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Cell. 2015 Nov 19;163(5):1204-1213. doi: 10.1016/j.cell.2015.10.049. Epub 2015 Nov 12.

Jagged 1 Rescues the Duchenne Muscular Dystrophy Phenotype.

Author information

1
The Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics and Genetics, Harvard Medical School, Boston, MA 02115, USA; Human Genome and Stem Cell Center, Biosciences Institute, University of São Paulo, São Paulo 05508-090, Brazil.
2
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Box 597, 751 24, Uppsala, Sweden.
3
The Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics and Genetics, Harvard Medical School, Boston, MA 02115, USA; The Stem Cell Program at Boston Children's Hospital, Boston, MA 02115, USA.
4
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil, 05508-000.
5
Department of Pediatrics and Genetics, Harvard Medical School, Boston, MA 02115, USA.
6
Human Genome and Stem Cell Center, Biosciences Institute, University of São Paulo, São Paulo 05508-090, Brazil.
7
The Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics and Genetics, Harvard Medical School, Boston, MA 02115, USA.
8
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
9
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil, 05508-000; Instituto Butantan, São Paulo 05508-050, Brazil.
10
The Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics and Genetics, Harvard Medical School, Boston, MA 02115, USA; The Manton Center for Orphan Disease Research at Boston Children's Hospital, Boston, MA 02115, USA. Electronic address: kunkel@enders.tch.harvard.edu.
11
Human Genome and Stem Cell Center, Biosciences Institute, University of São Paulo, São Paulo 05508-090, Brazil. Electronic address: mayazatz@usp.br.

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. PAPERCLIP.

KEYWORDS:

DMD; Jagged1; dystrophin; genetic modifier; muscle

PMID:
26582133
PMCID:
PMC4668935
DOI:
10.1016/j.cell.2015.10.049
[Indexed for MEDLINE]
Free PMC Article

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