Missense mutations have unexpected consequences: The McArdle disease paradigm.
Hum Mutat
; 39(10): 1338-1343, 2018 10.
Article
in En
| MEDLINE
| ID: mdl-30011114
ABSTRACT
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Glycogen Storage Disease Type V
/
Mutation, Missense
/
Genetic Association Studies
Type of study:
Diagnostic_studies
/
Prognostic_studies
Limits:
Adolescent
/
Adult
/
Aged
/
Female
/
Humans
/
Male
/
Middle aged
Language:
En
Journal:
Hum Mutat
Journal subject:
GENETICA MEDICA
Year:
2018
Document type:
Article
Affiliation country:
España