The level and turnover of phosphoinositides (PIs) are tightly controlled by a 
large set of PI-specific enzymes (PI kinases and phosphatases). Mammalian PI 
phosphatases are conserved through evolution and among this large family the 
dual-specificity phosphatase (PTP/DSP) are metal-independent enzymes displaying 
the amino acid signature Cys-X5-Arg-Thr/Ser (CX5RT/S) in their active site. Such 
catalytic site characterizes the myotubularin 3-phosphatases that 
dephosphorylate PtdIns3P and PtdIns(3,5)P₂ and produce PtdIns5P. Substrates of 
myotubularins have been implicated in endocytosis and membrane trafficking while 
PtdIns5P may have a role in signal transduction. As a paradox, 6 of the 14 
members of the myotubularin family lack enzymatic activity and are considered as 
dead phosphatases. Several myotubularins have been genetically linked to human 
diseases: MTM1 is mutated in the congenital myopathy X-linked centronuclear or 
myotubular myopathy (XLCNM) and MTMR14 (JUMPY) has been linked to an autosomal 
form of such disease, while MTMR2 and MTMR13 are mutated in Charcot-Marie-Tooth 
(CMT) neuropathies. Furthermore, recent evidences from genetic association 
studies revealed that several other myotubularins could be associated to chronic 
disorders such as cancer and obesity, highlighting their importance for human 
health. Here, we discuss cellular and physiological roles of myotubularins and 
their implication in human diseases, and we present potential pathological 
mechanisms affecting specific tissues in myotubularin-associated diseases.