Article Text

Novel mutations in patients with McArdle disease by analysis of skeletal muscle mRNA
  1. I García-Consuegra1,2,
  2. J C Rubio1,2,
  3. G Nogales-Gadea2,3,
  4. J Bautista4,
  5. S Jiménez1,2,
  6. A Cabello2,5,
  7. A Lucía6,
  8. A L Andreu2,3,
  9. J Arenas1,2,
  10. M A Martin1,2
  1. 1
    Centro de Investigación, Hospital Universitario 12 de Octubre, Madrid, Spain
  2. 2
    Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Barcelona, Spain
  3. 3
    Centre d’Investigacions en Bioquímica y Biología Molecular (CIBBIM), Hospital Universitari Vall d’Hebron, Barcelona, Spain
  4. 4
    Servicio de Neurología, Hospital Universitario Virgen del Rocío, Sevilla
  5. 5
    Servicio de Neuropatología, Hospital Universitario 12 de Octubre, Madrid, Spain
  6. 6
    Universidad Europea de Madrid, Madrid, Spain
  1. Dr M A Martín, Centro de Investigación, Hospital Universitario 12 de Octubre, Avda Córdoba s/n, 28041 Madrid, Spain; mamcasanueva{at}


Objective: To identify pathogenic mutant alleles of the PYGM gene in “genetic manifesting heterozygous” patients with McArdle disease—that is, those in whom we could only find a sole mutant allele by genomic DNA analysis.

Methods: We studied four unrelated patients. PCR-RFLP, gene sequencing, and muscle cDNA analysis were performed to search for mutations in the PYGM gene. The effects of the mutations were evaluated by in silico analysis, and gene expression was assessed by real-time polymerase chain reaction (PCR).

Results: Patient 1 was a compound heterozygous for the p.G205S missense mutation and for a novel “in frame” mutation, p.Q176_M177insVQ, resulting from a retention of six nucleotides from the 3′-end sequence of intron 4. Patient 2 was heterozygous for the common nonsense mutation p.R50X, and for a 1094 bp, c.1969+214_2177+369del mutation, spanning from intron 16 to intron 17 sequences. Furthermore, mRNA expression level was dramatically reduced consistent with nonsense mediated decay. Patient 3 was heterozygous for the p.R50X substitution, and patient 4 was heterozygous for the relatively common private Spanish mutation p.W798R. These two patients harboured a heterozygous exonic synonymous variant, p.K215K. Quantification of gene transcripts in patient 3 revealed a drastic decrease in the relative expression of the gene, which strongly supports the possibility of nonsense mediated decay.

Conclusions: Our results indicate that skeletal muscle cDNA studies in “genetic manifesting heterozygous” patients with McArdle disease are prone to identify their second mutant allele.

Statistics from


  • Competing interests: None declared.

  • Funding: G-CI was supported by a fellowship from Fondo de Investigacion Sanitaria (FIS) (PI04/0487) and by a contract from Fundación de Investigación Biomédica Hospital 12 de Octubre, Madrid, Spain. R-JC was supported by a contract from FIS (CA05-0039). GN-G was supported by a fellowship from FIS (PI04/0362), Instituto de Salud Carlos III. Grant sponsor: Fondo de Investigación Sanitaria (FIS); Grant numbers: PI040487; PI041157; PI040362. Grant sponsor: Spanish Network for Rare Diseases (CIBERER), Madrid, Barcelona.

  • Patient consent: Obtained

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.