Clinical Phenotypes of Different MPZ (P0) Mutations May Include Charcot–Marie–Tooth Type 1B, Dejerine–Sottas, and Congenital Hypomyelination

Warner, Laura E.; Hilz, Max J.; Appel, Stanley H.; Killian, James M.; Kolodny, Edwin H.; Karpati, George; Carpenter, Stirling; Watters, Gordon V.; Wheeler, Calvin; Witt, David R.; Bodell, Adria; Nelis, Eva; Broeckhoven, Christine Van; Lupski, James R.

doi:10.1016/s0896-6273(00)80177-4

Cited by 349 publications

(272 citation statements)

References 49 publications

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“…Moreover, it has been shown that Ser63del MPZ acts as a dominant negative that also results in wild‐type MPZ retention in the ER24; as such reducing S63del translation may permit more wild‐type MPZ to be released to reach the myelin membrane. Fifty percent of normal MPZ is known to be adequate for normal myelin formation as haploinsufficiency of MPZ does not cause a clinical neuropathy in patients 25, 26. Whether less than 50% of normal MPZ will also permit compact myelin formation is not yet known.…”

Section: Discussionmentioning

confidence: 99%

Myelin protein zero mutations and the unfolded protein response in Charcot Marie Tooth disease type 1B

Bai

Brennan

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo determine the prevalence of MPZ mutations that cause Charcot Marie Tooth neuropathy type 1B (CMT1B) and activate the unfolded protein Response (UPR).Background CMT1B is caused by >200 heterozygous mutations in MPZ, the major protein in peripheral nerve myelin. Mutations Ser63del MPZ and Arg98Cys MPZ cause the mutant protein to be retained in the ER and activate the generally adaptive UPR. Treatments that modulate UPR activation have improved cellular and rodent models of CMT1B raising the possibility that other MPZ mutations that activate the UPR would also respond favorably to similar treatment. The prevalence of MPZ mutations that activate the UPR is unknown.MethodsWe developed a dual luciferase reporter assay of Xbp1 splicing using stably transfected RT4 Schwann cells to assay the ability of cDNA constructs bearing 46 distinct MPZ mutations to activate the UPR. Constructs also carried an HA tag to permit detection of ER retention of mutant proteins. UPR activation and ER retention were correlated with clinical phenotypes.ResultsEighteen mutations demonstrated ER retention and UPR activation to a similar degree as Ser63del and Arg98Cys MPZ. Thirty‐five of the mutations activated the UPR > 1.5 fold compared to that of wild‐type MPZ. Correlation was high between firefly and Nano‐luciferase reporters and between both reporters and ER localization. UPR activity did not correlate with clinical onset or severity.ConclusionMany CMT1B causing mutations activate the UPR and may be susceptible to therapeutic efforts to facilitate UPR function.

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Section: Discussionmentioning

confidence: 99%

Myelin protein zero mutations and the unfolded protein response in Charcot Marie Tooth disease type 1B

Bai

Brennan

et al. 2018

Ann Clin Transl Neurol

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“…CMT1B is associated with mutations in the myelin protein zero (MPZ) gene on chromosome 1q22 -q23 (Hayasaka et al, 1993;Latour et al, 1995). Three clinical and electrophysiological phenotypes have been associated with MPZ gene mutations: CMT1B, which is characterized by slow MNCV (, 25 m/s) and onset in the first two decades of life, Dejerine -Sottas syndrome with onset in infancy and extremely reduced MNCV (, 10 m/s), and congenital hypomyelination (Warner et al, 1996). However, several axonopathies in CMT disease have been associated with a mutation in the MPZ gene (Marrosu et al, 1998;Chapon et al, 1999;Mastaglia et al, 1999;Misu et al, 2000;Senderek et al, 2000;Young et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Autonomic and respiratory dysfunction in Charcot–Marie–Tooth disease due to Thr124Met mutation in the myelin protein zero gene

Stojkovic

Seze

Dubourg³

et al. 2003

Clinical Neurophysiology

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Objective: To report the clinical and electrophysiological characteristics of a family presenting Charcot -Marie-Tooth disease (CMT) associated with autonomic nervous system disturbances.Methods: We studied nerve conduction values, postural adaptation, sympathetic skin reflex, the variation in heart rate by the Valsalva ratio and pupillometry in 7 members of a French family in which CMT due to a Thr124Met mutation in the myelin protein zero (MPZ) gene was diagnosed.Results: Clinical and laboratory evidence of autonomic nervous system disturbances were found in the affected individuals. The clinical phenotype was characterized by sensorimotor peripheral neuropathy, defined as axonal type by electrophysiological studies, and was associated with severe pain, bladder dysfunction, sudorimotor disturbances and abolished pupillary reflex to light. Moreover, two patients had severe restrictive respiratory insufficiency requiring noninvasive mechanical ventilation.Conclusions: Our study demonstrates that autonomic disturbances may be one of the major clinical signs associated with CMT secondary to MPZ gene mutation in codon 124. Testing of pupillary reflex allows the discrimination of affected and unaffected subjects in our family. However, involvement of the autonomic nervous system in this type of neuropathy is unclear and further studies are required to elucidate the role of the MPZ gene in the autonomic nervous system.

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“…This adhesion molecule belongs to the immunoglobulin superfamily and fulfills multiple functions during myelin development and maintenance. Studies have revealed a number of mutations in the P0 gene that appear to be causal of human genetic neuropathies, such as Charcot-Marie-Tooth disease type 1B or Dejerine-Sottas disease [1,2,15]. Mice with a homozygous null mutation in the gene for P0 (P0 -/-) typically develop overt signs of peripheral neuropathy within one month after birth [11,12].…”

Section: Introductionmentioning

confidence: 99%

Heterozygous null mutation of myelin P0 protein enhances susceptibility to autoimmune neuritis targeting P0 peptide

et al. 2003

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Mice with a heterozygous null mutation in myelin protein zero (P0 +/-) develop late-onset clinical paralysis associated with inflammatory pathology in the peripheral nerves. Although the development of this illness is known to require T cells and macrophages, little is understood regarding the immunological defect in the mice. Here we report that young P0 +/-mice, free from clinical manifestations, have a defect in central tolerance to P0, and are more prone to induction of experimental autoimmune neuritis (EAN) by sensitization against P0 180-199 peptide. Notably, we found that the P0 gene is transcribed in the thymus of wild-type and the P0 +/-mice in an amount proportional to the gene dosage. We then replaced the thymus of wild-type mice with that of the P0-deficient mice and vice versa. Immunization of these mice with P0 [180][181][182][183][184][185][186][187][188][189][190][191][192][193][194][195][196][197][198][199] revealed that a lower thymic P0 transcript would be associated with the higher recall T cell response to P0 [180][181][182][183][184][185][186][187][188][189][190][191][192][193][194][195][196][197][198][199] , thus accounting for the higher susceptibility of the P0 +/-mice to P0-induced EAN. These results imply that a heterozygous mutation in an autoantigen could cause defective central tolerance to the autoantigen. As such, autoimmune T cells may play some role in "genetic" diseases caused by a heterozygous gene defect.

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Clinical Phenotypes of Different MPZ (P0) Mutations May Include Charcot–Marie–Tooth Type 1B, Dejerine–Sottas, and Congenital Hypomyelination

Cited by 349 publications

References 49 publications

Myelin protein zero mutations and the unfolded protein response in Charcot Marie Tooth disease type 1B

Myelin protein zero mutations and the unfolded protein response in Charcot Marie Tooth disease type 1B

Autonomic and respiratory dysfunction in Charcot–Marie–Tooth disease due to Thr124Met mutation in the myelin protein zero gene

Heterozygous null mutation of myelin P0 protein enhances susceptibility to autoimmune neuritis targeting P0 peptide

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