Taking advantage of an old concept, "illegitimate transcription", for a proposed novel method of genetic diagnosis of McArdle disease

Ines Garcia-Consuegra, Alberto Blázquez, Juan Carlos Rubio, Joaquín Arenas, Alfonsina Ballester-Lopez, Adrián González-Quintana, Antoni L. Andreu, Tomàs Pinós, Jaume Coll-Cantí, Alejandro Lucia, Gisela Nogales-Gadea, Miguel A. Martín

Research output: Contribution to journalArticleResearchpeer-review

9 Citations (Scopus)


© American College of Medical Genetics and Genomics. Purpose:McArdle disease is a metabolic disorder caused by pathogenic mutations in the PYGM gene. Timely diagnosis can sometimes be difficult with direct genomic analysis, which requires additional studies of cDNA from muscle transcripts. Although the "nonsense-mediated mRNA decay" (NMD) eliminates tissue-specific aberrant transcripts, there is some residual transcription of tissue-specific genes in virtually all cells, such as peripheral blood mononuclear cells (PBMCs).Methods:We studied a subset of the main types of PYGM mutations (deletions, missense, nonsense, silent, or splicing mutations) in cDNA from easily accessible cells (PBMCs) in 12 McArdle patients.Results:Analysis of cDNA from PBMCs allowed detection of all mutations. Importantly, the effects of mutations with unknown pathogenicity (silent and splicing mutations) were characterized in PBMCs. Because the NMD mechanism does not seem to operate in nonspecific cells, PBMCs were more suitable than muscle biopsies for detecting the pathogenicity of some PYGM mutations, notably the silent mutation c.645G>A (p.K215=), whose effect in the splicing of intron 6 was unnoticed in previous muscle transcriptomic studies.Conclusion:We propose considering the use of PBMCs for detecting mutations that are thought to cause McArdle disease, particularly for studying their actual pathogenicity.
Original languageEnglish
Pages (from-to)1128-1135
JournalGenetics in Medicine
Issue number11
Publication statusPublished - 1 Nov 2016


  • diagnosis
  • glycogenosis type V
  • McArdle disease
  • PYGM mutations
  • transcript analysis


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