title: Expression of the muscle glycogen phosphorylase gene in patients with McArdle disease: the role of nonsense-mediated mRNA decay.
abstract: Nearly 35% of all mutations identified in the muscle glycogen phosphorylase gene (PYGM) in patients with McArdle disease result in premature termination codons (PTCs), particularly the p.R50X mutation. The latter accounts for more than 50% of the mutated alleles in most Caucasian patient populations. Mutations resulting in PTC could trigger the degradation of mRNA through a mechanism known as nonsense mediated decay (NMD). To investigate if NMD affects the levels of transcripts containing PYGM mutations, 28 Spanish patients with McArdle disease, harboring 17 different mutations with PTCs in 77% of their alleles, were studied. Transcripts levels of PYGM were measured and sequenced. We assessed that 92% of patients showed NMD. The most frequent mutation (p.R50X) elicited decay in all the genotypes tested. Other PTC producing mutations resulting in NMD were: p.L5VfsX22, p.Q73HfsX7, p.E125X, p.N134KfsX161, p.W388SfsX34, p.R491AfsX7, and p.D534VfsX5. Located in the last exon, the mutation p.E797VfsX19 was not affected by NMD. Missense mutations did not appear to be affected by NMD. In the cDNA sequences they appeared as homozygous, despite being heterozygous in the genomic DNA sequences. Exceptions to the rules governing NMD were found in the mutations p.A704 V and p.K754NfsX49.
authors.affiliation: Departament de Patologia Mitocondrial i Neuromuscular, Institut de Recerca, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Gisela
authors.initials: G
authors.lastname: Nogales-Gadea
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Rubio
authors.forename: Israel
authors.initials: I
authors.lastname: Fernandez-Cadenas
authors.forename: Ines
authors.initials: I
authors.lastname: Garcia-Consuegra
authors.forename: Alejandro
authors.initials: A
authors.lastname: Lucia
authors.forename: Ana
authors.initials: A
authors.lastname: Cabello
authors.forename: Elena
authors.initials: E
authors.lastname: Garcia-Arumi
authors.forename: Joaquin
authors.initials: J
authors.lastname: Arenas
authors.forename: Antoni L
authors.initials: AL
authors.lastname: Andreu
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Martín
mesh_terms: D018389:Codon, Nonsense / Q000235:genetics*; D004252:DNA Mutational Analysis; D004587:Electrophoresis, Agar Gel; D020869:Gene Expression Profiling; D024982:Glycogen Phosphorylase, Muscle Form / Q000235:genetics*; D006012:Glycogen Storage Disease Type V / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics; D020871:RNA Stability / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D018389:Codon, Nonsense; D024982:Glycogen Phosphorylase, Muscle Form