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Myotubularin Phosphoinositide Phosphatases in Human Diseases

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Phosphoinositides and Disease

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 362))

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.

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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Authors and Affiliations

  1. Department of Translational Medicine and Neurogenetics, IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Illkirch, France

    Leonela Amoasii, Karim Hnia & Jocelyn Laporte

  2. U964, Institut National de la Santé et de la Recherche Médicale, Illkirch, France

    Leonela Amoasii, Karim Hnia & Jocelyn Laporte

  3. UMR7104, Centre National de la Recherche Scientifique, Illkirch, France

    Leonela Amoasii, Karim Hnia & Jocelyn Laporte

  4. Université de Strasbourg, Strasbourg, France

    Leonela Amoasii, Karim Hnia & Jocelyn Laporte

  5. Chaire de Génétique Humaine, Collège de France, Illkirch, France

    Leonela Amoasii, Karim Hnia & Jocelyn Laporte

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  1. Leonela Amoasii
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  2. Karim Hnia
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  3. Jocelyn Laporte
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Correspondence to Jocelyn Laporte .

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  1. CTR DIABETES BARTS, Queen Mary University of London, UK, NEWARK ST 4, LONDON E1 2AT, United Kingdom

    MARCO FALASCA

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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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