Abstract
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)P 2 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.
Keywords
Authors: Leonela Amoasii, Karim Hnia are equally contributed.
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Abbreviations
- AAV:
-
Adeno-associated-virus
- BIN1:
-
Bridging integrator 1 gene coding for amphiphysin 2
- CC:
-
Coiled-coil
- CMT:
-
Charcot-Marie-Tooth neuropathies
- CMTX:
-
X-linked inherited CMT
- CNM:
-
Centronuclear myopathy
- Dlg1:
-
Disks large 1
- DI-CMT:
-
Dominant inherited CMT
- DRM:
-
Desmin related myopathies
- DRCM:
-
Desmin related cardiomyopathies
- PTP/DSP:
-
Protein Tyrosine Phosphatase/Dual-specificity phosphatase
- DNM2:
-
Dynamin 2
- EC:
-
Excitation–contraction
- EGF:
-
Epidermal growth factor
- GEFS+ :
-
Generalized epilepsy with febrile seizures plus
- ING2:
-
Inhibitor of growth 2
- KO:
-
Knockout
- MTM1:
-
Myotubularin
- MTMR:
-
Myotubularin-related
- NCV:
-
Nerve conduction velocity
- NF-L:
-
Neurofilament light chain protein
- Pi3K68D:
-
PI 3-kinase class II
- PIs:
-
Phosphoinositides
- PtdIns:
-
Phosphatidylinositol
- PHD:
-
Plant homeodomain
- PH-GRAM:
-
Pleckstrin homology, glucosyltransferases, rab-like GTPase activators and myotubularins
- RID:
-
Rac-induced recruitment domain
- RYR1:
-
Ryanodine receptor
- SAP97:
-
Synapse associated 97
- SID:
-
Set-interacting domain
- XLCNM:
-
X-linked recessive form of centronuclear myopathy
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Amoasii, L., Hnia, K., Laporte, J. (2012). Myotubularin Phosphoinositide Phosphatases in Human Diseases. In: FALASCA, M. (eds) Phosphoinositides and Disease. Current Topics in Microbiology and Immunology, vol 362. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5025-8_10
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