Identification of a New Locus for Autosomal Recessive Charcot–Marie–Tooth Disease with Focally Folded Myelin on Chromosome 11p15

Othmane, Kamel Ben; Johnson, Ellen M.; Menold, Marisa M.; Graham, Felicia L.; Hamida, M. Ben; Hasegawa, Osamu; Rogala, Allison D.; Ohnishi, Akio; Pericak‐Vance, Margaret A.; Hentati, Fayçal; Vance, Jeffery M.

doi:10.1006/geno.1999.6028

Cited by 64 publications

(52 citation statements)

References 19 publications

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“…CMT4B1 (MTMR2) and CMT4B2 (MTMR13) are autosomal recessive forms of demyelinating CMT, distinguished from other forms by the presence of a distinctive focal out-looping of myelin within peripheral nerves (4,6,7). These genetic findings, combined with the growing awareness that active MTMR phosphatases may be regulated via the association of inactive MTMR pseudophosphatases (26,32,52,53), led us to investigate whether the MTMR2 and MTMR13 proteins might physically associate.…”

Section: Discussionmentioning

confidence: 99%

The Phosphoinositide-3-phosphatase MTMR2 Associates with MTMR13, a Membrane-associated Pseudophosphatase Also Mutated in Type 4B Charcot-Marie-Tooth Disease

Robinson

Dixon

2005

Journal of Biological Chemistry

103

104

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Charcot-Marie-Tooth disease type 4B (CMT4B) is a severe, demyelinating peripheral neuropathy characterized by distinctive, focally folded myelin sheaths. CMT4B is caused by recessively inherited mutations in either myotubularin-related 2 (MTMR2) or MTMR13 (also called SET-binding factor 2). MTMR2 encodes a member of the myotubularin family of phosphoinositide-3-phosphatases, which dephosphorylate phosphatidylinositol 3-phosphate (PI(3)P) and bisphosphate PI(3,5)P 2 . MTMR13 encodes a large, uncharacterized member of the myotubularin family. The MTMR13 phosphatase domain is catalytically inactive because the essential Cys and Arg residues are absent. Given the genetic association of both MTMR2 and MTMR13 with CMT4B, we investigated the biochemical relationship between these two proteins. We found that the endogenous MTMR2 and MTMR13 proteins are associated in human embryonic kidney 293 cells. MTMR2-MTMR13 association is mediated by coiled-coil sequences present in each protein. We also examined the cellular localization of MTMR2 and MTMR13 using fluorescence microscopy and subcellular fractionation. We found that (i) MTMR13 is a predominantly membrane-associated protein; (ii) MTMR2 and MTMR13 cofractionate in both a light membrane fraction and a cytosolic fraction; and (iii) MTMR13 membrane association is mediated by the segment of the protein which contains the pseudophosphatase domain. This work, which describes the first cellular or biochemical investigation of the MTMR13 pseudophosphatase protein, suggests that MTMR13 functions in association with MTMR2. Loss of MTMR13 function in CMT4B2 patients may lead to alterations in MTMR2 function and subsequent alterations in 3-phosphoinositide signaling. Such a mechanism would explain the strikingly similar phenotypes of patients with recessive mutations in either MTMR2 or MTMR13.

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Section: Discussionmentioning

confidence: 99%

The Phosphoinositide-3-phosphatase MTMR2 Associates with MTMR13, a Membrane-associated Pseudophosphatase Also Mutated in Type 4B Charcot-Marie-Tooth Disease

Robinson

Dixon

2005

Journal of Biological Chemistry

103

104

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“…2L). Myelin outfolds are bounded by the Schwann cell plasma membrane, and the surrounding basal lamina appears morphologically normal ( In addition to myelin outfolding and infolding, biopsies from CMT4B2 patients show evidence of segmental demyelination/ remyelination (''onion bulbs''), hypomyelination, and a severe loss of large caliber axons (5,42,43). However, in Mtmr13 Ϫ/Ϫ mid-sciatic nerves, degenerating axons are observed only rather rarely, mostly in older mice ( Fig.…”

Section: Disruption Of Mtmr13mentioning

confidence: 99%

“…Sural nerve biopsies from CMT4B patients show evidence of segmental demyelination/ remyelination, severe axon loss, and distinctive myelin outfoldings and infoldings (5)(6)(7). Aberrant myelin folding of this nature has been reported in only a few other forms of CMT, and such folding is considered the pathological hallmark of CMT4B (9)(10)(11)(12).…”

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confidence: 99%

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Loss of the inactive myotubularin-related phosphatase Mtmr13 leads to a Charcot–Marie–Tooth 4B2-like peripheral neuropathy in mice

Robinson¹,

Niesman²,

Beiswenger

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Charcot-Marie-Tooth disease type 4B (CMT4B) is a severe, demyelinating peripheral neuropathy characterized by slowed nerve conduction velocity, axon loss, and distinctive myelin outfolding and infolding. CMT4B is caused by recessive mutations in either myotubularin-related protein 2 (MTMR2; CMT4B1) or MTMR13 (CMT4B2). Myotubularins are phosphoinositide (PI) 3-phosphatases that dephosphorylate phosphatidylinositol 3-phosphate (PtdIns3P) and PtdIns(3,5)P2, two phosphoinositides that regulate endosomal-lysosomal membrane traffic. Interestingly, nearly half of the metazoan myotubularins are predicted to be catalytically inactive. Both active and inactive myotubularins have essential functions in mammals and in Caenorhabditis elegans. MTMR2 and MTMR13 are active and inactive PI 3-phosphatases, respectively, and the two proteins have been shown to directly associate, although the functional significance of this association is not well understood. To establish a mouse model of CMT4B2, we disrupted the Mtmr13 gene. Mtmr13-deficient mice develop a peripheral neuropathy characterized by reduced nerve conduction velocity and myelin outfoldings and infoldings. Dysmyelination is evident in Mtmr13-deficient nerves at 14 days and worsens throughout life. Thus, loss of Mtmr13 in mice leads to a peripheral neuropathy with many of the key features of CMT4B2. Although myelin outfoldings and infoldings occur most frequently at the paranode, our morphological analyses indicate that the ultrastructure of the node of Ranvier and paranode is intact in Mtmr13-deficient nerve fibers. We also found that Mtmr2 levels are decreased by Ϸ50% in Mtmr13-deficient sciatic nerves, suggesting a mode of Mtmr2 regulation. Mtmr13-deficient mice will be an essential tool for studying how the loss of MTMR13 leads to CMT4B2.MTMR2 ͉ myelin ͉ PtdIns3P ͉ PtdIns(3,5)P2 ͉ endosomal traffic C harcot-Marie-Tooth (CMT) disease (also called hereditary motor and sensory neuropathy) describes a group of inherited peripheral neuropathies that are both clinically and genetically heterogeneous (1). With a worldwide incidence of Ϸ1 in 2,500, CMT is one of the most common inherited neurological disorders (www.charcot-marie-tooth.org). CMT leads to progressive degeneration of the muscles of the extremities and loss of sensory function (2). Patients with demyelinating CMT (types 1, 3, and 4) show reduced nerve conduction velocity (NCV) (Ͻ38 m/s). In contrast, the axonal forms of CMT (type 2) are associated with normal or near normal NCVs and decreased compound muscle action potential amplitudes. Nerve biopsies from patients with demyelinating CMT show axonal loss and evidence of demyelination/remyelination, whereas nerves from axonal CMT patients show axonal loss without signs of demyelination and remyelination (2). Genetic studies have identified CMT-causing mutations in Ϸ30 distinct genes of diverse function (1). However, the cellular mechanisms by which these mutations lead to disease are generally poorly understood (1-4). In general, demyelinating and axonal forms of...

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“…Στη συνέχεια έγιναν διάφορες προσπάθειες ταξινόμησης της νόσου μέχρι να καταλήξουμε στη σημερινή δομή ταξινόμησης όπως θα περιγραφεί πιο κάτω (Ben Bolino et al 1996;Kalaydjieva et al 1996;LeGuern et al 1996;Bouhouche et al 1999;Othmane et al 1999;Delague et al 2000). (Vance et al 1989).…”

Section: πολυνευροπαθεια Charcot-marie-tooth (Cmt)unclassified

Μοριακή γενετική μελέτη της κληρονομικής πολυνευροπάθειας Charcot - Marie - Tooth (CMT)

Νικολάου¹

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Η νόσος Charcot-Marie-Tooth (CMT) είναι η συχνότερη κληρονομική νευρολογική πάθηση με συχνότητα 17-40/100,000. Ταξινομείται στον απομυελινωτικό, αξονικό και μεικτό τύπο και κληρονομείται με επικρατητικό, υπολειπόμενο και φυλοσύνδετο τύπο. Τα κύρια χαρακτηριστικά της πάθησης είναι η αδυναμία των περιφερικών μυών των κάτω άκρων με τη χαρακτηριστική παραμόρφωση του άκρου ποδός (pes cavus), περιφερική αδυναμία των μυών των άνω άκρων και σε μικρότερο βαθμό αισθητικές διαταραχές. Έχουν αναγνωριστεί μέχρι σήμερα περίπου 25 γονίδια με μεγάλο αριθμό μεταλλάξεων, τα οποία ενέχονται στην αιτιοπαθογένεια της νόσου με έκφραση, είτε στα κύτταρα του Schwann, είτε στους άξονες ή και στα δύο. Στα πλαίσια της παρούσας διδακτορικής διατριβής διεξάχθηκε επιδημιολογική μελέτη της CMT στον Κυπριακό πληθυσμό. Διαγνώστηκαν 13 οικογένειες με το διπλασιασμό του γονιδίου PMP22, τρεις οικογένειες με σημειακή μετάλλαξη στο γονίδιο PMP22, τέσσερις οικογένειες με σημειακές μεταλλάξεις στο γονίδιο GJB1 (Cx32), δύο με σημειακές μεταλλάξεις στο γονίδιο MPZ και δύο με σημειακές μεταλλάξεις στο γονίδιο MFN2. Εννέα οικογένειες και οκτώ σποραδικοί ασθενείς αποκλείστηκαν από τα γνωστά γονίδια της CMT και χρήζουν περαιτέρω διερεύνησης. Επίσης μελετήθηκαν επιπρόσθετα έξι νέες οικογένειες και δύο νέοι ασθενείς υφιστάμενης οικογένειας από την Κύπρο καθώς και πέντε οικογένειες και τέσσερις σποραδικοί ασθενείς από τη Θεσσαλία. Από αυτές βρέθηκαν δύο νέες οικογένειες με τη μετάλλαξη S22F στο γονίδιο PMP22 και δυο οικογένειες από την Ελλάδα με διπλασιασμό του γονιδίου PMP22. Οι υπόλοιποι ασθενείς χρήζουν περαιτέρω διερεύνησης. Συμπερασματικά, η συχνότερη μετάλλαξη, όπως και παγκοσμίως, είναι ο διπλασιασμός του γονιδίου PMP22, καθώς επίσης και η παρουσία πέντε νέων μεταλλάξεων στον Κυπριακό πληθυσμό.

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Identification of a New Locus for Autosomal Recessive Charcot–Marie–Tooth Disease with Focally Folded Myelin on Chromosome 11p15

Cited by 64 publications

References 19 publications

The Phosphoinositide-3-phosphatase MTMR2 Associates with MTMR13, a Membrane-associated Pseudophosphatase Also Mutated in Type 4B Charcot-Marie-Tooth Disease

The Phosphoinositide-3-phosphatase MTMR2 Associates with MTMR13, a Membrane-associated Pseudophosphatase Also Mutated in Type 4B Charcot-Marie-Tooth Disease

Loss of the inactive myotubularin-related phosphatase Mtmr13 leads to a Charcot–Marie–Tooth 4B2-like peripheral neuropathy in mice

Μοριακή γενετική μελέτη της κληρονομικής πολυνευροπάθειας Charcot - Marie - Tooth (CMT)

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