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

Fecha de publicación: 01/03/2020 Fecha Ahead of Print: 03/01/2020

Autores de IIS La Fe

Nuria Muelas Gómez

Autor
Juan Jesús Vílchez Padilla

Autor

Participantes ajenos a IIS La Fe

Servián-Morilla E
Cabrera-Serrano M
Johnson K
Pandey A
Ito A
Rivas E
Chamova T
Mongini T
Nafissi S
Claeys KG
Grewal RP
Takeuchi M
Hao H
Bönnemann C
Lopes Abath Neto O
Medne L
Brandsema J
Töpf A
Taneva A
Tournev I
Haltiwanger RS
Takeuchi H
Jafar-Nejad H
Straub V
Paradas C

Grupos

Patología Neuromuscular y Ataxias

Investigador Principal

Teresa Sevilla Mantecón

Abstract

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 a-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 a-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 a-dystroglycan glycosylation provides excellent tools which will help diagnose and follow up LGMD R21 patients.

Datos de la publicación

ISSN/ISSNe:: 0001-6322, 1432-0533
Tipo:: Article
Páginas:: 565-582
DOI:: 10.1007/s00401-019-02117-6
Factor de Impacto:: 7,183 SCImago ℠
Cuartil:: Q1 SCImago ℠

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Métricas

Filiaciones

Servián-Morilla E:: Neuromuscular Disorders Unit, Department of Neurology, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain

Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Cabrera-Serrano M:: Neuromuscular Disorders Unit, Department of Neurology, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain

Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Johnson K:: The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE1 3BZ, UK

Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
Pandey A:: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
Ito A:: Complex Carbohydrate Research Center, University of Georgia, Athens, GA, 30602, USA
Rivas E:: Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain

Department of Neuropathology, Hospital U. Virgen del Rocío/Instituto de Biomedicina de Sevilla (IBiS), Sevilla, Spain
Chamova T:: Department of Neurology, Clinic of Nervous Diseases, University Hospital "Alexandrovska", Medical University Sofia, Sofia, Bulgaria
Muelas N:: Instituto de Investigación. Neuromuscular Disorders Unit, Department of Neurology and IIS La Fe, Hospital UiP La Fe, Centro de Investigación Biomédica en Red Sobre Enfermedades Raras (CIBERER), Valencia, Spain
Mongini T:: Neuromuscular Unit, Department of Neuroscience "Rita Levi Montalcini", University of Torino, Torino, Italy
Nafissi S:: Department of Neurology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
Claeys KG:: Department of Neurology, University Hospitals Leuven, Leuven, Belgium

Laboratory for Muscle Diseases and Neuropathies, Department of Neurosciences, KU Leuven, Leuven, Belgium
Grewal RP:: Department of Neuroscience, School of Health and Medical Sciences, Seton Hall University/Saint Francis Medical Center, Trenton, NJ, USA
Takeuchi M:: Complex Carbohydrate Research Center, University of Georgia, Athens, GA, 30602, USA
Hao H:: Complex Carbohydrate Research Center, University of Georgia, Athens, GA, 30602, USA
Bönnemann C:: Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
Lopes Abath Neto O:: Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
Medne L:: Divisions of Neurology and Human Genetics of Genomic Medicine, Children's Hospital of Philadelphia, Philadelphia, USA
Brandsema J:: Divisions of Neurology and Human Genetics of Genomic Medicine, Children's Hospital of Philadelphia, Philadelphia, USA
Töpf A:: The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE1 3BZ, UK
Taneva A:: Department of Neurology, Clinic of Nervous Diseases, University Hospital "Alexandrovska", Medical University Sofia, Sofia, Bulgaria
Vilchez JJ:: Instituto de Investigación. Neuromuscular Disorders Unit, Department of Neurology and IIS La Fe, Hospital UiP La Fe, Centro de Investigación Biomédica en Red Sobre Enfermedades Raras (CIBERER), Valencia, Spain
Tournev I:: Department of Neurology, Clinic of Nervous Diseases, University Hospital "Alexandrovska", Medical University Sofia, Sofia, Bulgaria

Department of Cognitive Science and Psychology, New Bulgarian University, Sofia, Bulgaria
Haltiwanger RS:: Complex Carbohydrate Research Center, University of Georgia, Athens, GA, 30602, USA
Takeuchi H:: Department of Molecular Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, 466-8550, Japan
Jafar-Nejad H:: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
Straub V:: The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE1 3BZ, UK
Paradas C:: Neuromuscular Disorders Unit, Department of Neurology, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.

Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.