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

Abstract

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...

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

“…MTMR2 interacts with the catalytically inactive pseudophosphatases MTMR5 (also named Set binding factor 1 or SBF1) (793) and MTMR13 (also called SBF2), and these interactions greatly enhance the phosphatase activity of MTMR2, as well as determine its cellular localization (123,1274). Mutations in MTMR13 cause Charcot-Marie-Tooth disease type 4B2 (CMT4B2) with similar defects to CMT4B1 (69,1381), and these deficiencies can be replicated in mice with MTMR13 gene disruption (1275,1545). In contrast, MTMR5 deletion in mice causes defective spermatogenesis without any peripheral neuropathy (440).…”

NADPH Oxidase-4 Maintains Neuropathic Pain after Peripheral Nerve Injury

“…The number of myelinated axons as well as the number of infoldings and outfoldings of the myelin sheath were counted, and the percentage of infoldings and outfoldings per total number of myelinated axons was calculated. An infolding and outfolding was defined as a fiber containing one or more myelin infolds (into the axon) or one containing one or more redundant loop(s) of myelin flanking a primary myelinated axon (Robinson et al, 2008). Axonal diameter was measured using NIH ImageJ software equipped with the MacBiophotonics MBF plugin.…”

Cdc42 regulates schwann cell radial sorting and myelin sheath folding through NF2/merlin‐dependent and independent signaling

“…Similar myelin abnormalities are observed in CMT disease, including mutation or loss of the myotubularin-related phosphatase MTMR (Previtali et al 2007) and the Cdc42 GEF FABIN/FGD4 (Delague et al, 2007; Stendel et al, 2007). Mouse models of Mtmr2 , Mtmr13 or Frabin disruption in mouse SCs show the myelin outfoldings (Bolino et al, 2004; Horn et al, 2012; Robinson et al, 2008; Tersar et al, 2007). Cdc42 activity was reduced in the absence of Fabin/FGD4, a Cdc42 GEF (Horn et al, 2012).…”