Jagged 1 Rescues the Duchenne Muscular Dystrophy Phenotype

Author(s):Show less -

Vieira, Natassia M. ^{[1, 2, 3]} ; Elvers, Ingegerd ^{[4, 5]} ; Alexander, Matthew S. ^{[1, 2, 6]} ; Moreira, Yuri B. ^[7] ; Eran, Alal ^[2] ; Gomes, Juliana P. ^[3] ; Marshall, Jamie L. ^{[1, 2]} ; Karlsson, Elinor K. ^{[4, 8]} ; Verjovski-Almeida, Sergio ^{[7, 9]} ; Lindblad-Toh, Kerstin ^{[4, 5]} ; Kunkel, Louis M. ^{[1, 2, 10]} ; Zatz, Mayana ^[3]

Affiliation

^[1] Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 - USA

^[2] Harvard Univ, Sch Med, Dept Pediat & Genet, Boston, MA 02115 - USA

^[3] Univ Sao Paulo, Biosci Inst, Human Genome & Stem Cell Ctr, BR-05508090 Sao Paulo - Brazil

^[4] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 - USA

^[5] Uppsala Univ, Dept Med Biochem & Microbiol, Sci Life Lab, S-75124 Uppsala - Sweden

^[6] Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 - USA

^[7] Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-05508000 Sao Paulo - Brazil

^[8] Univ Massachusetts, Sch Med, Program Bioinformat & Integrat Biol, Worcester, MA 01605 - USA

^[9] Inst Butantan, BR-05508050 Sao Paulo - Brazil

^[10] Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA 02115 - USA

• Document type: Journal article
• Source: Cell; v. 163, n. 5, p. 1204-1213, NOV 19 2015.
• Web of Science Citations: 54

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. (AU)

• FAPESP's process: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
• Grantee: Mayana Zatz
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC