Hereditary motor and sensory neuropathy with myelin folding and juvenile onset glaucoma

Kiwaki, Takashiro; Umehara, Fujio; Takashima, Hiroshi; Nakagawa, Masanori; Kamimura, Kenya; Kashio, Nobuyuki; Sakamoto, Yushi; Unoki, Kazuhiko; Nobuhara, Yukihiro; Michizono, Kumiko; Watanabe, O.; Arimura, Hidenobu; Osame, Mitsuhiro

doi:10.1212/wnl.55.3.392

Cited by 18 publications

(15 citation statements)

References 26 publications

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“…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%

“…2O). Onion bulb formations as developed as those found in sural nerves of CMT4B2 patients are not observed in Mtmr13 Ϫ/Ϫ sciatic nerves (5,42,43). Finally, decreased myelin thickness was not apparent in Mtmr13 Ϫ/Ϫ sciatic nerve fibers (data not shown).…”

Section: Disruption Of Mtmr13mentioning

confidence: 75%

“…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%

“…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%

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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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