title: A novel PtdIns3P and PtdIns(3,5)P2 phosphatase with an inactivating variant in centronuclear myopathy.
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 (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)P(2), 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.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Department of Molecular Pathology, Strasbourg, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Tosch
authors.forename: Holger M
authors.initials: HM
authors.lastname: Rohde
authors.forename: Hélène
authors.initials: H
authors.lastname: Tronchère
authors.forename: Edmar
authors.initials: E
authors.lastname: Zanoteli
authors.forename: Nancy
authors.initials: N
authors.lastname: Monroy
authors.forename: Christine
authors.initials: C
authors.lastname: Kretz
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dondaine
authors.forename: Bernard
authors.initials: B
authors.lastname: Payrastre
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mandel
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Laporte
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine; D019556:COS Cells; D020134:Catalytic Domain; D002460:Cell Line; D002522:Chlorocebus aethiops; D002893:Chromosomes, Human, Pair 3; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000166:cytology / Q000502:physiology; D020125:Mutation, Missense; D020914:Myopathies, Structural, Congenital / Q000235:genetics*; D010375:Pedigree; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry / Q000378:metabolism; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D016415:Sequence Alignment; D014162:Transfection
chemical_list: D018129:Phosphatidylinositol Phosphates; C106336:phosphatidylinositol 3,5-diphosphate; C055525:phosphatidylinositol 3-phosphate; D001120:Arginine; C515634:MTMR14 protein, human; D010744:Phosphoric Monoester Hydrolases; D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C099588:myotubularin