1. A New Glycogen Storage Disease Caused by a Dominant PYGM Mutation
- Author
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Pascal Laforêt, Roberto Silva-Rojas, Béatrice Lannes, Guy Brochier, Mai Thao Bui, Jocelyn Laporte, Andoni Echaniz-Laguna, Norma B. Romero, John Vissing, Johann Böhm, Evelina Edelweiss, Xavière Lornage, Mette Cathrine Ørngreen, Catherine Birck, Service de neurologie [Le Kremlin Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, National Reference Center for FAP (NNERF)/ APHP/ INSERM U 1191, Hôpital de Bicêtre, Petites Molécules de neuroprotection, neurorégénération et remyélinisation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Les Hôpitaux Universitaires de Strasbourg (HUS), Fondation pour la Recherche Médicale, FRM: PLP20170939073 Institut National de la Santé et de la Recherche Médicale, Inserm Fondation Maladies Rares, FMR: IPM05201114 Institut National des Sciences de l'Univers, Centre National de la Recherche Scientifique, INSU,CNRS Institut National de la Santé et de la Recherche Médicale, Inserm Centre National de la Recherche Scientifique, CNRS, This work was supported by Institut National de Santé et de Recherche Médicale (Inserm), Centre National de Recherche Scientifique (CNRS), Strasbourg University, and the Fondation Maladies Rares (IPM05201114). R.S.R. was funded by Fondation Recherche Médicale doctoral fellowship (PLP20170939073)., Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,Adult ,Male ,Mutant ,Biology ,medicine.disease_cause ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Glycogen storage disease ,Missense mutation ,Humans ,Exome sequencing ,Genetics ,Mutation ,Glycogen ,Middle Aged ,medicine.disease ,Glycogen Storage Disease ,3. Good health ,Pedigree ,030104 developmental biology ,Neurology ,chemistry ,Myophosphorylase ,Glycogen Phosphorylase, Muscle Form ,Desmin ,Female ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Neurology (clinical) ,030217 neurology & neurosurgery - Abstract
International audience; Objective: Glycogen storage diseases (GSDs) are severe human disorders resulting from abnormal glucose metabolism, and all previously described GSDs segregate as autosomal recessive or X-linked traits. In this study, we aimed to molecularly characterize the first family with a dominant GSD. Methods: We describe a dominant GSD family with 13 affected members presenting with adult-onset muscle weakness, and we provide clinical, metabolic, histological, and ultrastructural data. We performed exome sequencing to uncover the causative gene, and functional experiments in the cell model and on recombinant proteins to investigate the pathogenic effect of the identified mutation. Results: We identified a heterozygous missense mutation in PYGM segregating with the disease in the family. PYGM codes for myophosphorylase, the enzyme catalyzing the initial step of glycogen breakdown. Enzymatic tests revealed that the PYGM mutation impairs the AMP-independent myophosphorylase activity, whereas the AMP-dependent activity was preserved. Further functional investigations demonstrated an altered conformation and aggregation of mutant myophosphorylase, and the concurrent accumulation of the intermediate filament desmin in the myofibers of the patients. Interpretation: Overall, this study describes the first example of a dominant glycogen storage disease in humans, and elucidates the underlying pathomechanisms by deciphering the sequence of events from the PYGM mutation to the accumulation of glycogen in the muscle fibers. ANN NEUROL 2020;88:274–282.
- Published
- 2020