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Doctor of Philosophy (PhD)
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Congenital muscular dystrophy with megaconial myopathy (MDCMC) is an autosomal recessive disorder characterized by progressive muscle weakness and wasting. Megamitochondria in skeletal muscle biopsies and cognitive impairments in MDCMC patients are observations exclusive to this type of muscular dystrophy. 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 (PC). A rostro-caudal muscular dystrophy (rmd) mouse with a deletion in the Chkb gene resulting in MDCMC-like symptoms has been reported by our lab. In order to test if the rmd mice show signs of cognitive impairments as observed in MDCMC patients, I engineered a transgenic rmd mouse model (Tgrmd) which I used for MS/MSALL mass spectrometry analysis of brain tissue and to test for working memory and learning impairments. These tests show us that even though Tg-rmd mice showed significantly different lipid profiles in brain, these changes were not translated in the behavioral assays conducted. I have worked on the development of and tested gene therapy strategies for the rescue and alleviation of dystrophy symptoms using the rmd mouse model. I have observed that 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 AAV6 vector carrying a functional copy of Chkb gene is capable of rescuing the dystrophy phenotype in rmd mice. In addition, upregulating choline kinase alpha (Chka), a gene paralog of Chkb, via a similar AAV6 viral vector showed increased muscle regeneration and alleviation of muscular dystrophy symptoms as was observed with Chkb AAV injections. Together, my results suggest rmd mice do not model the cognitive impairments observed in MDCMC patients and that replacement of the Chkb gene or upregulation of endogenous Chka could serve as potential lines of therapy for MDCMC patients.
Sayed, Ambreen A., "Characterization and Functional Rescue of Congenital Muscular Dystrophy with Megaconial Myopathy in a Mouse Model of the Disease" (2018). Electronic Theses and Dissertations. 3014.
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