Missense mutations have unexpected consequences: The McArdle disease paradigm

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.

Long-Term Exercise Intervention in Patients with McArdle Disease: Clinical and Aerobic Fitness Benefits

“…The different PYGM genotypes of the 17 participants resulting in McArdle disease are shown in Supplemental File 1 (see Supplemental Digital Content 1, http:// links.lww.com/MSS/C564). Each of these genotypes results in total absence whatsoever of myophosphorylase activity (and thus in total inability to use muscle glycogen as a substrate) (23)(24)(25), and all the pathogenic PYGM mutations shown by the patients of the present study have been previously reported in the last update of the Spanish registry of patients with McArdle disease (1).…”

McArdle Disease: Clinical, Biochemical, Histological and Molecular Genetic Analysis of 60 Patients

“…These findings hint towards the severity of homozygous splice-site mutations over other mutations as the other two patients with heterozygous splice-site mutation (both compound heterozygous for p.Arg50Ter and c.1239+1G>A) had milder symptoms. However, large cohort studies including broad spectrum of PYGM mutations show the lack of distinct genotype-phenotype correlation [2,3,12,38]. In the present study, a clear genotype-phenotype correlation could not be established either as so many different genotypes were observed and all our patients presented with typical signs of exercise intolerance.…”

Clinical practice guidelines for glycogen storage disease V & VII (McArdle disease and Tarui disease) from an international study group

“…A recent publication explains the lack of genotype-phenotype correlation in GSD V. Most of the patients in the study did not have myophosphorylase activity, independent of the type of mutation (missense, nonsense, deletion, insertion, splicing, etc.) [31]. This indicates that myophosphorylase is not produced in the presence of PYGM mutations, except for very rare cases in which missense mutations lead to preserved myophosphorylase activity and ameliorated phenotypes [22].…”