Muscular dystrophies include a diverse group of genetically heterogeneous disorders that affect 1:2000 births worldwide. The diseases are characterized by progressive muscle weakness and wasting that lead to severe disability and often premature death. Rostrocaudal muscular dystrophy (rmd) is a new recessive mouse mutation causing a progressive muscular dystrophy with a rostral-to-caudal gradient of severity. We have identified the rmd mutation as a 1.6 kb deletion within the choline kinase beta (Chkb) gene, resulting in loss of CHKB protein and enzymatic activity. CHKB is one of two mammalian choline kinase (CHK) enzymes catalyzing the phosphorylation of choline to phosphocholine in the biosynthesis of the major membrane phospholipid phosphatidylcholine (PC). PC is the most abundant phospholipid in eukaryotic cells and it serves not only as a structural foundation for membrane bilayers, but also as a precursor for several lipid messengers. While mutant rmd mice show dramatically decreased CHK activity in all tissues examined, the disease is only evident in skeletal muscle tissues which display a 30% reduction in total PC content. Several muscular dystrophy mutations have been identified in membrane-associated proteins that function at the sarcolemma or nuclear envelope. However, the rmd mutant mouse is the first to demonstrate that alterations in membrane phospholipid composition can result in a progressive muscular dystrophy phenotype.
The aims of our proposal are: 1) To test the hypothesis that rmd muscular dystrophy is due to a cell autonomous loss of CHKB in skeletal muscles. 2) To test the hypothesis that mitochondrial dysfunction underlies the progressive skeletal muscle degeneration in primary mouse myoblast cultures and adult skeletal muscles. 3) To screen a large Brazilian population of congenital muscular dystrophy (CMD) and limb-girdle muscular dystrophy (LGMD) patients for mutations in the orthologous human CHKB gene. In collaboration with Dr. Mayana Zatz, we will test for human CHKB mutations in DNA samples from patients that have previously been screened and eliminated for known molecular causes of muscular dystrophy. The primary goals of this proposal are to use the novel mouse rmd mutation to explore the cell-autonomous nature of this defect in skeletal muscles, to dissect the molecular and genetic mechanisms of muscular degeneration and to determine the range of defects in CHKB that underlie previously unidentified human muscular dystrophies. The rmd mouse offers the first demonstration of a defect in a phospholipid biosynthetic enzyme causing muscular dystrophy and may reveal unique entry points in which to intervene in the disease process.
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