PUBLICATION

Loss of myotubularin function results in T-tubule disorganization in zebrafish and human myotubular myopathy

Authors
Dowling, J.J., Vreede, A.P., Low, S.E., Gibbs, E.M., Kuwada, J.Y., Bonnemann, C.G., and Feldman, E.L.
ID
ZDB-PUB-090217-12
Date
2009
Source
PLoS Genetics   5(2): e1000372 (Journal)
Registered Authors
Dowling, Jim, Kuwada, John, Low, Sean
Keywords
Embryos, Zebrafish, Morpholino, Phosphatases, Muscle functions, Biopsy, Lipids, Muscle contraction
MeSH Terms
  • Animals
  • Disease Models, Animal
  • Embryo, Nonmammalian/metabolism
  • Fluorescent Antibody Technique
  • Homeostasis
  • Humans
  • Muscle Fibers, Skeletal/pathology
  • Muscle Fibers, Skeletal/ultrastructure*
  • Muscle, Skeletal/metabolism
  • Mutation
  • Myopathies, Structural, Congenital/etiology*
  • Myopathies, Structural, Congenital/metabolism
  • Myopathies, Structural, Congenital/pathology*
  • Protein Tyrosine Phosphatases, Non-Receptor/genetics
  • Protein Tyrosine Phosphatases, Non-Receptor/physiology*
  • Zebrafish/genetics*
  • Zebrafish/metabolism
PubMed
19197364 Full text @ PLoS Genet.
Abstract
Myotubularin is a lipid phosphatase implicated in endosomal trafficking in vitro, but with an unknown function in vivo. Mutations in myotubularin cause myotubular myopathy, a devastating congenital myopathy with unclear pathogenesis and no current therapies. Myotubular myopathy was the first described of a growing list of conditions caused by mutations in proteins implicated in membrane trafficking. To advance the understanding of myotubularin function and disease pathogenesis, we have created a zebrafish model of myotubular myopathy using morpholino antisense technology. Zebrafish with reduced levels of myotubularin have significantly impaired motor function and obvious histopathologic changes in their muscle. These changes include abnormally shaped and positioned nuclei and myofiber hypotrophy. These findings are consistent with those observed in the human disease. We demonstrate for the first time that myotubularin functions to regulate PI3P levels in a vertebrate in vivo, and that homologous myotubularin-related proteins can functionally compensate for the loss of myotubularin. Finally, we identify abnormalities in the tubulo-reticular network in muscle from myotubularin zebrafish morphants and correlate these changes with abnormalities in T-tubule organization in biopsies from patients with myotubular myopathy. In all, we have generated a new model of myotubular myopathy and employed this model to uncover a novel function for myotubularin and a new pathomechanism for the human disease that may explain the weakness associated with the condition (defective excitation-contraction coupling). In addition, our findings of tubuloreticular abnormalities and defective excitation-contraction coupling mechanistically link myotubular myopathy with several other inherited muscle diseases, most notably those due to ryanodine receptor mutations. Based on our findings, we speculate that congenital myopathies, usually considered entities with similar clinical features but very disparate pathomechanisms, may at their root be disorders of calcium homeostasis.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes