Myotubularin is a ubiquitously expressed phosphatase that acts on 
phosphatidylinositol 3-monophosphate [PI(3)P], a lipid implicated in 
intracellular vesicle trafficking and autophagy. It is encoded by the MTM1 gene, 
which is mutated in X-linked myotubular myopathy (XLMTM), a muscular disorder 
characterized by generalized hypotonia and muscle weakness at birth leading to 
early death of most affected males. The disease was proposed to result from an 
arrest in myogenesis, as the skeletal muscle from patients contains hypotrophic 
fibers with centrally located nuclei that resemble fetal myotubes. To understand 
the physiopathological mechanism of XLMTM, we have generated mice lacking 
myotubularin by homologous recombination. These mice are viable, but their 
lifespan is severely reduced. They develop a generalized and progressive 
myopathy starting at around 4 weeks of age, with amyotrophy and accumulation of 
central nuclei in skeletal muscle fibers leading to death at 6-14 weeks. 
Contrary to expectations, we show that muscle differentiation in knockout mice 
occurs normally. We provide evidence that fibers with centralized myonuclei 
originate mainly from a structural maintenance defect affecting 
myotubularin-deficient muscle rather than a regenerative process. In addition, 
we demonstrate, through a conditional gene-targeting approach, that skeletal 
muscle is the primary target of murine XLMTM pathology. These mutant mice 
represent animal models for the human disease and will be a valuable tool for 
understanding the physiological role of myotubularin.