2. Academic Validation
  3. A form of muscular dystrophy associated with pathogenic variants in JAG2

A form of muscular dystrophy associated with pathogenic variants in JAG2

  • Am J Hum Genet. 2021 May 6;108(5):840-856. doi: 10.1016/j.ajhg.2021.03.020.
Sandra Coppens 1,  Alison M Barnard 2,  Sanna Puusepp 3,  Sander Pajusalu 3,  Katrin Õunap 3,  Dorianmarie Vargas-Franco 4,  Christine C Bruels 4,  Sandra Donkervoort 5,  Lynn Pais 6,  Katherine R Chao 6,  Julia K Goodrich 6,  Eleina M England 7,  Ben Weisburd 6,  Vijay S Ganesh 8,  Sanna Gudmundsson 7,  Anne O'Donnell-Luria 7,  Mait Nigul 9,  Pilvi Ilves 10,  Payam Mohassel 5,  Teepu Siddique 11,  Margherita Milone 12,  Stefan Nicolau 12,  Reza Maroofian 13,  Henry Houlden 13,  Michael G Hanna 13,  Ros Quinlivan 13,  Mehran Beiraghi Toosi 14,  Ehsan Ghayoor Karimiani 15,  Sabine Costagliola 16,  Nicolas Deconinck 17,  Hazim Kadhim 18,  Erica Macke 19,  Brendan C Lanpher 20,  Eric W Klee 20,  Anna Łusakowska 21,  Anna Kostera-Pruszczyk 21,  Andreas Hahn 22,  Bertold Schrank 23,  Ichizo Nishino 24,  Masashi Ogasawara 24,  Rasha El Sherif 25,  Tanya Stojkovic 26,  Isabelle Nelson 27,  Gisèle Bonne 27,  Enzo Cohen 27,  Anne Boland-Augé 28,  Jean-François Deleuze 28,  Yao Meng 29,  Ana Töpf 30,  Catheline Vilain 1,  Christina A Pacak 31,  Marie L Rivera-Zengotita 32,  Carsten G Bönnemann 5,  Volker Straub 30,  Penny A Handford 29,  Isabelle Draper 33,  Glenn A Walter 34,  Peter B Kang 35
Affiliations

Affiliations

  • 1 Center of Human Genetics, Université Libre de Bruxelles, 1070 Brussels, Belgium.
  • 2 Department of Physical Therapy, University of Florida College of Public Health and Health Professions, Gainesville, FL 32610, USA.
  • 3 Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu 50406, Estonia; Institute of Clinical Medicine, University of Tartu, Tartu 50406, Estonia.
  • 4 Division of Pediatric Neurology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL 32610, USA.
  • 5 Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, NINDS, NIH, Bethesda, MD 20892, USA.
  • 6 Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
  • 7 Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 8 Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • 9 Department of Radiology, Tartu University Hospital, Tartu 50406, Estonia.
  • 10 Institute of Clinical Medicine, University of Tartu, Tartu 50406, Estonia; Department of Radiology, Tartu University Hospital, Tartu 50406, Estonia.
  • 11 Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
  • 12 Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
  • 13 Department of Neuromuscular Disorders, University College London Institute of Neurology, London WC1E 6BT, UK.
  • 14 Pediatric Neurology Department, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad 9176999311, Iran.
  • 15 Molecular and Clinical Sciences Institute, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK; Innovative Medical Research Center, Mashhad Branch, Islamic Azad University, Mashhad 9187147578, Iran.
  • 16 Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire, Université Libre de Bruxelles, 1070 Brussels, Belgium.
  • 17 Centre de Référence Neuromusculaire and Paediatric Neurology Department, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, 1020 Brussels, Belgium.
  • 18 Neuropathology Unit, Department of Anatomic Pathology and Reference Center for Neuromuscular Pathology, Brugmann University Hospital-Children's Hospital, Université Libre de Bruxelles, 1020 Brussels, Belgium.
  • 19 Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA.
  • 20 Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA; Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA.
  • 21 Department of Neurology, Medical University of Warsaw, 02-091 Warsaw, Poland.
  • 22 Department of Child Neurology, Justus-Liebig-University Giessen, 35390 Giessen, Germany.
  • 23 Department of Neurology, DKD HELIOS Klinik Wiesbaden, 65191 Wiesbaden, Germany.
  • 24 Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan.
  • 25 Myo-Care Neuromuscular Center, Myo-Care National Foundation, Cairo 11865, Egypt.
  • 26 APHP, Nord-Est/Ile-de-France Neuromuscular Reference Center, Myology Institute, Pitié-Salpêtrière Hospital, 75013 Paris, France; Sorbonne Université, INSERM, Center of Research in Myology, UMRS974, 75651 Paris Cedex 13, France.
  • 27 Sorbonne Université, INSERM, Center of Research in Myology, UMRS974, 75651 Paris Cedex 13, France.
  • 28 Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, 91057 Evry, France.
  • 29 Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
  • 30 John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 3BZ, UK.
  • 31 Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL 32610, USA; Paul and Sheila Wellstone Muscular Dystrophy Center, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
  • 32 Department of Pathology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
  • 33 Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
  • 34 Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL 32610, USA.
  • 35 Division of Pediatric Neurology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL 32610, USA; Paul and Sheila Wellstone Muscular Dystrophy Center, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Institute for Translational Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA. Electronic address: [email protected].
PMID: 33861953 DOI: 10.1016/j.ajhg.2021.03.020
Abstract

JAG2 encodes the Notch ligand Jagged2. The conserved Notch signaling pathway contributes to the development and homeostasis of multiple tissues, including skeletal muscle. We studied an international cohort of 23 individuals with genetically unsolved muscular dystrophy from 13 unrelated families. Whole-exome sequencing identified rare homozygous or compound heterozygous JAG2 variants in all 13 families. The identified bi-allelic variants include 10 missense variants that disrupt highly conserved Amino acids, a nonsense variant, two frameshift variants, an in-frame deletion, and a microdeletion encompassing JAG2. Onset of muscle weakness occurred from infancy to young adulthood. Serum creatine kinase (CK) levels were normal or mildly elevated. Muscle histology was primarily dystrophic. MRI of the lower extremities revealed a distinct, slightly asymmetric pattern of muscle involvement with cores of preserved and affected muscles in quadriceps and tibialis anterior, in some cases resembling patterns seen in POGLUT1-associated muscular dystrophy. Transcriptome analysis of muscle tissue from two participants suggested misregulation of genes involved in myogenesis, including PAX7. In complementary studies, Jag2 downregulation in murine myoblasts led to downregulation of multiple components of the Notch pathway, including Megf10. Investigations in Drosophila suggested an interaction between Serrate and Drpr, the fly orthologs of JAG1/JAG2 and MEGF10, respectively. In silico analysis predicted that many Jagged2 missense variants are associated with structural changes and protein misfolding. In summary, we describe a muscular dystrophy associated with pathogenic variants in JAG2 and evidence suggests a disease mechanism related to Notch pathway dysfunction.

Keywords

JAG2, Jagged2, Serrate, Notch signaling pathway, muscular dystrophy, muscle MRI, POGLUT1, MEGF10, exome sequencing, satellite cell.

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