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J. Biol. Chem., Vol. 281, Issue 8, 4938-4948, February 24, 2006

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A Rostrocaudal Muscular Dystrophy Caused by a Defect in Choline Kinase Beta, the First Enzyme in Phosphatidylcholine Biosynthesis^*

Roger B. Sher, Chieko Aoyama¹, Kimberly A. Huebsch, Shaonin Ji^¶, Janos Kerner^||, Yan Yang, Wayne N. Frankel, Charles L. Hoppel^**, Philip A. Wood^¶, Dennis E. Vance², and Gregory A. Cox³

From the The Jackson Laboratory, Bar Harbor, Maine 04609, the Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 252, Canada, the ^¶Department of Genetics, University of Alabama, Birmingham, Alabama 35294, the Departments of ^||Nutrition, ^**Pharmacology, and Medicine, Case Western Reserve University, Cleveland, Ohio 44106, and the Louis Stokes Veterans Affairs Medical Center, Cleveland, Ohio 44106

Muscular dystrophies include a diverse group of genetically heterogeneous disorders that together affect 1 in 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 that causes a rapidly progressive muscular dystrophy and a neonatal forelimb bone deformity. The rmd mutation is a 1.6-kb intragenic deletion within the choline kinase beta (Chkb) gene, resulting in a complete loss of CHKB protein and enzymatic activity. CHKB is one of two mammalian choline kinase (CHK) enzymes ( and ) that catalyze the phosphorylation of choline to phosphocholine in the biosynthesis of the major membrane phospholipid phosphatidylcholine. While mutant rmd mice show a dramatic decrease of CHK activity in all tissues, the dystrophy is only evident in skeletal muscle tissues in an unusual rostral-to-caudal gradient. Minor membrane disruption similar to dysferlinopathies suggest that membrane fusion defects may underlie this dystrophy, because severe membrane disruptions are not evident as determined by creatine kinase levels, Evans Blue infiltration, and unaltered levels of proteins in the dystrophin-glycoprotein complex. The rmd mutant mouse offers the first demonstration of a defect in a phospholipid biosynthetic enzyme causing muscular dystrophy, representing a unique model for understanding mechanisms of muscle degeneration.

Received for publication, November 23, 2005 , and in revised form, December 20, 2005.

^* This work was supported in part by National Institutes of Health Grant AR-49043 (to G. A. C.), Muscular Dystrophy Association development Grant 3883 (to R. B. S.), NCI-CA34196 (Cancer Center Support Grant) to scientific services at the Jackson Laboratory, National Institutes of Health Grant RO1-RR-02599 (to P. A. W.), and a grant from the Canadian Institutes of Health Research (to D. E. V.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Postdoctoral Fellow of the Alberta Heritage Foundation for Medical Research.

² Holds the Canada Research Chair in Molecular and Cell Biology of Lipids and is a Heritage Scientist of the Alberta Heritage Foundation for Medical Research.

³ To whom correspondence should be addressed: The Jackson Laboratory, 600 Main St., Bar Harbor, ME 04609. Tel.: 207-288-6502; Fax: 207-288-6073; E-mail: gac{at}jax.org.

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