Two divergent types of nerve pathology in patients with different P sub 0 mutations in Charcot-Marie-Tooth disease

Gabreëls-Festen, A.A.W.M.; Hoogendijk, Jessica E.; Meijerink, P.H.S.; Gabreëls, F.J.M.; Bolhuis, P. A.; Beersum, Sylvia E. C. van; Kulkens, T.; Nelis, Eva; Jennekens, F. G. I.; Visser, Mike; Engelen, B.G.M. van; Broeckhoven, Christine Van; Mariman, E.C.M.

doi:10.1212/wnl.47.3.761

Cited by 144 publications

(113 citation statements)

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“…In previous studies MPZ mutations have been shown to cause demyelinating neuropathy with the phenotypic variability of CMT1B (Hayasaka et al, 1993c;Gabreëls-Festen et al, 1996), Dejerine-Sottas Neuropathy (Hayasaka et al, 1993b;Rautenstrauß, Nelis, Grehl, Van Broeckhoven, & Pfeiffer, 1994;Warner et al, 1996) and congenital hypomyelination (Warner et al, 1996). As in this study, not only demyelination, but also axonal degeneration is associated with MPZ mutations (Marrosu et al, 1998;Senderek et al, 2000;Young et al, 2001).…”

Section: A a G C T T T T T T T T T T T T T T T T T T T T T T T T G Csupporting

confidence: 74%

A Costa Rican family affected with Charcot-Marie-Tooth disease due to the myelin protein zero (MPZ) p.Thr124Met mutation shares the Belgian haplotype

Leal

Berghoff

et al. 2014

RBT

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The p.Thr124Met mutation in the myelin protein zero (MPZ) causes the Charcot-Marie-Tooth disease type 2J, a peripheral neuropathy with additional symptoms as pupillary alterations and deafness. It was observed in several families around the world originating e. g. from Germany, Belgium, Japan, Italy and North America. Here we report Central American patients originating from a family in Costa Rica carrying this mutation. Clinical, electrophysiological and molecular analysis of patients and controls were performed, including gene and linked markers´ sequencing. Carriers share almost the entire haplotype with two non related Belgian CMT patients. As a result of the haplotype analysis, based on ten markers (seven SNPs, two microsatellites and an intronic polyA stretch), the founder effect hypothesis for this allele migration is suggestive. Rev. Biol. Trop. 62 (4): 1285-1293. Epub 2014 December 01. Key words:Charcot-Marie-Tooth, peripheral neuropathy, Myelin protein zero, mutation, Costa Rica.Hereditary motor and sensory neuropathy (HMSN), also called Charcot-Marie-Tooth disease (CMT), is a clinically and genetically heterogeneous group of inherited peripheral neuropathies. It is characterized by progressive muscular weakness and atrophy of the distal muscles (Lupski, 1998). By means of electrophysiological and morphological studies, CMT can be divided into two major forms: a predominantly demyelinating (HMSN type I) and an axonal form (HMSN type II) (Dyck, Chance, Lebo, & Carney, 1993).MPZ had been initially related with a hereditary motor and sensorial neuropathy type I (HMSN I), presenting myelin disturbances resulting in reduced nerve conduction velocity (NCV<38m/s) (Hayasaka et al., 1993a). However, families with normal NCV values (HMSN II) have also been associated with MPZ (Senderek et al., 2000). The mutation Thr124Met in the third exon of the protein was found to be responsible for CMT in families with a clinically distinct phenotype, including axonal involvement, frequently deafness, Argyll Robertson-like pupils and dysphagia (Chapon, Latour, Diraison, Schaeffer, & Vandenberghe, 1999;De Jonghe et al., 1999). This mutation has been found in several CMT families. When the polymorphic markers close to the gene and an intronic polymorphism were analyzed it was associated with the same haplotype as two Belgian families. Due to this, it has been suggested that a common ancestor was the founder of this particular mutation (De Jonghe et al., 1999). Nevertheless, Senderek et al. (2000) reported a family with an identical mutation embedded in a distinct haplotype, thus suggesting the existence of a hot-spot in this codon. Not only Belgian (De Jonghe et al., 1999) families with the mutation p.Thr124Met have been reported, also French (Chapon et al., 1999), German (Senderek et al., 2000;Hanemann et al., 2001), Italian (Schiavon et al., 1998), North American (Baloh, Jen, Kim, & Baloh, 2004 and Japanese Kurihara et al., 2002;Numakura, Lin, Ikegami, Guldberg, & Hayasaka, 2002;Kurihara, 2003).Here we report a ...

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Section: A a G C T T T T T T T T T T T T T T T T T T T T T T T T G Csupporting

confidence: 74%

A Costa Rican family affected with Charcot-Marie-Tooth disease due to the myelin protein zero (MPZ) p.Thr124Met mutation shares the Belgian haplotype

Leal

Berghoff

et al. 2014

RBT

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“…Moreover, many prior reports have outlined other potential pathogenic mechanisms including disruption of compaction,27 myelin packing,28 signaling from the cytoplasmic domain,29 disruption of adhesion,2 or disruption of glycosylation 30. Therefore, we recognize that UPR activation by itself cannot be the sole cause of the phenotypes of CMT1B and that these other mechanisms likely participate as well.…”

Section: Discussionmentioning

confidence: 86%

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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“…Biopsies from C MT1B patients revealed that, dependent on the mutation in the P 0 gene, divergent pathological hallmarks can be found. Such hallmarks comprise either formation of myelin tomacula, i.e., focally thickened myelin sheaths of reduced stability or, alternatively, myelin decompaction and demyelination (Thomas et al, 1994;Gabreëls-Festen et al, 1996;Tachi et al, 1997). Recently, we have shown that heterozygous P 0 null mutant mice (P 0 ϩ/Ϫ ) are appropriate models for mild CMT1B forms with an initially normal myelin formation followed by myelin decompaction and demyelination starting at 4 months of life (Martini et al, 1995a; for review, see Martini, 1997).…”

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confidence: 99%

Immune Deficiency in Mouse Models for Inherited Peripheral Neuropathies Leads to Improved Myelin Maintenance

Schmid

Stienekemeier

Oehen³

et al. 2000

J. Neurosci.

113

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The adhesive cell surface molecule P 0 is the most abundant glycoprotein in peripheral nerve myelin and fulfills pivotal functions during myelin formation and maintenance. Mutations in the corresponding gene cause hereditary demyelinating neuropathies. In mice heterozygously deficient in P 0 (P 0 ϩ/Ϫ mice), an established animal model for a subtype of hereditary neuropathies, T-lymphocytes are present in the demyelinating nerves. To monitor the possible involvement of the immune system in myelin pathology, we cross-bred P 0 ϩ/Ϫ mice with null mutants for the recombination activating gene 1 (RAG-1) or with mice deficient in the T-cell receptor ␣-subunit. We found that in P 0 ϩ/Ϫ mice myelin degeneration and impairment of nerve conduction properties is less severe when the immune system is deficient. Moreover, isolated T-lymphocytes from P 0 ϩ/Ϫ mice show enhanced reactivity to myelin components of the peripheral nerve, such as P 0 , P 2 , and myelin basic protein. We hypothesize that autoreactive immune cells can significantly foster the demyelinating phenotype of mice with a primarily genetically based peripheral neuropathy.

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Two divergent types of nerve pathology in patients with different P sub 0 mutations in Charcot-Marie-Tooth disease

Cited by 144 publications

References 16 publications

A Costa Rican family affected with Charcot-Marie-Tooth disease due to the myelin protein zero (MPZ) p.Thr124Met mutation shares the Belgian haplotype

A Costa Rican family affected with Charcot-Marie-Tooth disease due to the myelin protein zero (MPZ) p.Thr124Met mutation shares the Belgian haplotype

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

Immune Deficiency in Mouse Models for Inherited Peripheral Neuropathies Leads to Improved Myelin Maintenance

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