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

Roger B Sher,Chieko Aoyama,Kimberly A Huebsch,Shaonin Ji,Janos Kerner,Yan Yang,Wayne N Frankel,Charles L Hoppel,Philip A Wood,Dennis E Vance,Gregory A Cox

doi:10.1074/jbc.m512578200

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.

Highlights

Muscular dystrophies are a variable class of more than 20 human disorders characterized by progressive muscle wasting and weakness resulting from myofiber degeneration and regeneration
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
The most common forms of muscular dystrophy result from mutations in genes coding for sarcolemmal and extracellular matrix proteins in the dystrophin-glycoprotein complex (DGC) [4], which acts as a linker between the cytoskeleton of the muscle cell and the extracellular matrix, providing mechanical support to the plasma membrane during myofiber contraction [5]

Summary

Choline Kinase Beta and Muscular Dystrophy

Ations in repair-vesicle fusion with the phospholipid membrane, resulting in necrosis of muscle fibers in both humans [13] and mice [14]. By positional cloning we have identified the molecular defect in rmd mutant mice as an intragenic deletion in the choline kinase beta (Chkb) gene, one of two mammalian choline kinase (CHK) enzymes (␣ and ␤). The rmd mouse offers the first demonstration that a defect in a phospholipid biosynthetic enzyme can cause muscular dystrophy, suggesting that membrane phospholipids as well as sarcolemma-associated proteins are critical to the disease process. Mutant rmd mice share several phenotypic features with dysferlin-null mouse models that have a primary defect in sarcolemma repair and are a model for human limb-girdle muscular dystrophy 2B (LGMD2B). Our discovery of a mouse mutation in Chkb will provide important insights into the phospholipid biosynthetic pathways necessary for the development and maintenance of healthy muscle tissue

EXPERIMENTAL PROCEDURES

RESULTS

Cholesterol ester

DISCUSSION