TY - JOUR
T1 - Jagged 1 Rescues the Duchenne Muscular Dystrophy Phenotype
AU - Vieira, Natassia M.
AU - Elvers, Ingegerd
AU - Alexander, Matthew S.
AU - Moreira, Yuri B.
AU - Eran, Alal
AU - Gomes, Juliana P.
AU - Marshall, Jamie L.
AU - Karlsson, Elinor K.
AU - Verjovski-Almeida, Sergio
AU - Lindblad-Toh, Kerstin
AU - Kunkel, Louis M.
AU - Zatz, Mayana
N1 - Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/11/19
Y1 - 2015/11/19
N2 - 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.
AB - 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.
KW - DMD
KW - Jagged1
KW - dystrophin
KW - genetic modifier
KW - muscle
UR - http://www.scopus.com/inward/record.url?scp=84947793689&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2015.10.049
DO - 10.1016/j.cell.2015.10.049
M3 - Article
AN - SCOPUS:84947793689
SN - 0092-8674
VL - 163
SP - 1204
EP - 1213
JO - Cell
JF - Cell
IS - 5
ER -