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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 publication

DOI

10.1016/j.ajhg.2021.03.020

Type

Journal article

Journal

Am J Hum Genet

Publication Date

06/05/2021

Volume

108

Pages

840 - 856

Keywords

JAG2, Jagged2, Serrate, Notch signaling pathway, muscular dystrophy, muscle MRI, POGLUT1, MEGF10, exome sequencing, satellite cell, Adolescent, Adult, Amino Acid Sequence, Animals, Cell Line, Child, Child, Preschool, Drosophila Proteins, Drosophila melanogaster, Female, Glucosyltransferases, Haplotypes, Humans, Jagged-1 Protein, Jagged-2 Protein, Male, Membrane Proteins, Mice, Middle Aged, Models, Molecular, Muscles, Muscular Dystrophies, Myoblasts, Pedigree, Phenotype, Receptors, Notch, Signal Transduction, Whole Exome Sequencing, Young Adult