A form of muscular dystrophy associated with pathogenic variants in JAG2

Sandra Coppens, Alison M Barnard, Sanna Puusepp, Sander Pajusalu, Katrin Õunap, Dorianmarie Vargas-Franco, Christine C Bruels, Sandra Donkervoort, Lynn Pais, Katherine R Chao, Julia K Goodrich, Eleina M England, Ben Weisburd, Vijay S Ganesh, Sanna Gudmundsson, Anne O'Donnell-Luria, Mait Nigul, Pilvi Ilves, Payam Mohassel, Teepu SiddiqueMargherita Milone, Stefan Nicolau, Reza Maroofian, Henry Houlden, Michael G Hanna, Ros Quinlivan, Mehran Beiraghi Toosi, Ehsan Ghayoor Karimiani, Sabine Costagliola, Nicolas Deconinck, Hazim Kadhim, Erica Macke, Brendan C Lanpher, Eric W Klee, Anna Łusakowska, Anna Kostera-Pruszczyk, Andreas Hahn, Bertold Schrank, Ichizo Nishino, Masashi Ogasawara, Rasha El Sherif, Tanya Stojkovic, Isabelle Nelson, Gisèle Bonne, Enzo Cohen, Anne Boland-Augé, Jean-François Deleuze, Yao Meng, Ana Töpf, Catheline Vilain, Christina A Pacak, Marie L Rivera-Zengotita, Carsten G Bönnemann, Volker Straub, Penny A Handford, Isabelle Draper, Glenn A Walter, Peter B Kang

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)840-856
Number of pages17
JournalAmerican Journal of Human Genetics
Issue number5
Early online dateApr 9 2021
StatePublished - May 6 2021

Bibliographical note

Publisher Copyright:
© 2021 American Society of Human Genetics


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

PubMed: MeSH publication types

  • Journal Article


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