Charcot–Marie–Tooth type 4B demyelinating neuropathy: deciphering the role of MTMR phosphatases

Previtali, Stefano C.; Quattrini, Angelo; Bolino, Alessandra

doi:10.1017/s1462399407000439

Cited by 59 publications

(79 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Third, as in CMT4B2, both motor and sensory nerves are affected. Finally, the early onset and progressive nature of the phenotype described here correlate well with the clinical picture of CMT4B2 (5,8,42,43). The neuropathy observed in Mtmr13 Ϫ/Ϫ animals is also very similar to that of mice lacking Mtmr2, an active PI 3-phosphatase that associates with Mtmr13 (44,45,50).…”

Section: Mtmr13-deficient Mice As a Model Of Cmt4b2supporting

confidence: 72%

“…First, Mtmr13 Ϫ/Ϫ mice possess substantially slowed NCV. Second, the myelin outfoldings and infoldings observed in Mtmr13 Ϫ/Ϫ nerves are remarkably similar to those found in the nerves of CMT4B2 patients (5,8,42,43). Third, as in CMT4B2, both motor and sensory nerves are affected.…”

Section: Mtmr13-deficient Mice As a Model Of Cmt4b2supporting

confidence: 69%

“…Nerve biopsies from CMT4B2 patients show severe axon loss, hypomyelination of axons, and evidence of demyelination/remyelination (onion bulbs) (5,8,42,43). However, these features are rather limited in Mtmr13 Ϫ/Ϫ sciatic nerves, even those from mice 14 months of age.…”

Section: Mtmr13-deficient Mice As a Model Of Cmt4b2mentioning

confidence: 99%

“…CMT type 4B (CMT4B) is a severe, autosomal-recessive form of demyelinating CMT characterized by slowed NCV (9-35 m/s) and an early-childhood onset (5)(6)(7)(8). Sural nerve biopsies from CMT4B patients show evidence of segmental demyelination/ remyelination, severe axon loss, and distinctive myelin outfoldings and infoldings (5)(6)(7).…”

mentioning

confidence: 99%

See 3 more Smart Citations

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.

View full text Add to dashboard Cite

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...

show abstract

Section: Mtmr13-deficient Mice As a Model Of Cmt4b2supporting

confidence: 72%

Section: Mtmr13-deficient Mice As a Model Of Cmt4b2supporting

confidence: 69%

Section: Mtmr13-deficient Mice As a Model Of Cmt4b2mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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.

View full text Add to dashboard Cite

show abstract

“…Charcot-Marie-Tooth type 4B1 (CMT4B1) is an autosomal recessive demyelinating neuropathy with childhood onset caused by loss of the myotubularin-related protein 2 (MTMR2) phospholipid phosphatase (Bolino et al, 2000;Bolis et al, 2007;Previtali et al, 2007). The hallmark of the pathology is the presence of redundant loops of myelin around large myelinated axons in nerve, also known as "myelin outfoldings."…”

Section: Introductionmentioning

confidence: 99%

Dlg1, Sec8, and Mtmr2 Regulate Membrane Homeostasis in Schwann Cell Myelination

Bolis¹,

Coviello²,

Visigalli³

et al. 2009

Journal of Neuroscience

107

102

View full text Add to dashboard Cite

How membrane biosynthesis and homeostasis is achieved in myelinating glia is mostly unknown. We previously reported that loss of myotubularin-related protein 2 (MTMR2) provokes autosomal recessive demyelinating Charcot-Marie-Tooth type 4B1 neuropathy, characterized by excessive redundant myelin, also known as myelin outfoldings. We generated a Mtmr2-null mouse that models the human neuropathy. We also found that, in Schwann cells, Mtmr2 interacts with Discs large 1 (Dlg1), a scaffold involved in polarized trafficking and membrane addition, whose localization in Mtmr2-null nerves is altered. We here report that, in Schwann cells, Dlg1 also interacts with kinesin 13B (kif13B) and Sec8, which are involved in vesicle transport and membrane tethering in polarized cells, respectively. Taking advantage of the Mtmr2-null mouse as a model of impaired membrane formation, we provide here the first evidence for a machinery that titrates membrane formation during myelination. We established Schwann cell/DRG neuron cocultures from Mtmr2-null mice, in which myelin outfoldings were reproduced and almost completely rescued by Mtmr2 replacement. By exploiting this in vitro model, we propose a mechanism whereby kif13B kinesin transports Dlg1 to sites of membrane remodeling where it coordinates a homeostatic control of myelination. The interaction of Dlg1 with the Sec8 exocyst component promotes membrane addition, whereas with Mtmr2, negatively regulates membrane formation. Myelin outfoldings thus arise as a consequence of the loss of negative control on the amount of membrane, which is produced during myelination.

show abstract