Investigation of NOTCH Rare SNV as Protective Modifiers in Duchenne Muscular Dystrophy

Abstract

Specific aims: This proposal investigates the potential protectiveness of Notch signaling modulation in muscle satellite cells (MuSC) of Duchenne Muscular Dystrophy (DMD) patients. Hypothesis: Modulation of the Notch pathway signaling may delay motor function impairment of DMD patients by conserving the MuSC pool. Previous studies: Our group showed that the enhanced expression of the Notch ligand, Jagged1, in skeletal muscles of two exceptional golden retriever muscular dystrophy (GRMD) led to a mild phenotype. These dogs had a normal survival, they were able to breed, and presented skills comparable to non-dystrophic dogs. These findings using the GRMD were validated in dystrophic Sapje zebrafish. Preliminary data: We report two unrelated mildly affected DMD patients, able to walk independently beyond age 20. One of them had a maternal uncle with a comparable mild course. Whole exome sequencing revealed that both patients carry rare missense mutations in the same NOTCH gene. Each mutation changes a highly conserved arginine in the same EGF domain. We generated iPSC lineages from both patients and close relatives. PCR array for the Notch Pathway revealed an upregulation of the Notch signaling in iPSC-derived muscle cells from the mild patient. Relevance: A well-established literature points to the Notch pathway as an important ruler on MuSC fate. Thus, based on the uniqueness of these patients, we believe that investigating the NOTCH variants may have great relevance to improve therapies for DMD and other muscular dystrophies.