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Human Molecular Genetics Advance Access published online on September 28, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl250
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received June 24, 2006
Revised September 7, 2006
Accepted September 7, 2006

Article

A novel PtdIns3P and PtdInsP(3,5)P2 phosphatase with an inactivating variant in centronuclear myopathy

Valérie Tosch 1, Holger M. Rohde 1, Hélène Tronchère 2, Edmar Zanoteli 3, Nancy Monroy 1, Christine Kretz 1, Nicolas Dondaine 4, Bernard Payrastre 2, Jean-Louis Mandel 5, and Jocelyn Laporte 6 *

1 Department of Molecular Pathology, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U596, CNRS UMR 7104, Université Louis Pasteur de Strasbourg, Collège de France, 67404 Illkirch, France
2 INSERM U563, Département d'Oncogénèse et Signalisation dans les Cellules Hématopoïétiques, CPTP, IFR 30, Hôpital Purpan, 31059 Toulouse, France
3 Department of Neurology, UNIFESP-EPM, Sao Paulo 04023-900, Brazil
4 Laboratoire de Diagnostic Génétique, Faculté de Médecine and Hôpitaux Universitaires, 67085 Strasbourg, France
5 Department of Molecular Pathology, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U596, CNRS UMR 7104, Université Louis Pasteur de Strasbourg, Collège de France, 67404 Illkirch, France; Laboratoire de Diagnostic Génétique, Faculté de Médecine and Hôpitaux Universitaires, 67085 Strasbourg, France; Chaire de Génétique Humaine, Collège de France, 75231 Paris, France
6 Department of Molecular Pathology, IGBMC, 1, rue Laurent Fries, B.P. 10142, 67404 Illkirch, France

* To whom correspondence should be addressed.
Jocelyn Laporte, E-mail: mtm{at}igbmc.u-strasbg.fr


  Abstract

In eukaryotic cells, phosphoinositides are lipid second messengers important for many cellular processes and have been found dysregulated in several human diseases. X-linked myotubular (centronuclear) myopathy is a severe congenital myopathy caused by mutations in a phosphatidylinositol 3-phosphate (PtdIns3P) phosphatase called myotubularin, and mutations in dominant centronuclear myopathy cases were identified in the dynamin 2 gene. The genes mutated in autosomal recessive cases of centronuclear myopathies have not been found. We have identified a novel phosphoinositides phosphatase (hJUMPY) conserved through evolution, which dephosphorylates the same substrates as myotubularin, PtdIns3P and PtdIns(3,5)P2, in vitro and ex vivo. We found, in sporadic cases of centronuclear myopathies, two missense variants that affect the enzymatic function. One of these appeared de novo in a patient also carrying ade novo mutation in the dynamin 2 gene. The other missense (R336Q) found in another patient changes the catalytic arginine residue of the core phosphatase signature present in protein tyrosine and dual-specificity phosphatases (PTP/DSP) and in phosphoinositides phosphatases, and drastically reduces the enzymatic activity both in vitro and in transfected cells. The inheritance of the phenotype with regard to this variant is still unclear, and could be either recessive with an undetected second allele or digenic. We propose that impairment of hJUMPY function is implicated in some cases of autosomal centronuclear myopathy, and that hJUMPY cooperates with myotubularin to regulate the level of phosphoinositides in skeletal muscle.


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