title: Jagged 1 Rescues the Duchenne Muscular Dystrophy Phenotype.
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.
authors.affiliation: 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.
authors.forename: Natassia M
authors.initials: NM
authors.lastname: Vieira
authors.affiliation: 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.
authors.forename: Ingegerd
authors.initials: I
authors.lastname: Elvers
authors.affiliation: 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.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Alexander
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil, 05508-000.
authors.forename: Yuri B
authors.initials: YB
authors.lastname: Moreira
authors.affiliation: Department of Pediatrics and Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alal
authors.initials: A
authors.lastname: Eran
authors.affiliation: Human Genome and Stem Cell Center, Biosciences Institute, University of São Paulo, São Paulo 05508-090, Brazil.
authors.forename: Juliana P
authors.initials: JP
authors.lastname: Gomes
authors.affiliation: 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.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Marshall
authors.affiliation: 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.
authors.forename: Elinor K
authors.initials: EK
authors.lastname: Karlsson
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil, 05508-000; Instituto Butantan, São Paulo 05508-050, Brazil.
authors.forename: Sergio
authors.initials: S
authors.lastname: Verjovski-Almeida
authors.affiliation: 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.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Lindblad-Toh
authors.affiliation: 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.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Kunkel
authors.affiliation: Human Genome and Stem Cell Center, Biosciences Institute, University of São Paulo, São Paulo 05508-090, Brazil. Electronic address: mayazatz@usp.br.
authors.forename: Mayana
authors.initials: M
authors.lastname: Zatz
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004283:Dog Diseases / Q000235:genetics; D004285:Dogs; D016189:Dystrophin / Q000172:deficiency / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009137:Muscular Dystrophy, Animal / Q000235:genetics; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance; D000072099:Serrate-Jagged Proteins; D059467:Transcriptome; D015027:Zebrafish; D029961:Zebrafish Proteins
chemical_list: D002135:Calcium-Binding Proteins; D016189:Dystrophin; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D000072099:Serrate-Jagged Proteins; D029961:Zebrafish Proteins; C000606276:jag1a protein, zebrafish
keywords: DMD; Jagged1; dystrophin; genetic modifier; muscle