<i>SET binding factor 2 (SBF2)</i>
            mutation causes CMT4B with juvenile onset glaucoma

Hirano, Ryuki; Takashima, Hiroshi; Umehara, Fujio; Arimura, Hidenobu; Michizono, Kumiko; Okamoto, Yuji; Nakagawa, Miyuki; Boerkoel, Cornelius F.; Lupski, James R.; Osame, Mitsuhiro; Arimura, Kimiyoshi

doi:10.1212/01.wnl.0000133211.40288.9a

Cited by 38 publications

(29 citation statements)

References 12 publications

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“…Thus, the ⌬352-432 mutation may lead to a partially functional MTMR13 protein that is sufficient to prevent glaucoma but unable to support normal peripheral nerve myelination, as suggested in Ref. 10. Because early onset glaucoma has not been reported in association with CMT4B1, this disease phenotype likely indicates a specific function for MTMR13 which does not involve MTMR2.…”

Section: Discussionmentioning

confidence: 94%

“…In contrast, CMT4B2 patients homozygous for a small in-frame deletion within the DENN domain (⌬352-432) do not develop glaucoma (8). Mutations R482X, Q959X, and R1196X are predicted to induce the nonsense-mediated mRNA decay response (66), which will likely lead to a complete loss of the MTMR13 protein, as suggested by Hirano et al (10). CMT4B2 patients homozygous for the ⌬352-432 deletion express a mutant MTMR13 mRNA containing this deletion (8), suggesting that this deletion may affect MTMR13 at the protein rather than mRNA level.…”

Section: Discussionmentioning

confidence: 99%

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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

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: 94%

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

104

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“…Early onset glaucoma is described in some patients showing MTMR13 mutations associated with CMT4B2 [38,39]. Neutropenia has been observed in DI-CMT carrying mutations in the dynamin 2 gene [10].…”

Section: Other Specific Featuresmentioning

confidence: 99%

Hereditary neuropathies

Parman

2007

Current Opinion in Neurology

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Rapid advances in the molecular genetics and cell biology of hereditary neuropathies have highlighted the great genetic complexity of Charcot-Marie-Tooth disease. The evolution from a simple clinical classification to a complex molecular one has not facilitated our understanding of the disease. Moreover, the new molecular classification is not simple to use as different mutations of the same gene produce a range of phenotypes. The clinicians have to look for specific clinical and electrophysiological clues to direct the patient to appropriate genetic testing.

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“…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). CMT4B is caused by mutations in either myotubularinrelated protein 2 (MTMR2; CMT4B1) or MTMR13 (CMT4B2) (13)(14)(15)(16).…”

mentioning

confidence: 99%

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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SET binding factor 2 (SBF2) mutation causes CMT4B with juvenile onset glaucoma

Cited by 38 publications

References 12 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

Hereditary neuropathies

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

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