genetics , gene , glycogen storage disease , phenotype , mutation , genotype , gene isoform , glycogen , medicine , endocrinology
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.