title: A rostrocaudal muscular dystrophy caused by a defect in choline kinase beta, the first enzyme in phosphatidylcholine biosynthesis.
abstract: 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 (alpha and beta) 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.
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
authors.forename: Roger B
authors.initials: RB
authors.lastname: Sher
authors.forename: Chieko
authors.initials: C
authors.lastname: Aoyama
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Huebsch
authors.forename: Shaonin
authors.initials: S
authors.lastname: Ji
authors.forename: Janos
authors.initials: J
authors.lastname: Kerner
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.forename: Wayne N
authors.initials: WN
authors.lastname: Frankel
authors.forename: Charles L
authors.initials: CL
authors.lastname: Hoppel
authors.forename: Philip A
authors.initials: PA
authors.lastname: Wood
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Vance
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Cox
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D002384:Catalysis; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D002797:Choline Kinase / Q000235:genetics* / Q000502:physiology*; D002874:Chromosome Mapping; D004396:Coloring Agents / Q000494:pharmacology; D003402:Creatine Kinase / Q000378:metabolism; D003433:Crosses, Genetic; D016189:Dystrophin / Q000378:metabolism; D005070:Evans Blue / Q000494:pharmacology; D005260:Female; D005838:Genotype; D006023:Glycoproteins / Q000378:metabolism; D015151:Immunoblotting; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism; D008957:Models, Genetic; D009124:Muscle Proteins / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000648:ultrastructure; D009132:Muscles / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000201:enzymology* / Q000473:pathology; D009154:Mutation; D010641:Phenotype; D010713:Phosphatidylcholines / Q000737:chemistry*; D020161:Physical Chromosome Mapping; D011995:Recombination, Genetic; D012508:Sarcolemma / Q000648:ultrastructure; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism
chemical_list: D004396:Coloring Agents; D016189:Dystrophin; D006023:Glycoproteins; D008055:Lipids; D009124:Muscle Proteins; D010713:Phosphatidylcholines; D014280:Triglycerides; D005070:Evans Blue; D002784:Cholesterol; D002334:Carnitine O-Palmitoyltransferase; D002797:Choline Kinase; D003402:Creatine Kinase