Peripheral neuropathies caused by mutations in the myelin protein zero

Shy, Michael E.

doi:10.1016/j.jns.2005.11.015

Cited by 84 publications

(87 citation statements)

References 62 publications

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“…These mutations and polymorphisms have been found in both the extracellular and intracellular regions (5). If L-MPZ has a similar structure as P0 and is involved in myelination, mutations in specific regions of L-MPZ may also modulate the adhesion and compaction of PNS myelin and cause cryptogenic neuropathies.…”

Section: Discussionmentioning

confidence: 99%

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L-MPZ, a Novel Isoform of Myelin P0, Is Produced by Stop Codon Readthrough

Yamaguchi

Hayashi

Campagnoni

et al. 2012

Journal of Biological Chemistry

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Background:The structure and function of myelin P0-related 36-kDa protein are totally unknown. Results: A novel isoform of P0, L-MPZ, contains an extra C terminus derived from 3Ј-UTR of P0 mRNA and is expressed in peripheral myelin. Conclusion: L-MPZ is produced by stop codon readthrough and probably related with peripheral myelinogenesis. Significance: Analyses of L-MPZ are crucial for understanding readthrough mechanism in mammals and myelinogenesis.

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Section: Discussionmentioning

confidence: 99%

“…In particular, sequences from mouse, rat, bovine, and human have Ͼ90% identity. Thus, P0 is important for the function of the PNS, and a large number of P0 mutations cause hereditary motor sensory neuropathies (5).…”

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confidence: 99%

L-MPZ, a Novel Isoform of Myelin P0, Is Produced by Stop Codon Readthrough

Yamaguchi

Hayashi

Campagnoni

et al. 2012

Journal of Biological Chemistry

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“…On the other hand, the second group is affected by a mild-axonal CMT, probably originated by mutations that do not permit Schwann cell -axon interactions. The mutations p.Ser78Leu (named p.Ser49Leu in 10 ) and p.Arg98His (named p.Ser69Leu in 10 ) proved exceptions to the rule as they have been associated with both phenotypes. 10 However, p.Ser78Leu was also found within our cohort, and it is associated with a very late onset CMT1 phenotype, thus further enlarging the phenotypic spectrum associated with this mutation.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, those mutations producing a subtly abnormal myelin sheath, which causes alterations in Schwann cell -axon interactions, are associated with late-onset mild axonal neuropathies. 10 The molecular mechanisms underlying these phenotypes have been investigated in both mouse and cellular models. These models evaluated the effects of missense and deletion mutations, at late and early onset, on intracellular protein trafficking, glycosylation and intercellular adhesion.…”

Section: Introductionmentioning

confidence: 99%

Clinical features and molecular modelling of novel MPZ mutations in demyelinating and axonal neuropathies

et al. 2009

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Mutations in the myelin protein zero (MPZ) gene have been associated with different Charcot-MarieTooth disease (CMT) phenotypes, including classical demyelinating CMT1B and the axonal form of the disease (CMT2). The MPZ role in the pathogenesis of both demyelinating and axonal inherited neuropathies was evaluated in the Italian population by screening a cohort of 214 patients with CMT1 or CMT2. A MPZ mutation frequency of 7.9% in demyelinating cases and of 4.8% in axonal cases was observed. In the total cohort (264 patients), including those with mutations in other genes, a mutation frequency of 5.8% (7/121) in demyelinating cases and 4.2% (6/143) in axonal cases was found. Three novel MPZ mutations, two missense (p.Ser111Cys, p.Thr124Ala) and one frameshift (p.Tyr145fs) were found, and a molecular modelling approach was used to test the effects of these mutations on the protein structure. Electrostatic distribution changes within the protein, caused by the amino acid substitution, fit in with phenotypes presented by patients herein described. Our findings suggest that the clinical features associated with MPZ mutations depend partly on the nature of amino acid change and that molecular modelling may provide useful support, based on effects on secondary and tertiary protein structure, to predict the phenotype associated with MPZ mutations.

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“…Impaired myelin formation and maintenance have been implicated in various neurological and psychiatric disorders including schizophrenia, multiple sclerosis, and Charcot-Marie-Tooth neuropathy disease (1,2). Myelination is a tightly controlled, complex process.…”

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confidence: 99%

Erbin regulates NRG1 signaling and myelination

Tao

Dai

Liu

et al. 2009

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

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Neuregulin 1 (NRG1) plays a critical role in myelination. However, little is known about regulatory mechanisms of NRG1 signaling. We show here that Erbin, a protein that contains leucine-rich repeats (LRR) and a PSD95-Dlg-Zol (PDZ) domain and that interacts specifically with ErbB2, is necessary for NRG1 signaling and myelination of peripheral nervous system (PNS). In Erbin null mice, myelinated axons were hypomyelinated with reduced expression of P0, a marker of mature myelinating Schwann cells (SCs), whereas unmyelinated axons were aberrantly ensheathed in Remak bundles, with increased numbers of axons in the bundles and in pockets. The morphological deficits were associated with decreased nerve conduction velocity and increased sensory threshold to mechanistic stimulation. These phenotypes were duplicated in erbin ⌬C/⌬C mice, in which Erbin lost the PDZ domain to interact with ErbB2. Moreover, ErbB2 was reduced at protein levels in both Erbin mutant sciatic nerves, and ErbB2 became unstable and NRG1 signaling compromised when Erbin expression was suppressed. These observations indicate a critical role of Erbin in myelination and identify a regulatory mechanism of NRG1 signaling. Our results suggest that Erbin, via the PDZ domain, binds to and stabilizes ErbB2, which is necessary for NRG1 signaling that has been implicated in tumorigenesis, heart development, and neural function.ErbB2 ͉ PDZ ͉ protein stability ͉ Schwann cells ͉ Akt M yelin sheath wraps axons to ensure the velocity and timing of action potential propagation and insulates neuronal activity. Impaired myelin formation and maintenance have been implicated in various neurological and psychiatric disorders including schizophrenia, multiple sclerosis, and Charcot-Marie-Tooth neuropathy disease (1, 2). Myelination is a tightly controlled, complex process. In the peripheral nervous system (PNS), neuregulin 1 (NRG1) has emerged as a key axon-derived factor that regulates myelination. Disruption of NRG1 signaling by ablating either the EGF domain that is contained in all isoforms or type III isoform leads to an almost complete loss of SCs and of the sensory and motor neurons that they support (3, 4). Recent studies have suggested that the level of NRG1 in the axon is critical for myelination (5, 6).NRG1 acts by stimulating a family of single transmembrane receptor tyrosine kinases called ErbB proteins (1). Although NRG1 was isolated as a ''ligand'' to activate ErbB2, it does not interact with the receptor (7). However, ErbB3 can bind NRG1 but its homodimers are catalytically inactive, indicating impaired kinase function (8). Therefore, ErbB2 and ErbB3, major ErbB proteins in SCs, need to form heterodimers with each other to be functional (9). This notion is supported by mouse genetic studies that mutation of NRG1, ErbB2, or ErbB3 genes causes severe deficits of peripheral neurons and SCs (3, 4, 10-13). Disruption of NRG1/ErbB signaling by a dominant negative approach led to deficits in myelinating and nonmyelinating SCs (14,15). Intracellularly, NRG1 stimu...

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Peripheral neuropathies caused by mutations in the myelin protein zero

Cited by 84 publications

References 62 publications

L-MPZ, a Novel Isoform of Myelin P0, Is Produced by Stop Codon Readthrough

L-MPZ, a Novel Isoform of Myelin P0, Is Produced by Stop Codon Readthrough

Clinical features and molecular modelling of novel MPZ mutations in demyelinating and axonal neuropathies

Erbin regulates NRG1 signaling and myelination

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