Effect of an R69C Mutation in the Myelin Protein Zero Gene on Myelination and Ion Channel Subtypes

Bai, Yunhong; Ianokova, Emilia; Qin, Pu; Ghandour, Khaled; Levinson, Rock; Martin, J. J.; Groote, Chantal Ceuterick‐de; Mazanec, Radim; Seeman, Pavel; Shy, Michael E.; Li, Jun

doi:10.1001/archneur.63.12.1787

Cited by 41 publications

(42 citation statements)

References 38 publications

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“…It showed active segmental demyelination and extremely shortened internodes (as little as 20μM) (Devaux et al, 2005). Similar findings were also observed in the sural biopsies from patients with missense mutations in MPZ (Bai YH et al, 2006). These findings are also consistent with the extreme slowing of conduction velocities in humans with the missense mutation.…”

Section: Ncs Behavior In Inherited Neuropathiessupporting

confidence: 82%

Molecular regulators of nerve conduction — Lessons from inherited neuropathies and rodent genetic models

2015

Experimental Neurology

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Myelinated nerve fibers are highly compartmentalized. Helically wrapped lipoprotein membranes of myelin are integrated with subsets of proteins specifically in each compartment to shape the physiological behavior of these nerve fibers. With the advance of molecular biology and genetics, many functions of these proteins have been revealed over the past decade. In this review, we will first discuss how action potential propagation has been understood by classical electrophysiological studies. In particular, the discussion will be concentrated on how the geometric dimensions of myelinated nerve fibers (such as internodal length and myelin thickness) may affect nerve conduction velocity. This discussion will then extend into how specific myelin proteins may shape these geometric parameters, thereby regulating action potential propagation. For instance, periaxin may specifically affect the internodal length, but not other parameters. In contrast, neuregulin-1 may affect myelin thickness, but not axon diameter or internodal length. Finally, we will discuss how these basic neurobiological observations can be applied to inherited peripheral nerve diseases.

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Section: Ncs Behavior In Inherited Neuropathiessupporting

confidence: 82%

Molecular regulators of nerve conduction — Lessons from inherited neuropathies and rodent genetic models

2015

Experimental Neurology

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“…Morphological studies of the early-and late-onset forms of CMT1B have shown distinct molecular and pathological abnormalities, 18,19 and the molecular mechanisms underlying these differences have been investigated in mouse and cellular models. Wrabetz et al 11 produced a transgenic mouse carrying two distinct MPZ mutations, p.Ser63Cys and p.Ser63del, both causing a demyelinating neuropathy.…”

Section: Discussionmentioning

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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“…A subset of P0 mutations associated with altered P0 trafficking have been described, among which the best characterized are the R98C and S63del mutations in the extracellular domain of P0 (P0-ECD) (Figure 3B and Table 1; Shames et al, 2003; Khajavi et al, 2005; Wrabetz et al, 2006; Grandis et al, 2008; Prada et al, 2012; Saporta et al, 2012). In humans the R98C mutation results in severe early onset dysmyelinating and demyelinating neuropathy, partially recapitulated in R98C knock-in mice (Gabreëls-Festen et al, 1996; Bai et al, 2006; Saporta et al, 2012). The S63del mutation instead is associated with a milder form of CMT1B characterized by thinner myelin and late-onset demyelination, reproduced in S63del transgenic mice (Kulkens et al, 1993; Gabreëls-Festen et al, 1996; Wrabetz et al, 2006; Miller et al, 2012).…”

Section: Erqc and Charcot-marie-tooth (Cmt) Neuropathiesmentioning

confidence: 95%

Endoplasmic Reticulum Protein Quality Control Failure in Myelin Disorders

Volpi¹,

Touvier²,

D’Antonio³

2017

Front. Mol. Neurosci.

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Reaching the correct three-dimensional structure is crucial for the proper function of a protein. The endoplasmic reticulum (ER) is the organelle where secreted and transmembrane proteins are synthesized and folded. To guarantee high fidelity of protein synthesis and maturation in the ER, cells have evolved ER-protein quality control (ERQC) systems, which assist protein folding and promptly degrade aberrant gene products. Only correctly folded proteins that pass ERQC checkpoints are allowed to exit the ER and reach their final destination. Misfolded glycoproteins are detected and targeted for degradation by the proteasome in a process known as endoplasmic reticulum-associated degradation (ERAD). The excess of unstructured proteins in the ER triggers an adaptive signal transduction pathway, called unfolded protein response (UPR), which in turn potentiates ERQC activities in order to reduce the levels of aberrant molecules. When the situation cannot be restored, the UPR drives cells to apoptosis. Myelin-forming cells of the central and peripheral nervous system (oligodendrocytes and Schwann cells) synthesize a large amount of myelin proteins and lipids and therefore are particularly susceptible to ERQC failure. Indeed, deficits in ERQC and activation of ER stress/UPR have been implicated in several myelin disorders, such as Pelizaeus-Merzbacher and Krabbe leucodystrophies, vanishing white matter disease and Charcot-Marie-Tooth neuropathies. Here we discuss recent evidence underlying the importance of proper ERQC functions in genetic disorders of myelinating glia.

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Effect of an R69C Mutation in the Myelin Protein Zero Gene on Myelination and Ion Channel Subtypes

Cited by 41 publications

References 38 publications

Molecular regulators of nerve conduction — Lessons from inherited neuropathies and rodent genetic models

Molecular regulators of nerve conduction — Lessons from inherited neuropathies and rodent genetic models

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

Endoplasmic Reticulum Protein Quality Control Failure in Myelin Disorders

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