Implication of phosphoinositide phosphatases in genetic diseases: the case of myotubularin

Abstract

Phosphoinositides play a central role in the control of major eukaryotic cell signaling mechanisms. Accordingly, the list of phosphoinositide-metabolizing enzymes implicated in human diseases has considerably increased these last years. Here we will focus on myotubularin, the protein mutated in the X-linked myotubular myopathy (XLMTM) and the founding member of a family of 13 related proteins. Recent data demonstrate that myotubularin and several other members of the family are potent lipid phosphatases showing a marked specificity for phosphatidylinositol 3-phosphate [PtdIns(3)P]. This finding has raised considerable interest as PtdIns(3)P is implicated in vesicular trafficking and sorting through its binding to specific protein domains. The structure of myotubularin, the molecular mechanisms of its function and its implication in the etiology of XLMTM will be discussed, as well as the potential function and role of the other members of the family.

Phosphoinositide phosphatases in a network of signalling reactions

“…Subsequently, MTM1 became the prototype of a large MTM-related (MTMR) family comprised of 14 members in humans [18,107]. MTM1 and MTMR 1, 2, 3, 4, 6 and 7 are 3-phosphatases with a substrate specificity restricted to PtdIns3P and PtdIns(3,5)P 2 [107,129,130]. The crystal structure of MTMR2 complexed with PtdIns3P and PtdIns (3,5)P 2 has been recently solved.…”

Mutations in Phosphoinositide Metabolizing Enzymes and Human Disease

“…The myotubularin family also comprises catalytically inactive members, which are thought to help regulate the active members (72, 93). Several myotubularin family members have been implicated in disease.…”

Phosphoinositide phosphatases in cell biology and disease

“…The myotubularins are recognized as key components of the homeostatic strategy for regulation of PtdIns 3-phosphate and PtdIns-3,5-P 2 levels in eukaryotic cells (Maehama et al , 2001; Tronchere et al , 2003; Tronchere et al , 2004). Human MTM1, and MTMR1,2,3,4,6,7 are phosphoinositide 3-phosphate phosphatases with substrate preferences restricted to PtdIns-3-P and PtdIns-3,5-P 2 (Tronchere et al , 2003; Tronchere et al , 2004).…”