Loss of myotubularin function results in T-tubule disorganization in zebrafish
and human myotubular myopathy.
Authors Dowling JJ, Vreede AP, Low SE, Gibbs EM, Kuwada JY, Bonnemann CG, Feldman EL
Submitted By Eva Feldman on 2/8/2009
Status Published
Journal PLoS genetics
Year 2009
Date Published 2/1/2009
Volume : Pages 5(2) : e1000372
PubMed Reference 19197364
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

Investigators with authorship
Eva FeldmanUniversity of Michigan