Functional rescue in a mouse model of congenital muscular dystrophy with megaconial myopathy.
Document Type
Article
Publication Date
8-15-2019
Keywords
JMG
JAX Source
Hum Mol Genet 2019 Aug 15; 28(16):2635-2647
Volume
28
Issue
16
First Page
2635
Last Page
2647
ISSN
1460-2083
PMID
31216357
DOI
https://doi.org/10.1093/hmg/ddz068
Grant
AR054170
Abstract
Congenital muscular dystrophy with megaconial myopathy (MDCMC) is an autosomal recessive disorder characterized by progressive muscle weakness and wasting. The observation of megamitochondria in skeletal muscle biopsies is exclusive to this type of MD. The disease is caused by loss of function mutations in the choline kinase beta (CHKB) gene which results in dysfunction of the Kennedy pathway for the synthesis of phosphatidylcholine. We have previously reported a rostrocaudal MD (rmd) mouse with a deletion in the Chkb gene resulting in an MDCMC-like phenotype, and we used this mouse to test gene therapy strategies for the rescue and alleviation of the dystrophic phenotype. Introduction of a muscle-specific Chkb transgene completely rescues motor and behavioral function in the rmd mouse model, confirming the cell-autonomous nature of the disease. Intramuscular gene therapy post-disease onset using an adeno-associated viral 6 (AAV6) vector carrying a functional copy of Chkb is also capable of rescuing the dystrophy phenotype. In addition, we examined the ability of choline kinase alpha (Chka), a gene paralog of Chkb, to improve dystrophic phenotypes when upregulated in skeletal muscles of rmd mutant mice using a similar AAV6 vector. The sum of our results in a preclinical model of disease suggest that replacement of the Chkb gene or upregulation of endogenous Chka could serve as potential lines of therapy for MDCMC patients.
Recommended Citation
Sayed-Zahid A,
Sher R,
Sukoff Rizzo S,
Anderson LC,
Patenaude K,
Cox GA.
Functional rescue in a mouse model of congenital muscular dystrophy with megaconial myopathy. Hum Mol Genet 2019 Aug 15; 28(16):2635-2647
Comments
We would like to thank David G. Schroeder for assistance with general laboratory procedures and in colony maintenance, Jennifer Stauffer for assistance in laboratory procedures, Pete Finger for assistance with electron microscopy, Nick Gott for assistance with histology procedures and Gaylynn Wells and Traci McGarr for assistance with behavioral procedures.