Premium
A New Glycogen Storage Disease Caused by a Dominant PYGM Mutation
Author(s) -
EchanizLaguna Andoni,
Lornage Xavière,
Laforêt Pascal,
Orngreen Mette C.,
Edelweiss Evelina,
Brochier Guy,
Bui Mai T.,
SilvaRojas Roberto,
Birck Catherine,
Lannes Béatrice,
Romero Norma B.,
Vissing John,
Laporte Jocelyn,
Böhm Johann
Publication year - 2020
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.25771
Subject(s) - missense mutation , biology , glycogen , mutation , glycogen storage disease , exome sequencing , genetics , glycogen synthase , desmin , glycogen debranching enzyme , gene , biochemistry , vimentin , immunohistochemistry , immunology
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.