Skip Navigation


Human Molecular Genetics Advance Access originally published online on August 12, 2003
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
12/suppl_2/R285    most recent
ddg273v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Laporte, J.
Right arrow Articles by Mandel, J.-L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Laporte, J.
Right arrow Articles by Mandel, J.-L.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Human Molecular Genetics, 2003, Vol. 12, Review Issue 2 R285-R292
DOI: 10.1093/hmg/ddg273
© 2003 Oxford University Press

Myotubularins, a large disease-associated family of cooperating catalytically active and inactive phosphoinositides phosphatases

Jocelyn Laporte1, Florence Bedez1, Alessandra Bolino2 and Jean-Louis Mandel1,*

1IGBMC, CNRS/INSERM/ULP, Illkirch, France and 2Dulbecco Telethon Institute, DIBIT, San Raffaele Scientific Institute, Milan, Italy

Received July 28, 2003; Accepted August 4, 2003


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 THE MYOTUBULARIN FAMILY
 FUNCTIONS AND REGULATION
 ASSOCIATED DISEASES AND...
 CONCLUSION
 REFERENCES
 
The myotubularin family is a large eukaryotic group within the tyrosine/dual-specificity phosphatase super-family (PTP/DSP). Among the 14 human members, three are mutated in genetic diseases: myotubular myopathy and two forms of Charcot–Marie–Tooth neuropathy. We present an analysis of the myotubularin family in sequenced genomes. The myotubularin family encompasses catalytically active and inactive phosphatases, and both classes are well conserved from nematode to man. Catalytically active myotubularins dephosphorylate phosphatidylinositol 3-phosphate (PtdIns3P) and PtdIns3,5P2, leading to the production of PtdIns and PtdIns5P. This activity may be modulated by direct interaction with catalytically inactive myotubularins. These phosphoinositides are signaling molecules that are notably involved in vacuolar transport and membrane trafficking. Myotubularins are thus proposed to be implicated in these cellular mechanisms, and recent observations on myotubularins homologues in the nematode Caenorhabditis elegans indicate a role in endocytosis.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
THE MYOTUBULARIN FAMILY
 FUNCTIONS AND REGULATION
 ASSOCIATED DISEASES AND...
 CONCLUSION
 REFERENCES
 
The myotubularin family constitutes a large group within the tyrosine/dual-specificity phosphatase super-family (PTP/DSP) and members are present in almost all eukaryotic organisms (see below), including yeasts and plants. The founder member, myotubularin (encoded by the MTM1 gene), was shown to be mutated in X-linked myotubular myopathy (XLMTM) by positional cloning. Two other members were more recently found mutated in two forms of demyelinating Charcot–Marie–Tooth (CMT) neuropathy type 4B. These ubiquitously expressed myotubularins are thus implicated in diseases affecting different tissues. The myotubularin family encompasses catalytically active and inactive phosphatases. Surprisingly, recent data suggest that there is a functional cooperation between members of these two classes. This review focuses on recent advances concerning the biochemical and putative cellular functions of myotubularins and the associated human diseases or phenotypes in model organisms. We also present an overview of the evolution of this family based on the analysis of sequenced genomes.


   THE MYOTUBULARIN FAMILY
TOP
 ABSTRACT
 INTRODUCTION
 THE MYOTUBULARIN FAMILY
FUNCTIONS AND REGULATION
 ASSOCIATED DISEASES AND...
 CONCLUSION
 REFERENCES
 
The myotubularin family contains 14 genes in human, named MTM1 and MTMRelated 1 to 13, and at least two pseudogenes (see legend to Fig. 1). In Metazoa, it can be divided into six subgroups, each with one member in Caenorhabditis elegans and Drosophila melanogaster (1–4) (Figs 1 and 2). They all share homologies with the active site of tyrosine and dual-specificity phosphatases (5). Interestingly, three of the subgroups encompass catalytically inactive myotubularins bearing conserved mutations of the residues essential for the phosphatase activity (cysteine and arginine in the CX5R motif present in all PTP/DSP; Fig. 1). However, the overall homology with PTP/DSP remains and the aspartate at position 380 in human MTM1 is conserved in all members.



View larger version (26K):
[in this window]
[in a new window]
  		Figure 1. Human myotubularins: scaled representation of the protein domains of human myotubularins. Vertical bars on the left indicate the six subgroups. All myotubularins have the following domains in a conserved order (amino acid positions with respect to the human MTM1 protein): GRAM (amino acid 29–97 or up to 160), RID (within amino acid 161–272), PTP/DSP homology (amino acid 273–471; catalytic cysteine is amino acid 375), and SID (amino acid 435–486). Coiled-coil domains are predicted in most myotubularins (amino acid 553–580). Protein domain predictions were performed using SMART (http://smart.embl-heidelberg.de/) and PFSCAN (http://hits.isb-sib.ch/cgi-bin/PFSCAN). Amino acid length and chromosomal localization are given for each myotubularin, together with the sequence at the catalytic site. Red amino acids represent divergent residues compared to the catalytically active CX5R myotubularin consensus (VHCSDGDWRT). Physical and genetic (in bracket*) interactors are also indicated. HRX is the human homologue of Trithorax. NFL stands for neurofilament light chain and is mutated in axonal Charcot–Marie–Tooth neuropathy type 2E and severe cases initially diagnosed as Dejerine–Sottas syndrome. Two intron-less pseudogenes related to MTMR5 are located at 1p36 and 8q11. A potential gene/pseudogene closer to MTMR9 is located at 1p34 and corresponds to several spliced cDNAs and ESTs without a clear open reading frame (LOC339483).

 


View larger version (50K):
[in this window]
[in a new window]
  		Figure 2. Phylogenetic relationship of myotubularins: myotubularins are classified into six subgroups in higher eukaryotes with one protein for each subgroup in Drosophila melanogaster and Caenorhabditis elegans. Protein sequences were aligned using Clustal X (70) and the sequences encompassing the common domains were realigned (amino acids 39–514 in HsMTM1) using the distance method based on amino acid identity. Protein sequences used can be found at http://www-igbmc.u-strasbg.fr/Mandel. Scale represents the percentage of divergence. Phenotypes related to myotubularins loss-of-function in human genetic disorders and animal models are indicated: CMT4B1 and CMT4B2, Charcot–Marie–Tooth type 4B1 and 4B2, XLMTM, X-linked myotubular myopathy. The group of P. Harte reported that the CG9115 drosophila mutant is embryonic lethal (http://www.mdausa.org/publications/Quest/q76myopathy.html). (Hs, Homo sapiens; Dm, Drosophila melanogaster; Ce, Caenorhabditis elegans; Sc, Saccharomyces cerevisiae.)

 
Protein domains
Myotubularins all share the same protein domains core. Sequences alignment, domain prediction and functional analysis suggest that they all consist of the four following domains: GRAM, RID, PTP/DSP active site homology and SID (Fig. 1). In addition, some members bear phosphoinositides binding and protein interaction domains.

The GRAM domain (Glucosyltransferase, Rab-like GTPase Activator and Myotubularins) is also found in a number of proteins implicated in the regulation of membrane processes (6). It represents a divergent PH (Pleckstrin Homology) domain and may have the capacity to bind phosphoinositides (4,7).

The RID (Rac-Induced recruitment Domain) was defined as necessary for the recruitment of myotubularin and homologues (MTMR2, MTMR3 and MTMR9) to plasma membrane ruffles induced by constitutively activated Rac GTPase (8,9). This region may also mediate interaction with the neurofilament light chain (NF-L) protein in the case of MTMR2 (amino acids 160–300) (10).

The catalytic activity of myotubularins should implicate, as for the PTP/DSPs, three essential amino acids. The cysteine and arginine residues of the CX5R motif in the catalytic pocket form a covalent thiophosphate intermediate and stabilize the phosphoryl group respectively (5). An aspartate residue participates in the release of the substrate. Although this amino acid has not been unambiguously identified, mutation of aspartate 278 in MTM1, conserved in all active members from yeast to human, leads to complete loss of phosphatase activity and to specific localization at plasma membrane extensions (11). Whether the degenerated phosphatase consensus of the catalytically inactive myotubularins can still bind the substrates is not known.

The SET-interacting domain (SID) consists of a pair of amphipatic helices and was initially described as mediating interaction of the catalytically inactive myotubularin homologue MTMR5 with the SET (Su(var), Enhancer of zeste, Trithorax) domain of ALL1, the human orthologue of trithorax implicated in leukaemias (12,13). The SET domain has a histone methyltransferase activity (13,14). While myotubularins appear in general to have a cytoplasmic or plasma membrane localization in transfection studies, nuclear localization has been reported in some studies (10,15). For instance, while MTMR5 is cytoplasmic, deletion of part of its DENN domain leads to localization in the nucleus and acquisition of transforming properties (16). Thus, although a role of myotubularins in the nucleus has not yet been directly demonstrated, they could participate in the regulation of chromatin remodeling. The SID has also been recently proposed to mediate interaction between myotubularin (MTM1) and the catalytically inactive phosphatase MTMR12 (3-PAP) (see below) (17).

Disease-causing missense mutations have been found in each of these domains, suggesting that they all participate in the function of myotubularins (18–22). Missense mutations are, however, predominant in the RID and in the PTP/DSP homology region of MTM1, in myotubular myopathy.

Other domains are found only in a subset of myotubularins but are interestingly related to phosphoinositides and membrane-trafficking pathways. FYVE (Fab1p, YO1B, Vac1p and EEA1) and PH domains are proposed to bind either specifically to PtdIns3P or to various phosphoinositides, respectively (23). Only the PH domain of MTMR5 was confirmed to bind to PtdIns3,4P2 and PtdIns3,4,5P3 (24). The MTMR5/R13 subgroup also contains a DENN (differentially expressed in neoplastic versus normal cells) domain found in some regulators of GTPases (for example, Rab3GEF involved in exocytosis), which could represent a new GTPase effector domain (25). Additional domains include predicted coiled-coil domains at the C-terminus of nearly all myotubularins, which appear important for heterodimerization between MTMR2 and MTMR5 and between MTMR7 and MTMR9 (see below) (26,27), and a PDZ (PSD-95/Dlg/ZO-1) binding site at the C-terminus of human proteins of the MTM1 and MTMR5 subgroups (28).

Phylogenetic relationship and evolution
As numerous genomes have been recently sequenced, the phylogeny and timescale evoution of gene families are becoming better understood (29). We looked for the appearance and possible co-evolution of myotubularins subgroups. Procaryotes do not contain clear myotubularin homologues. Fungi genomes contains one myotubularin with a consensus active site, except the fully sequenced Aspergillus terreus, which has no myotubularin. The obligate intracellular parasite Encephalitozoon cuniculi (Microsporidia) does not have myotubularins, also suggesting that these proteins appeared in yeast. In both budding yeast (S. cerevisiae) and fission yeast (S. pombe), deletion of the single myotubularin gene does not cause an obvious phenotype, indicating that in these unicellular organisms, myotubularin function is dispensable at least under laboratory conditions (11,30).

Catalytically inactive myotubularins appear very early in evolution, as they are found in Giardia lamblia, Dictyostelium discoideum and Entamoeba histolytica. These organisms also have several myotubularins with CX5R consensus active sites, like in the kinetoplastida (leshmania and trypanosoma). In contrast, absence of myotubularins in the apicomplexa Plasmodium vivax suggests that its functions have been lost or replaced in this intracellular parasitic organism. No catalytically inactive myotubularins have been found in plants to date and Arabidopsis thaliana contains only two putatively active myotubularins.

In all metazoa, the myotubularin family is divided into three catalytically active and three catalytically inactive subgroups (Fig. 2), except in the urochordate Ciona intestinalis where we have found no MTMR3 subgroup member to date. The functional separation of MTM1, MTMR1 and MTMR2, and of MTMR5 and MTMR13 appeared with the vertebrates, as individual orthologues of these genes are found in fugu and zebrafish. At present, it is uncertain whether the three catalytically inactive phosphatase subgroups evolved from a single inactive ancestor or by recurrent very ancient events from active phosphatases. The HsMTMR6/7/8 subgroup appears the most closely related to the yeast orthologues and has lost its FYVE domain in vertebrates (present in C. elegans and drosophila but absent in human and fishes).


   FUNCTIONS AND REGULATION
TOP
 ABSTRACT
 INTRODUCTION
 THE MYOTUBULARIN FAMILY
 FUNCTIONS AND REGULATION
ASSOCIATED DISEASES AND...
 CONCLUSION
 REFERENCES
 
Biochemical functions
Although catalytically active myotubularins share extensive conservation with the active site of PTP/DSP, it was surprising to find that they dephosphorylate phosphoinositides instead of phosphoaminoacids (11,30). Phosphoinositides are second messengers implicated in a wide range of cellular processes from growth factor response and proliferation to differentiation and transport. In vitro, catalytically active myotubularins (MTM1, MTMR2, MTMR3, MTMR4, MTMR6 and MTMR7) are specific 3-phosphatases for phosphatidylinositol 3-monophosphate (PtdIns3P) (9,11,27,30–34) and phosphatidylinositol 3,5-biphosphate (PtdIns3,5P2) (7,31,33) (see Fig. 3A for the structure of phosphatidylinositol and metabolism of phosphoinositides). Dephosphorylation of PtdIns3P has also been shown in yeast and mammalian cells. PtdIns3P and Rab GTPases are the two key players that regulate endosome trafficking and fusion (35,36). The activated state of Rab GTPases (GTP-bound) is regulated by Rab GAP (GTPase activating proteins) and GEF (GTPases effectors) while PtdIns3P is synthetized by the type III PI 3-kinase homologue of yeast VPS (vacuolar protein sorting) (35). Thus myotubularins could represent a fourth type of regulator of endosome trafficking, by dephosphorylating PtdIns3P.



View larger version (23K):
[in this window]
[in a new window]
  		Figure 3. Functional and regulation hypotheses. (A) Structure of phosphatidylinositol and partial phosphoinositides metabolism in higher eukaryotes showing the possible roles of myotubularins together with the implicated phosphoinositides kinases (VPS34 is the PI 3-kinase type III). D3, D4 and D5 correspond to the phosphorylable OH groups. PtdIns3P regulates endocytosis, PtdIns3,5P2 is implicated in vacuolar homeostasis and the function of PtdIns5P is not known. Myotubularins deficiency might lead to increased level of PtdIns3P and PtdIns3,5P2 and/or decreased PtdIns5P. (B) Competition or cooperation: Catalytically active myotubularins dephosphorylate phosphoinositides while catalytically inactive myotubularins might bind to and protect the substrates (competition). However, recent data indicate that catalytically inactive myotubularins can heterodimerize with active ones and enhance their enzymatic activity, or possibly recruit the complex to specific substrate pools (cooperation). Heterodimers might also have a different substrate specificity or acquire new functions.

 
The role of PtdIns3,5P2 has mainly been studied in yeast and it was shown to be important for vacuolar homeostasis and membrane trafficking (37,38). PtdIns3,5P2 dephosphorylation by myotubularins produces PtdIns5P, a recently discovered phosphoinositide of unknown function (39). Lately, the PtdIns5P binding property of the nuclear protein ING2, a modulator of histone acetyl transferase and deacetylase activities, has been shown to be required for its ability to activate p53-dependent apoptotic pathways (40). It has also been proposed that PtdIns5P acts as a positive allosteric regulator of myotubularin enzymatic activity, and addition of PtdIns3P and PtdIns5P in vitro promotes oligomerization of myotubularin into a ring heptameric structure (7). The physiological action of catalytically active myotubularins (regulation of PtdIns3P and/or PtdIns3,5P2 levels, or production of PtdIns5P) remains to be discovered (Fig. 3A). For some myotubularins, the same phosphoinositide can act both as a ligand and as a substrate. For example, MTMR3 contains a FYVE domain and dephosphorylates PtdIns3P, which is also a substrate for the formation of PtdIns3,5P2 by PtdIns3P 5-kinase (39).

Putative cellular functions
Catalytically active myotubularins are cytoplasmic proteins that do not co-localize with PtdIns3P onto endosomes in transfected cells (8). Thus there should be some mechanisms to target these enzymes to their site of action, either directly through a phosphoinositides binding domain (such as the GRAM or FYVE domains), or indirectly through protein interactors. MTMR2 (the gene mutated in CMT4B) interacts with NF-L, the neurofilament light chain protein specifically expressed in the nervous system both in Schwann cells and in neurons (10). NF-L is one of the major component of the neuronal cytoskeleton. Membrane trafficking is very important for the plasma membrane remodeling of myelin forming Schwann cells.

Overexpression of human myotubularins in yeast (MTM1, MTMR2 and MTMR3) or mammalian cells (MTMR3 inactive mutant) leads to enlarged vacuoles (9,11,31), suggesting that endogenous myotubularins could be implicated in vacuolar transport or fusion. Ablation of the mouse orthologues of MTM1 and MTMR5 also leads to the formation of abnormal vacuoles respectively in muscle (41) and Sertoli cells (42). In the nematode C. elegans, decreased expression of the orthologue of the human MTMR6 subgroup (called F53a2.8) compensates for the loss-of-function of the VPS34 PI 3-kinase homologue, strongly suggesting that this myotubularin subgroup indeed participates in the regulation of PtdIns3P level (43). RNA inhibition of orthologues of human MTMR3/4, MTMR6/7/8 and MTMR9 subgroups (T24a11.1, F53a2.8 and Y39h10a.3) disrupts endocytosis by C. elegans coelomocytes, scavenger cells (43,44). Interestingly, these experiments suggest that both catalytically active (MTMR6/7/8) and inactive (MTMR9) myotubularins are implicated in the same uptake pathway. The mechanisms by which myotubularins may regulate endocytosis have not been reported yet.

A role of myotubularins at the plasma membrane is also suspected as overexpression of the MTM1 protein in mammalian cells lead to altered shape and plasma membrane projections (8,34). Moreover, constitutively activated Rac1 GTPase leads to recruitment of myotubularins and homologues to plasma membrane ruffles independent of catalytic activity (8,9).

Functional redundancy and specificity
One can wonder why there are so many myotubularins in human and mouse. The catalytically active ones show identical substrate specificity in vitro, high sequence homology (especially within a subgroup) and an overall ubiquitous expression. The fact that loss-of-function of MTM1, MTMR2 or MTMR13 leads to observable and rather severe phenotypes (myotubular myopathy and CMT4B neuropathies) indicates that they possess some tissue-specific role that cannot be compensated by other members of the family. Lack of MTM1 causes a very similar muscle phenotype in man and mouse (41,45) indicating that this specificity is indeed a characteristic of the gene (muscle-specific regulation) and/or of the protein (muscle-specific function). MTM1 is increased at the RNA and protein level during myoblasts fusion in culture (34,46). In contrast, expression of Mtmr2 mRNA is stronger in peripheral nervous system, the tissue affected in CMT4B, with high level in neurons (33,47). In vivo, MTMR2 protein is both cytoplasmic and nuclear in Schwann cells and motor neurons and only cytoplasmic in sensory neurons (10). Further suggestions for a specific protein function is the observation that subcellular localization differs slightly between myotubularins when co-localization is performed in transfected cells. MTMR2 and MTMR3 are more concentrated around the nucleus compared to MTM1 and MTMR1 (9,34,48). Such results suggest that different myotubularins may regulate different phosphoinositides subcellular pools.

Functional regulation and cooperation
The fact that two forms of demyelinating CMT4B neuropathy are due to loss-of-function mutations in either a catalytically active phosphatase, MTMR2 (18), or inactive phosphatase, MTMR13 (49,50), is not in accordance with the hypothesis that the so-called ‘dead-phosphatases’ would compete with their active homologues for the substrate (12,51) (competition model in Fig. 3B). Recent studies have shown that catalytically inactive myotubularins can heterodimerize with active homologues. This might promote a higher substrate turnover either by increasing the enzymatic activity or by recruitment to specific phosphoinositides subpools (cooperation model in Fig. 3B). Physical interactions have been reported to date between MTMR2 and MTMR5 (26) and between MTM1 and MTMR12 (17,52) and between MTMR7 and MTMR9 (27). Interaction of MTM1 and MTMR2 with inactive homologues appears to promote their recruitment to specific subcellular localizations while MTMR7 in vitro enzymatic activity is increased in the heterodimer MTMR7/MTMR9. The heterodimers might also have a modified substrate specificity, as the MTM1–MTMR12 heterodimer purified from platelets can dephosphorylate PtdIns3,4P2 (52). However, isolated MTM1 activity on this substrate was not tested in this report. Heterodimers might also acquire new functions (Fig. 3B). These results suggest that there might be complex interactions between the 14 human myotubularin proteins. The formation of these heterodimers might have a key role in the regulation of the function of myotubularins in different tissues.


   ASSOCIATED DISEASES AND PHENOTYPES
TOP
 ABSTRACT
 INTRODUCTION
 THE MYOTUBULARIN FAMILY
 FUNCTIONS AND REGULATION
 ASSOCIATED DISEASES AND...
CONCLUSION
 REFERENCES
 
Congenital myopathies
Myotubular myopathy (XLMTM) is a usually very severe congenital myopathy associated with major hypotonia at birth (45,53). The histopathology of skeletal muscle reveals small rounded fibers with central nuclei. The nuclei are surrounded by a region devoid of contractile apparatus but with a high density of mitochondria and other organites. This pattern is somewhat similar to the structure of fetal myotubes, while mature muscle fibers have peripherally located nuclei. Central nuclei can also be observed in regenerating muscle (for instance in the mdx mouse model of Duchenne muscular dystrophy). MTM1 mutations have been reported in more than 300 patients, including more than 60 different missense mutations that affect conserved domains of myotubularin (20–22,54). Some of these missense mutations are found in patients with a mild phenotype. The oldest surviving patient reported, a 67-year-old male, carries a N180K missense affecting a residue between the GRAM and the RID domains. Involvement of nonmuscle tissues has been observed in some patients with prolonged survival (55), such as hepatic peliosis, an internal bleeding disorder. The Mtm1 knockout mice recapitulate the histopathological signs of XLMTM and show a progressive myopathy starting a few weeks after birth while muscle histology appears normal at birth. This suggests that the disorganized appearance of the muscle fibers is due to a defect in structural maintenance rather than an impairment in myogenesis as previously hypothesized. No signs of active regeneration were observed in the mouse model. Specific ablation of the gene in skeletal muscle showed that it is the primary tissue involved in the pathology (41). The MTMR1 gene is adjacent to MTM1 on the X chromosome. No mutations associated to MTMR1 have been found to date in myotubular myopathy (56). However, a muscle-specific transcript, which appears after myoblasts fusion, is decreased in cells and muscle from patients with the congenital form of myotonic dystrophy (cDM1) (48). The cause of cDM1 is a large CTG expansion in the 3'UTR of the DMPK gene and is believed to interfere with transcription and splicing of other genes (57). MTMR1 altered splicing might thus account for part of the cDM1 phenotype, which is clinically close to myotubular myopathy.

Charcot–Marie–Tooth neuropathies
Charcot–Marie–Tooth (CMT) disease is the most frequent class of inherited disorder of the peripheral nervous system and is classified into demyelinating and axonal neuropathies. Of the 30 mapped loci, 15 disease genes have been identified so far (58) and code for structural proteins of myelin (PMP22, MPZ, GJB1, periaxin), of axons (neurofilament light chain and kinesin 1B), and of the nuclear envelope (lamin A/C) (59), for the EGR2 transcription factor, the Rab7 GTPase (60), GDAP1 (61,62), LITAF/SIMPLE (63), the glycyl tRNA synthetase (64) and the N-myc downstream regulated protein 1.

Recently, a catalytically active and an inactive member of the myotubularin family (MTMR2 and MTMR13/Sbf2 respectively) have been identified as mutated in two demyelinating recessive forms of CMT type 4B (CMT4B). CMT4B1 is caused by MTMR2 loss-of-function mutations (18), while mutations in MTMR13/Sbf2 are responsible for CMT4B2 associated or not with infantile glaucoma (49,50). This disease is characterized by childhood onset, symmetrical distal and proximal muscular weakness starting at the lower extremities, sensory loss and severely decreased nerve conduction velocity. A hallmark of this disorder is the presence of myelin outfoldings in peripheral nerves. The fact that CMT4B2 phenotype is very similar to CMT4B1, and that MTMR5 (the closest homologue of MTMR13) interacts with MTMR2, strongly suggests that MTMR13 may directly regulate MTMR2 activity. The interaction between MTMR2 and NF-L support the notion that hereditary demyelinating and axonal neuropathies may represent different clinical manifestations of a common pathological mechanism.

MTMR13 is the first catalytically inactive phosphatase mutated in a human disorder. Loss-of-function of other dead-phosphatases have been achieved recently in mouse for STYX (65) and MTMR5. For the latter, mice demonstrate impaired spermatogenesis and azoospermia (42). Interestingly, expression of the rat Mtmr2 gene is high in testis and increases when inter-Sertoli junctions are formed in vitro (66). Moreover, the follow-up of one CMT4B male patient has revealed the presence of azoospermia (Dr Paola Mandich, personal communication), suggesting that MTMR2, in association with MTMR5, also has a role in spermatogenesis and/or spermiogenesis.

Candidate diseases
Myotubularin homologues are very good candidate genes for other forms of CMT neuropathies, Dejerine–Sottas syndrome, and congenital hypomyelinating neuropathies (58,67), centronuclear myopathies with histopathology related to XLMTM (68) and glaucomas (69). The role of the murine MTMR5 gene in spermatogenesis makes the human gene a good candidate for male infertility on chromosome 22qter. The chromosomal localization of the genes encoding myotubularins (Fig. 1) and the nascent understanding of their cellular functions provide good candidates for disease with intracellular transport anomalies.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 THE MYOTUBULARIN FAMILY
 FUNCTIONS AND REGULATION
 ASSOCIATED DISEASES AND...
 CONCLUSION
REFERENCES
 
Future studies of the myotubularin family should decipher the physiological functions and tissue-specificity of the different members. The hypothesis that catalytically inactive phosphatases could regulate phosphorylation level by cooperating with active phosphatases is a new concept and brings a third player into the opposing couple kinase/phosphatase. Myotubularins could also be responsible for the production of PtdIns5P, the function of which remains unknown. Their action on PtdIns3P and PtdIns3,5P2 suggests that anomalies of membrane trafficking and protein transport are the cause of the associated human disorders. However, the relationship between such mechanisms and the tissue phenotype observed in myotubular myopathy and type 4B Charcot–Marie–Tooth neuropathy remains mysterious.


   ACKNOWLEDGEMENTS
 
We wish to thank Harshal Nandurkar, Hanna Fares and Paola Mandich for sharing unpublished results and Laurent Bianchetti and Olivier Poch for help with bio-informatics analysis. This work was supported by INSERM, CNRS, Hôpital Universitaire de Strasbourg and by grants from the Association Francaise contre les Myopathies. A.B. is supported by Telethon-Italy and is an Assistant Telethon Scientist from the Dulbecco Telethon Institute.


   FOOTNOTES
 
* To whom correspondence should be addressed at: IGBMC, 1 rue Laurent Fries, BP 10142, 67404 Illkirch, France. Tel: +33 388653244; Fax: +33 388653246; Email: mtm{at}titus.u-strasbg.fr Back


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 THE MYOTUBULARIN FAMILY
 FUNCTIONS AND REGULATION
 ASSOCIATED DISEASES AND...
 CONCLUSION
 REFERENCES
 

  1. Laporte, J., Blondeau, F., Buj-Bello, A., Tentler, D., Kretz, C., Dahl, N. and Mandel, J.L. (1998) Characterization of the myotubularin dual specificity phosphatase gene family from yeast to human. Hum. Mol. Genet., 7, 1703–1712.[Abstract/Free Full Text]

  2. Laporte, J., Blondeau, F., Buj-Bello, A. and Mandel, J.L. (2001) The myotubularin family: from genetic disease to phosphoinositide metabolism. Trends Genet., 17, 221–228.[CrossRef][Web of Science][Medline]

  3. Nandurkar, H.H. and Huysmans, R. (2002) The myotubularin family: novel phosphoinositide regulators. IUBMB Life, 53, 37–43.[Web of Science][Medline]

  4. Wishart, M.J. and Dixon, J.E. (2002) PTEN and myotubularin phosphatases: from 3-phosphoinositide dephosphorylation to disease. Phosphatase and tensin homolog deleted on chromosome ten. Trends Cell Biol., 12, 579–585.[CrossRef][Web of Science][Medline]

  5. Denu, J.M., Stuckey, J.A., Saper, M.A. and Dixon, J.E. (1996) Form and function in protein dephosphorylation. Cell, 87, 361–364.[CrossRef][Web of Science][Medline]

  6. Doerks, T., Strauss, M., Brendel, M. and Bork, P. (2000) GRAM, a novel domain in glucosyltransferases, myotubularins and other putative membrane-associated proteins. Trends Biochem. Sci., 25, 483–485.[CrossRef][Web of Science][Medline]

  7. Schaletzky, J., Dove, S.K., Short, B., Lorenzo, O., Clague, M.J. and Barr, F.A. (2003) Phosphatidylinositol-5-phosphate activation and conserved substrate specificity of the myotubularin phosphatidylinositol 3-phosphatases. Curr. Biol., 13, 504–509.[CrossRef][Web of Science][Medline]

  8. Laporte, J., Blondeau, F., Gansmuller, A., Lutz, Y., Vonesch, J.L. and Mandel, J.L. (2002) The PtdIns3P phosphatase myotubularin is a cytoplasmic protein that also localizes to Rac1-inducible plasma membrane ruffles. J. Cell. Sci., 115, 3105–3117.[Abstract/Free Full Text]

  9. Laporte, J., Liaubet, L., Blondeau, F., Tronchere, H., Mandel, J.L. and Payrastre, B. (2002) Functional redundancy in the myotubularin family. Biochem. Biophys. Res. Commun., 291, 305–312.[CrossRef][Web of Science][Medline]

  10. Previtali, S.C., Zerega, B., Sherman, D.L., Brophy, P.J., Dina, G., King, R.H.M., Salih, M.M., Feltri, L., Quattrini, A., Ravazzolo, R. et al. (2003) Myotubularin-related 2 protein phosphatase and neurofilament light chain protein, both mutated in CMT neuropathies, interact in peripheral nerve. Hum. Mol. Genet., 12, 1713–1723.[Abstract/Free Full Text]

  11. Blondeau, F., Laporte, J., Bodin, S., Superti-Furga, G., Payrastre, B. and Mandel, J.L. (2000) Myotubularin, a phosphatase deficient in myotubular myopathy, acts on phosphatidylinositol 3-kinase and phosphatidylinositol 3-phosphate pathway. Hum. Mol. Genet., 9, 2223–2229.[Abstract/Free Full Text]

  12. Cui, X., De Vivo, I., Slany, R., Miyamoto, A., Firestein, R. and Cleary, M.L. (1998) Association of SET domain and myotubularin-related proteins modulates growth control. Nature Genet., 18, 331–337.[CrossRef][Web of Science][Medline]

  13. Schneider, R., Bannister, A.J. and Kouzarides, T. (2002) Unsafe SETs: histone lysine methyltransferases and cancer. Trends Biochem. Sci., 27, 396–402.[CrossRef][Web of Science][Medline]

  14. Nakamura, T., Mori, T., Tada, S., Krajewski, W., Rozovskaia, T., Wassell, R., Dubois, G., Mazo, A., Croce, C.M. and Canaani, E. (2002) ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation. Mol. Cell, 10, 1119–1128.[CrossRef][Web of Science][Medline]

  15. Petruk, S., Sedkov, Y., Smith, S., Tillib, S., Kraevski, V., Nakamura, T., Canaani, E., Croce, C.M. and Mazo, A. (2001) Trithorax and dCBP acting in a complex to maintain expression of a homeotic gene. Science, 294, 1331–1334.[Abstract/Free Full Text]

  16. Firestein, R. and Cleary, M.L. (2001) Pseudo-phosphatase Sbf1 contains an N-terminal GEF homology domain that modulates its growth regulatory properties. J. Cell Sci., 114, 2921–2927.

  17. Nandurkar, H.H., Layton, M., Laporte, J., Selan, C., Corcoran, L., Caldwell, K.K., Mochizuka, Y., Majerus, P.W. and Mitchell, C.A. (2003) Identification of myotubularin as the lipid phosphatase catalytic subunit associated with the 3-phosphatase adapter protein, 3-PAP. Proc. Natl Acad. Sci. USA, 100, 8660–8665.[Abstract/Free Full Text]

  18. Bolino, A., Muglia, M., Conforti, F.L., LeGuern, E., Salih, M.A., Georgiou, D.M., Christodoulou, K., Hausmanowa-Petrusewicz, I., Mandich, P., Schenone, A. et al. (2000) Charcot–Marie–Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2. Nat. Genet., 25, 17–19.[CrossRef][Web of Science][Medline]

  19. Nelis, E., Erdem, S., Tan, E., Lofgren, A., Ceuterick, C., De Jonghe, P., Van Broeckhoven, C., Timmerman, V. and Topaloglu, H. (2002) A novel homozygous missense mutation in the myotubularin-related protein 2 gene associated with recessive Charcot–Marie–Tooth disease with irregularly folded myelin sheaths. Neuromuscul. Disord., 12, 869–873.[CrossRef][Web of Science][Medline]

  20. Laporte, J., Biancalana, V., Tanner, S.M., Kress, W., Schneider, V., Wallgren-Pettersson, C., Herger, F., Buj-Bello, A., Blondeau, F., Liechti-Gallati, S. et al. (2000) MTM1 mutations in X-linked myotubular myopathy. Hum. Mutat., 15, 393–409.[CrossRef][Web of Science][Medline]

  21. Herman, G.E., Kopacz, K., Zhao, W., Mills, P.L., Metzenberg, A. and Das, S. (2002) Characterization of mutations in fifty North American patients with X-linked myotubular myopathy. Hum. Mutat., 19, 114–121.[CrossRef][Web of Science][Medline]

  22. Biancalana, V., Caron, O., Gallati, S., Baas, F., Kress, W., Novelli, G., D'Apice, M.R., Lagier-Tourenne, C., Buj-Bello, A., Romero, N.B. et al. (2003) Characterisation of mutations in 77 patients with X-linked myotubular myopathy, including a family with a very mild phenotype. Hum. Genet., 112, 135–142.[Web of Science][Medline]

  23. Itoh, T. and Takenawa, T. (2002) Phosphoinositide-binding domains: Functional units for temporal and spatial regulation of intracellular signalling. Cell Signal., 14, 733–743.[CrossRef][Web of Science][Medline]

  24. Isakoff, S.J., Cardozo, T., Andreev, J., Li, Z., Ferguson, K.M., Abagyan, R., Lemmon, M.A., Aronheim, A. and Skolnik, E.Y. (1998) Identification and analysis of PH domain-containing targets of phosphatidylinositol 3-kinase using a novel in vivo assay in yeast. EMBO J., 17, 5374–5387.[CrossRef][Web of Science][Medline]

  25. Levivier, E., Goud, B., Souchet, M., Calmels, T.P., Mornon, J.P. and Callebaut, I. (2001) uDENN, DENN, and dDENN: indissociable domains in Rab and MAP kinases signaling pathways. Biochem. Biophys. Res. Commun., 287, 688–695.[CrossRef][Web of Science][Medline]

  26. Kim, S.A., Vacratsis, P.O., Firestein, R., Cleary, M.L. and Dixon, J.E. (2003) Regulation of myotubularin-related (MTMR)2 phosphatidylinositol phosphatase by MTMR5, a catalytically inactive phosphatase. Proc. Natl Acad. Sci. USA, 100, 4492–4497.[Abstract/Free Full Text]

  27. Mochizuki, Y. and Majerus, P.W. (2003) Characterization of myotubularin-related protein 7 and its binding partner, myotubularin-related protein 9. Proc. Natl Acad. Sci. USA, 100, 9763–9773.

  28. Fabre, S., Reynaud, C. and Jalinot, P. (2000) Identification of functional PDZ domain binding sites in several human proteins. Mol. Biol. Rep., 27, 217–224.[CrossRef][Web of Science][Medline]

  29. Hedges, S.B. (2002) The origin and evolution of model organisms. Nat. Rev. Genet., 3, 838–849.[CrossRef][Web of Science][Medline]

  30. Taylor, G.S., Maehama, T. and Dixon, J.E. (2000) Inaugural article: myotubularin, a protein tyrosine phosphatase mutated in myotubular myopathy, dephosphorylates the lipid second messenger, phosphatidylinositol 3-phosphate. Proc. Natl Acad. Sci. USA, 97, 8910–8915.[Abstract/Free Full Text]

  31. Walker, D.M., Urbe, S., Dove, S.K., Tenza, D., Raposo, G. and Clague, M.J. (2001) Characterization of MTMR3. an inositol lipid 3-phosphatase with novel substrate specificity. Curr. Biol., 11, 1600–1605.[CrossRef][Web of Science][Medline]

  32. Zhao, R., Qi, Y., Chen, J. and Zhao, Z.J. (2001) FYVE-DSP2, a FYVE domain-containing dual specificity protein phosphatase that dephosphorylates phosphotidylinositol 3-phosphate. Exp. Cell Res., 265, 329–338.[CrossRef][Web of Science][Medline]

  33. Berger, P., Bonneick, S., Willi, S., Wymann, M. and Suter, U. (2002) Loss of phosphatase activity in myotubularin-related protein 2 is associated with Charcot–Marie–Tooth disease type 4B1. Hum. Mol. Genet., 11, 1569–1579.[Abstract/Free Full Text]

  34. Kim, S.A., Taylor, G.S., Torgersen, K.M. and Dixon, J.E. (2002) Myotubularin and MTMR2, phosphatidylinositol 3-phosphatases mutated in myotubular myopathy and type 4B Charcot–Marie–Tooth disease. J. Biol. Chem., 277, 4526–4531.[Abstract/Free Full Text]

  35. Gillooly, D.J., Morrow, I.C., Lindsay, M., Gould, R., Bryant, N.J., Gaullier, J.M., Parton, R.G. and Stenmark, H. (2000) Localization of phosphatidylinositol 3-phosphate in yeast and mammalian cells. EMBO J., 19, 4577–4588.[CrossRef][Web of Science][Medline]

  36. Zerial, M. and McBride, H. (2001) Rab proteins as membrane organizers. Nat. Rev. Mol. Cell Biol., 2, 107–117.[CrossRef][Web of Science][Medline]

  37. Dove, S.K., Cooke, F.T., Douglas, M.R., Sayers, L.G., Parker, P.J. and Michell, R.H. (1997) Osmotic stress activates phosphatidylinositol-3,5-bisphosphate synthesis. Nature, 390, 187–192.[CrossRef][Medline]

  38. DeWald, D.B. (2002) Phosphoinositide signaling: vac to the future in fab1 kinase regulation. Curr. Biol., 12, R491–492.[CrossRef][Web of Science][Medline]

  39. Shisheva, A. (2001) PIKfyve: the road to PtdIns 5-P and PtdIns 3,5-P(2). Cell Biol. Int., 25, 1201–1206.[CrossRef][Web of Science][Medline]

  40. Gozani, O., Karuman, P., Jones, D.R., Ivanov, D., Cha, J., Lugovskoy, A.A., Baird, C.L., Zhu, H., Field, S.J., Lessnick, S.L. et al. (2003) The PHD finger of the chromatin-associated protein ING2 functions as a nuclear phosphoinositide receptor. Cell, 114, 99–111.[CrossRef][Web of Science][Medline]

  41. Buj-Bello, A., Laugel, V., Messaddeq, N., Zahreddine, H., Laporte, J., Pellissier, J.F. and Mandel, J.L. (2002) The lipid phosphatase myotubularin is essential for skeletal muscle maintenance but not for myogenesis in mice. Proc. Natl Acad. Sci. USA, 99, 15060–15065.[Abstract/Free Full Text]

  42. Firestein, R., Nagy, P.L., Daly, M., Huie, P., Conti, M. and Cleary, M.L. (2002) Male infertility, impaired spermatogenesis, and azoospermia in mice deficient for the pseudophosphatase Sbf1. J. Clin. Invest., 109, 1165–1172.[CrossRef][Web of Science][Medline]

  43. Xue, Y., Fares, H., Grant, B., Li, Z., Rose, A.M., Clark, S.G. and Skolnik, E.Y. (2003) Genetic analysis of the myotubularin family of phosphatases in Caenorhabditis elegans. J. Biol. Chem., in press.

  44. Fares, H. and Greenwald, I. (2001) Genetic analysis of endocytosis in Caenorhabditis elegans: coelomocyte uptake defective mutants. Genetics, 159, 133–145.[Abstract/Free Full Text]

  45. Mandel, J.-L., Laporte, J., Buj-Bello, A., Sewry, C. and Wallgren-Pettersson, C. (2002) Structural and molecular basis of skeletal muscle diseases. In Karpati, G. (ed.), Developmental Disorders: X-linked myotubular myopathy. ISN Neuropath Press, Basel, pp. 124–129.

  46. Laporte, J., Kress, W. and Mandel, J.L. (2001) Diagnosis of X-linked myotubular myopathy by detection of myotubularin. Ann. Neurol., 50, 42–46.[CrossRef][Web of Science][Medline]

  47. Bolino, A., Marigo, V., Ferrera, F., Loader, J., Romio, L., Leoni, A., Di Duca, M., Cinti, R., Cecchi, C., Feltri, M.L. et al. (2002) Molecular characterization and expression analysis of Mtmr2, mouse homologue of MTMR2, the myotubularin-related 2 gene, mutated in CMT4B. Gene, 283, 17–26.[CrossRef][Web of Science][Medline]

  48. Buj-Bello, A., Furling, D., Tronchere, H., Laporte, J., Lerouge, T., Butler-Browne, G.S. and Mandel, J.L. (2002) Muscle-specific alternative splicing of myotubularin-related 1 gene is impaired in DM1 muscle cells. Hum. Mol. Genet., 11, 2297–2307.[Abstract/Free Full Text]

  49. Azzedine, H., Bolino, A., Taieb, T., Birouk, N., Di Duca, M., Bouhouche, A., Benamou, S., Mrabet, A., Hammadouche, T., Chkili, T. et al. (2003) Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot–Marie–Tooth disease associated with early-onset glaucoma. Am. J. Hum. Genet., 72, 1141–1153.[CrossRef][Web of Science][Medline]

  50. Senderek, J., Bergmann, C., Weber, S., Ketelsen, U.P., Schorle, H., Rudnik-Schoneborn, S., Buttner, R., Buchheim, E. and Zerres, K. (2003) Mutation of the SBF2 gene, encoding a novel member of the myotubularin family, in Charcot–Marie–Tooth neuropathy type 4B2/11p15. Hum. Mol. Genet., 12, 349–356.[Abstract/Free Full Text]

  51. Hunter, T. (1998) Anti-phosphatases take the stage. Nat. Genet., 18, 303–305.[CrossRef][Web of Science][Medline]

  52. Nandurkar, H.H., Caldwell, K.K., Whisstock, J.C., Layton, M.J., Gaudet, E.A., Norris, F.A., Majerus, P.W. and Mitchell, C.A. (2001) Characterization of an adapter subunit to a phosphatidylinositol (3)P 3-phosphatase: identification of a myotubularin-related protein lacking catalytic activity. Proc. Natl Acad. Sci. USA, 98, 9499–9504.[Abstract/Free Full Text]

  53. Van Wijngaarden, G.K., Fleury, P., Bethlem, J. and Hugo Meijer, A.E.F. (1969) Familial myotubular myopathy. Neurology, 19, 901–908.[Free Full Text]

  54. Laporte, J., Hu, L.J., Kretz, C., Mandel, J.L., Kioschis, P., Coy, J.F., Klauck, S.M., Poustka, A. and Dahl, N. (1996) A gene mutated in X-linked myotubular myopathy defines a new putative tyrosine phosphatase family conserved in yeast. Nat. Genet., 13, 175–182.[CrossRef][Web of Science][Medline]

  55. Herman, G.E., Finegold, M., Zhao, W., de Gouyon, B. and Metzenberg, A. (1999) Medical complications in long-term survivors with X-linked myotubular myopathy. J. Pediatr., 134, 206–214.[CrossRef][Web of Science][Medline]

  56. Copley, L.M., Zhao, W.D., Kopacz, K., Herman, G.E., Kioschis, P., Poustka, A., Taudien, S. and Platzer, M. (2002) Exclusion of mutations in the MTMR1 gene as a frequent cause of X-linked myotubular myopathy. Am. J. Med. Genet., 107, 256–258.[CrossRef][Web of Science][Medline]

  57. Timchenko, L.T., Tapscott, S.J., Cooper, T.A. and Monckton, D.G. (2002) Myotonic dystrophy: discussion of molecular basis. Adv. Exp. Med. Biol., 516, 27–45.[Web of Science][Medline]

  58. Boerkoel, C.F., Takashima, H., Garcia, C.A., Olney, R.K., Johnson, J., Berry, K., Russo, P., Kennedy, S., Teebi, A.S., Scavina, M. et al. (2002) Charcot–Marie–Tooth disease and related neuropathies: mutation distribution and genotype–phenotype correlation. Ann. Neurol., 51, 190–201.[CrossRef][Web of Science][Medline]

  59. De Sandre-Giovannoli, A., Chaouch, M., Kozlov, S., Vallat, J.M., Tazir, M., Kassouri, N., Szepetowski, P., Hammadouche, T., Vandenberghe, A., Stewart, C.L. et al. (2002) Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot–Marie–Tooth disorder type 2) and mouse. Am. J. Hum. Genet., 70, 726–736.[CrossRef][Web of Science][Medline]

  60. Verhoeven, K., De Jonghe, P., Coen, K., Verpoorten, N., Auer-Grumbach, M., Kwon, J.M., FitzPatrick, D., Schmedding, E., De Vriendt, E., Jacobs, A. et al. (2003) Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot–Marie–Tooth type 2B neuropathy. Am. J. Hum. Genet., 72, 722–727.[CrossRef][Web of Science][Medline]

  61. Baxter, R.V., Ben Othmane, K., Rochelle, J.M., Stajich, J.E., Hulette, C., Dew-Knight, S., Hentati, F., Ben Hamida, M., Bel, S., Stenger, J.E. et al. (2002) Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot–Marie–Tooth disease type 4A/8q21. Nat. Genet., 30, 21–22.[CrossRef][Web of Science][Medline]

  62. Cuesta, A., Pedrola, L., Sevilla, T., Garcia-Planells, J., Chumillas, M.J., Mayordomo, F., LeGuern, E., Marin, I., Vilchez, J.J. and Palau, F. (2002) The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot–Marie–Tooth type 4A disease. Nat. Genet., 30, 22–25.[CrossRef][Web of Science][Medline]

  63. Street, V.A., Bennett, C.L., Goldy, J.D., Shirk, A.J., Kleopa, K.A., Tempel, B.L., Lipe, H.P., Scherer, S.S., Bird, T.D. and Chance, P.F. (2003) Mutation of a putative protein degradation gene LITAF/SIMPLE in Charcot–Marie–Tooth disease 1C. Neurology, 60, 22–26.[Abstract/Free Full Text]

  64. Antonellis, A., Ellsworth, R.E., Sambuughin, N., Puls, I., Abel, A., Lee-Lin, S.Q., Jordanova, A., Kremensky, I., Christodoulou, K., Middleton, L.T. et al. (2003) Glycyl tRNA synthetase mutations in Charcot–Marie–Tooth disease type 2D and distal spinal muscular atrophy type V. Am. J. Hum. Genet., 72, 1293–1299.[CrossRef][Web of Science][Medline]

  65. Wishart, M.J. and Dixon, J.E. (2002) The archetype STYX/dead-phosphatase complexes with a spermatid mRNA-binding protein and is essential for normal sperm production. Proc. Natl Acad. Sci. USA, 99, 2112–2117.[Abstract/Free Full Text]

  66. Li, J.C., Samy, E.T., Grima, J., Chung, S.S., Mruk, D., Lee, W.M., Silvestrini, B. and Cheng, C.Y. (2000) Rat testicular myotubularin, a protein tyrosine phosphatase expressed by Sertoli and germ cells, is a potential marker for studying cell–cell interactions in the rat testis. J. Cell Physiol., 185, 366–385.[CrossRef][Web of Science][Medline]

  67. Berger, P., Young, P. and Suter, U. (2002) Molecular cell biology of Charcot–Marie–Tooth disease. Neurogenetics, 4, 1–15.[CrossRef][Web of Science][Medline]

  68. Wallgren-Pettersson, C., Clarke, A., Samson, F., Fardeau, M., Dubowitz, V., Moser, H., Grimm, T., Barohn, R.J. and Barth, P.G. (1995) The myotubular myopathies: differential diagnosis of the X linked recessive, autosomal dominant, and autosomal recessive forms and present state of DNA studies. J. Med. Genet., 32, 673–679.[Abstract/Free Full Text]

  69. Sarfarazi, M. and Stoilov, I. (2000) Molecular genetics of primary congenital glaucoma. Eye, 14, 422–428.

  70. Thompson, J.D., Gibson, T.J., Plewniak, F., Jeanmougin, F. and Higgins, D.G. (1997) The CLUSTAL_X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res., 25, 4876–4882.[Abstract/Free Full Text]


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
J. Zou, S.-C. Chang, J. Marjanovic, and P. W. Majerus
MTMR9 Increases MTMR6 Enzyme Activity, Stability, and Role in Apoptosis
J. Biol. Chem., January 23, 2009; 284(4): 2064 - 2071.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
F. L. Robinson, I. R. Niesman, K. K. Beiswenger, and J. E. Dixon
Loss of the inactive myotubularin-related phosphatase Mtmr13 leads to a Charcot-Marie-Tooth 4B2-like peripheral neuropathy in mice
PNAS, March 25, 2008; 105(12): 4916 - 4921.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
K. Tersar, M. Boentert, P. Berger, S. Bonneick, C. Wessig, K. V. Toyka, P. Young, and U. Suter
Mtmr13/Sbf2-deficient mice: an animal model for CMT4B2
Hum. Mol. Genet., December 15, 2007; 16(24): 2991 - 3001.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
P. D. Allaire, B. Ritter, S. Thomas, J. L. Burman, A. Yu. Denisov, V. Legendre-Guillemin, S. Q. Harper, B. L. Davidson, K. Gehring, and P. S. McPherson
Connecdenn, A Novel DENN Domain-Containing Protein of Neuronal Clathrin-Coated Vesicles Functioning in Synaptic Vesicle Endocytosis
J. Neurosci., December 20, 2006; 26(51): 13202 - 13212.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
P. Choudhury, S. Srivastava, Z. Li, K. Ko, M. Albaqumi, K. Narayan, W. A. Coetzee, M. A. Lemmon, and E. Y. Skolnik
Specificity of the Myotubularin Family of Phosphatidylinositol-3-phosphatase Is Determined by the PH/GRAM Domain
J. Biol. Chem., October 20, 2006; 281(42): 31762 - 31769.
[Abstract] [Full Text] [PDF]

Home page
 J. Cell Sci.Home page
O. Lorenzo, S. Urbe, and M. J. Clague
Systematic analysis of myotubularins: heteromeric interactions, subcellular localisation and endosomerelated functions
J. Cell Sci., July 15, 2006; 119(14): 2953 - 2959.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
P. Berger, I. Berger, C. Schaffitzel, K. Tersar, B. Volkmer, and U. Suter
Multi-level regulation of myotubularin-related protein-2 phosphatase activity by myotubularin-related protein-13/set-binding factor-2
Hum. Mol. Genet., February 15, 2006; 15(4): 569 - 579.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
M. J. Begley, G. S. Taylor, M. A. Brock, P. Ghosh, V. L. Woods, and J. E. Dixon
Molecular basis for substrate recognition by MTMR2, a myotubularin family phosphoinositide phosphatase
PNAS, January 24, 2006; 103(4): 927 - 932.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Biol. CellHome page
S. Srivastava, P. Choudhury, Z. Li, G. Liu, V. Nadkarni, K. Ko, W. A. Coetzee, and E. Y. Skolnik
Phosphatidylinositol 3-Phosphate Indirectly Activates KCa3.1 via 14 Amino Acids in the Carboxy Terminus of KCa3.1
Mol. Biol. Cell, January 1, 2006; 17(1): 146 - 154.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
S. Bonneick, M. Boentert, P. Berger, S. Atanasoski, N. Mantei, C. Wessig, K. V. Toyka, P. Young, and U. Suter
An animal model for Charcot-Marie-Tooth disease type 4B1
Hum. Mol. Genet., December 1, 2005; 14(23): 3685 - 3695.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
A. Bolis, S. Coviello, S. Bussini, G. Dina, C. Pardini, S. C. Previtali, M. Malaguti, P. Morana, U. Del Carro, M. L. Feltri, et al.
Loss of Mtmr2 Phosphatase in Schwann Cells But Not in Motor Neurons Causes Charcot-Marie-Tooth Type 4B1 Neuropathy with Myelin Outfoldings
J. Neurosci., September 14, 2005; 25(37): 8567 - 8577.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
F. L. Robinson and J. E. Dixon
The Phosphoinositide-3-phosphatase MTMR2 Associates with MTMR13, a Membrane-associated Pseudophosphatase Also Mutated in Type 4B Charcot-Marie-Tooth Disease
J. Biol. Chem., September 9, 2005; 280(36): 31699 - 31707.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
O. Nakagawa, M. Arnold, M. Nakagawa, H. Hamada, J. M. Shelton, H. Kusano, T. M. Harris, G. Childs, K. P. Campbell, J. A. Richardson, et al.
Centronuclear myopathy in mice lacking a novel muscle-specific protein kinase transcriptionally regulated by MEF2
Genes & Dev., September 1, 2005; 19(17): 2066 - 2077.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
M. Pele, L. Tiret, J.-L. Kessler, S. Blot, and J.-J. Panthier
SINE exonic insertion in the PTPLA gene leads to multiple splicing defects and segregates with the autosomal recessive centronuclear myopathy in dog
Hum. Mol. Genet., July 1, 2005; 14(13): 1905 - 1906.
[Full Text] [PDF]

Home page
 Hum Mol GenetHome page
M. Pele, L. Tiret, J.-L. Kessler, S. Blot, and J.-J. Panthier
SINE exonic insertion in the PTPLA gene leads to multiple splicing defects and segregates with the autosomal recessive centronuclear myopathy in dogs
Hum. Mol. Genet., June 1, 2005; 14(11): 1417 - 1427.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
S. Srivastava, Z. Li, L. Lin, G. Liu, K. Ko, W. A. Coetzee, and E. Y. Skolnik
The Phosphatidylinositol 3-Phosphate Phosphatase Myotubularin- Related Protein 6 (MTMR6) Is a Negative Regulator of the Ca2+-Activated K+ Channel KCa3.1
Mol. Cell. Biol., May 1, 2005; 25(9): 3630 - 3638.
[Abstract] [Full Text] [PDF]

Home page
 J. Cell Sci.Home page
O. Lorenzo, S. Urbe, and M. J. Clague
Analysis of phosphoinositide binding domain properties within the myotubularin-related protein MTMR3
J. Cell Sci., May 1, 2005; 118(9): 2005 - 2012.
[Abstract] [Full Text] [PDF]

Home page
 JCBHome page
A. Bolino, A. Bolis, S. C. Previtali, G. Dina, S. Bussini, G. Dati, S. Amadio, U. Del Carro, D. D. Mruk, M. L. Feltri, et al.
Disruption of Mtmr2 produces CMT4B1-like neuropathy with myelin outfolding and impaired spermatogenesis
J. Cell Biol., November 22, 2004; 167(4): 711 - 721.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Biol. CellHome page
W. R. Parrish, C. J. Stefan, and S. D. Emr
Essential Role for the Myotubularin-related Phosphatase Ymr1p and the Synaptojanin-like Phosphatases Sjl2p and Sjl3p in Regulation of Phosphatidylinositol 3-Phosphate in Yeast
Mol. Biol. Cell, August 1, 2004; 15(8): 3567 - 3579.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
12/suppl_2/R285    most recent
ddg273v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Laporte, J.
Right arrow Articles by Mandel, J.-L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Laporte, J.
Right arrow Articles by Mandel, J.-L.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?