Myotubularin-related genes define a novel highly conserved family of eukaryotic 
proteins of at least 11 human members. The hMTM1 gene that codes for 
myotubularin is mutated in X-linked myotubular myopathy, a severe congenital 
disease. Recently, we and others have characterized myotubularin as a potent and 
specific phosphatidylinositol 3-phosphate 3-phosphatase. In the present study we 
investigated the lipid phosphatase activity and the subcellular localization of 
two other members of the family, hMTMR2 protein that is mutated in the 
demyelinating neuropathy Charcot-Marie-Tooth type 4B and the FYVE-finger 
containing hMTMR3 protein. Our results show that both proteins are potent 
phosphatidylinositol 3-phosphate 3-phosphatases either in vitro or in yeast 
where they interfered with vesicular trafficking. Their localization is mainly 
cytoplasmic, with however strong labeling of Rac-inducible plasma membrane 
ruffles. The fact that the ubiquitously expressed hMTM1 and hMTMR2 genes are 
involved in different pathologies indicates that despite their shared enzymatic 
activity, they are not functionally redundant, at least in certain cell types. 
This might be explained by subtle differences in expression and/or in 
recruitment and regulation at their specific site of action.