Human Molecular Genetics Advance Access originally published online on September 28, 2006
Human Molecular Genetics 2006 15(21):3098-3106; doi:10.1093/hmg/ddl250
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A novel PtdIns3P and PtdIns(3,5)P2 phosphatase with an inactivating variant in centronuclear myopathy
1 Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Department of Molecular Pathology; INSERM, U596; CNRS, UMR 7104; Université Louis Pasteur de Strasbourg; Collège de France; 1, rue Laurent Fries, B.P. 10142, 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 and 5 Chaire de Génétique Humaine, Collège de France, 75231 Paris, France
* To whom correspondence should be addressed. Tel: +33 388653412; Fax: +33 388653246; Email: mtm{at}igbmc.u-strasbg.fr
Received June 24, 2006; Accepted September 7, 2006
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 (CNM) cases were identified in the dynamin 2 gene. The genes mutated in autosomal recessive cases of CNMs have not been found. We have identified a novel phosphoinositide 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 CNMs, two missense variants that affect the enzymatic function. One of these appeared de novo in a patient also carrying a de 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/dual-specificity phosphatases and in phosphoinositide 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 CNM and that hJUMPY cooperates with myotubularin to regulate the level of phosphoinositides in skeletal muscle.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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