Jagged 1 Rescues the Duchenne Muscular Dystrophy Phenotype

Natassia M. Vieira, Ingegerd Elvers, Matthew S. Alexander, Yuri B. Moreira, Alal Eran, Juliana P. Gomes, Jamie L. Marshall, Elinor K. Karlsson, Sergio Verjovski-Almeida, Kerstin Lindblad-Toh, Louis M. Kunkel, Mayana Zatz

Research output: Contribution to journalArticlepeer-review

109 Scopus citations

Abstract

Duchenne muscular dystrophy (DMD), caused by mutations at the dystrophin gene, is the most common form of muscular dystrophy. There is no cure for DMD and current therapeutic approaches to restore dystrophin expression are only partially effective. The absence of dystrophin in muscle results in dysregulation of signaling pathways, which could be targets for disease therapy and drug discovery. Previously, we identified two exceptional Golden Retriever muscular dystrophy (GRMD) dogs that are mildly affected, have functional muscle, and normal lifespan despite the complete absence of dystrophin. Now, our data on linkage, whole-genome sequencing, and transcriptome analyses of these dogs compared to severely affected GRMD and control animals reveals that increased expression of Jagged1 gene, a known regulator of the Notch signaling pathway, is a hallmark of the mild phenotype. Functional analyses demonstrate that Jagged1 overexpression ameliorates the dystrophic phenotype, suggesting that Jagged1 may represent a target for DMD therapy in a dystrophin-independent manner.

Original languageEnglish
Pages (from-to)1204-1213
Number of pages10
JournalCell
Volume163
Issue number5
DOIs
StatePublished - 19 Nov 2015
Externally publishedYes

Keywords

  • DMD
  • Jagged1
  • dystrophin
  • genetic modifier
  • muscle

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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