POGLUT1 biallelic mutations cause myopathy with reduced satellite cells, α-dystroglycan hypoglycosylation and a distinctive radiological pattern.

TitlePOGLUT1 biallelic mutations cause myopathy with reduced satellite cells, α-dystroglycan hypoglycosylation and a distinctive radiological pattern.
Publication TypeJournal Article
Year of Publication2020
AuthorsServián-Morilla, E, Cabrera-Serrano, M, Johnson, K, Pandey, A, Ito, A, Rivas, E, Chamova, T, Muelas, N, Mongini, T, Nafissi, S, Claeys, KG, Grewal, RP, Takeuchi, M, Hao, H, Bönnemann, C, O Neto, LAbath, Medne, L, Brandsema, J, Töpf, A, Taneva, A, Vilchez, JJ, Tournev, I, Haltiwanger, RS, Takeuchi, H, Jafar-Nejad, H, Straub, V, Paradas, C
JournalActa Neuropathol
Date Published2020 03
KeywordsAnimals, Animals, Genetically Modified, Drosophila melanogaster, Dystroglycans, Female, Genetic Association Studies, Glucosyltransferases, Glycosylation, Humans, Male, Muscle, Skeletal, Muscular Dystrophies, Limb-Girdle, Mutation, Pedigree, Satellite Cells, Skeletal Muscle

Protein O-glucosyltransferase 1 (POGLUT1) activity is critical for the Notch signaling pathway, being one of the main enzymes responsible for the glycosylation of the extracellular domain of Notch receptors. A biallelic mutation in the POGLUT1 gene has been reported in one family as the cause of an adult-onset limb-girdle muscular dystrophy (LGMD R21; OMIM# 617232). As the result of a collaborative international effort, we have identified the first cohort of 15 patients with LGMD R21, from nine unrelated families coming from different countries, providing a reliable phenotype-genotype and mechanistic insight. Patients carrying novel mutations in POGLUT1 all displayed a clinical picture of limb-girdle muscle weakness. However, the age at onset was broadened from adult to congenital and infantile onset. Moreover, we now report that the unique muscle imaging pattern of "inside-to-outside" fatty degeneration observed in the original cases is indeed a defining feature of POGLUT1 muscular dystrophy. Experiments on muscle biopsies from patients revealed a remarkable and consistent decrease in the level of the NOTCH1 intracellular domain, reduction of the pool of satellite cells (SC), and evidence of α-dystroglycan hypoglycosylation. In vitro biochemical and cell-based assays suggested a pathogenic role of the novel POGLUT1 mutations, leading to reduced enzymatic activity and/or protein stability. The association between the POGLUT1 variants and the muscular phenotype was established by in vivo experiments analyzing the indirect flight muscle development in transgenic Drosophila, showing that the human POGLUT1 mutations reduced its myogenic activity. In line with the well-known role of the Notch pathway in the homeostasis of SC and muscle regeneration, SC-derived myoblasts from patients' muscle samples showed decreased proliferation and facilitated differentiation. Together, these observations suggest that alterations in SC biology caused by reduced Notch1 signaling result in muscular dystrophy in LGMD R21 patients, likely with additional contribution from α-dystroglycan hypoglycosylation. This study settles the muscular clinical phenotype linked to POGLUT1 mutations and establishes the pathogenic mechanism underlying this muscle disorder. The description of a specific imaging pattern of fatty degeneration and muscle pathology with a decrease of α-dystroglycan glycosylation provides excellent tools which will help diagnose and follow up LGMD R21 patients.

Alternate JournalActa Neuropathol
PubMed ID31897643
PubMed Central IDPMC7196238
Grant ListUM1 HG008900 / HG / NHGRI NIH HHS / United States
R01 GM084135 / GM / NIGMS NIH HHS / United States
R01 GM061126 / GM / NIGMS NIH HHS / United States
R35 GM130317 / GM / NIGMS NIH HHS / United States
P50 HD103555 / HD / NICHD NIH HHS / United States
P40 OD018537 / OD / NIH HHS / United States
U54 HD083092 / HD / NICHD NIH HHS / United States