Missense mutations have unexpected consequences: The McArdle disease paradigm
Por:
Garcia-Consuegra, I, Asensio-Pena, S, Ballester-Lopez, A, Francisco-Velilla, R, Pinos, T, Pintos-Morell, G, Coll-Canti, J, Gonzalez-Quintana, A, Andreu, AL, Arenas, J, Lucia, A, Nogales-Gadea, G and Martin, MA
Publicada:
1 oct 2018
Resumen:
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.
Filiaciones:
Garcia-Consuegra, I:
Inst Invest Hosp 12 Octubre I 12, Grp Invest Enfermedades Mitocondriales & Neuromus, Madrid, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid, Spain
Asensio-Pena, S:
Inst Invest Hosp 12 Octubre I 12, Grp Invest Enfermedades Mitocondriales & Neuromus, Madrid, Spain
:
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid, Spain
Univ Autonoma Barcelona, Inst Invest Ciencies Salut Germans Trias & Pujol, Dept Neurosci, Grp Recerca Malalties Neuromusculars & Neuropedia, Cami Escoles S-N, Badalona 08916, Spain
Francisco-Velilla, R:
CSIC UAM, Ctr Biol Mol Severo Ochoa, Madrid, Spain
Pinos, T:
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid, Spain
Univ Autonoma Barcelona, Inst Recerca VHIR, Hosp Univ Vall dHebron, Dept Patol Mitocondrial & Neuromuscular, Barcelona, Spain
:
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid, Spain
Univ Autonoma Barcelona, Inst Invest Ciencies Salut Germans Trias & Pujol, Dept Neurosci, Grp Recerca Malalties Neuromusculars & Neuropedia, Cami Escoles S-N, Badalona 08916, Spain
Univ Hosp Vall dHebron, Div Rare Dis, Barcelona, Spain
:
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid, Spain
Univ Autonoma Barcelona, Inst Invest Ciencies Salut Germans Trias & Pujol, Dept Neurosci, Grp Recerca Malalties Neuromusculars & Neuropedia, Cami Escoles S-N, Badalona 08916, Spain
Hosp Badalona Germans Trias & Pujol, Serv Neurol, Badalona, Spain
Gonzalez-Quintana, A:
Inst Invest Hosp 12 Octubre I 12, Grp Invest Enfermedades Mitocondriales & Neuromus, Madrid, Spain
Andreu, AL:
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid, Spain
Univ Autonoma Barcelona, Inst Recerca VHIR, Hosp Univ Vall dHebron, Dept Patol Mitocondrial & Neuromuscular, Barcelona, Spain
Arenas, J:
Inst Invest Hosp 12 Octubre I 12, Grp Invest Enfermedades Mitocondriales & Neuromus, Madrid, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid, Spain
Lucia, A:
Univ Europea, Fac Sport Sci, Madrid, Spain
Inst Invest Hosp 12 Octubre I 12, Madrid, Spain
:
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid, Spain
Univ Autonoma Barcelona, Inst Invest Ciencies Salut Germans Trias & Pujol, Dept Neurosci, Grp Recerca Malalties Neuromusculars & Neuropedia, Cami Escoles S-N, Badalona 08916, Spain
Martin, MA:
Inst Invest Hosp 12 Octubre I 12, Grp Invest Enfermedades Mitocondriales & Neuromus, Madrid, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid, Spain
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