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https://academic.oup.com/nar/article/doi/10.1093/nar/gkaa606/5872470

https://www.ncbi.nlm.nih.gov/pubmed/32672815?dopt=Abstract

Egr2-guided histone H2B monoubiquitination is required for peripheral nervous system myelination.

Egr2-guided histone H2B monoubiquitination is required for peripheral nervous system myelination.

Nucleic Acids Res. 2020 Jul 16;:

Authors: Wüst HM, Wegener A, Fröb F, Hartwig AC, Wegwitz F, Kari V, Schimmel M, Tamm ER, Johnsen SA, Wegner M, Sock E

Abstract

Schwann cells are the nerve ensheathing cells of the peripheral nervous system. Absence, loss and malfunction of Schwann cells or their myelin sheaths lead to peripheral neuropathies such as Charcot-Marie-Tooth disease in humans. During Schwann cell development and myelination chromatin is dramatically modified. However, impact and functional relevance of these modifications are poorly understood. Here, we analyzed histone H2B monoubiquitination as one such chromatin modification by conditionally deleting the Rnf40 subunit of the responsible E3 ligase in mice. Rnf40-deficient Schwann cells were arrested immediately before myelination or generated abnormally thin, unstable myelin, resulting in a peripheral neuropathy characterized by hypomyelination and progressive axonal degeneration. By combining sequencing techniques with functional studies we show that H2B monoubiquitination does not influence global gene expression patterns, but instead ensures selective high expression of myelin and lipid biosynthesis genes and proper repression of immaturity genes. This requires the specific recruitment of the Rnf40-containing E3 ligase by Egr2, the central transcriptional regulator of peripheral myelination, to its target genes. Our study identifies histone ubiquitination as essential for Schwann cell myelination and unravels new disease-relevant links between chromatin modifications and transcription factors in the underlying regulatory network.

PMID: 32672815 [PubMed – as supplied by publisher]

PubMed:32672815

Wüst HM, Wegener A, Fröb F, Hartwig AC, Wegwitz F, Kari V, Schimmel M, Tamm ER, Johnsen SA, Wegner M, Sock E

https://academic.oup.com/braincomms/article/2/1/fcaa012/5734661

https://www.ncbi.nlm.nih.gov/pubmed/32954280?dopt=Abstract

Intraepidermal nerve fibre density as biomarker in Charcot-Marie-Tooth disease type 1A.

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Intraepidermal nerve fibre density as biomarker in Charcot-Marie-Tooth disease type 1A.

Brain Commun. 2020;2(1):fcaa012

Authors: Hartmannsberger B, Doppler K, Stauber J, Schlotter-Weigel B, Young P, Sereda MW, Sommer C

Abstract

Charcot-Marie-Tooth disease type 1A, caused by a duplication of the gene peripheral myelin protein 22 kDa, is the most frequent subtype of hereditary peripheral neuropathy with an estimated prevalence of 1:5000. Patients suffer from sensory deficits, muscle weakness and foot deformities. There is no treatment approved for this disease. Outcome measures in clinical trials were based mainly on clinical features but did not evaluate the actual nerve damage. In our case-control study, we aimed to provide objective and reproducible outcome measures for future clinical trials. We collected skin samples from 48 patients with Charcot-Marie-Tooth type 1A, 7 patients with chronic inflammatory demyelinating polyneuropathy, 16 patients with small fibre neuropathy and 45 healthy controls. To analyse skin innervation, 40-µm cryosections of glabrous skin taken from the lateral index finger were double-labelled by immunofluorescence. The disease severity of patients with Charcot-Marie-Tooth type 1A was assessed by the Charcot-Marie-Tooth neuropathy version 2 score, which ranged from 3 (mild) to 27 (severe) and correlated with age (P < 0.01, R = 0.4). Intraepidermal nerve fibre density was reduced in patients with Charcot-Marie-Tooth type 1A compared with the healthy control group (P < 0.01) and negatively correlated with disease severity (P < 0.05, R = -0.293). Meissner corpuscle (MC) density correlated negatively with age in patients with Charcot-Marie-Tooth type 1A (P < 0.01, R = -0.45) but not in healthy controls (P = 0.07, R = 0.28). The density of Merkel cells was reduced in patients with Charcot-Marie-Tooth type 1A compared with healthy controls (P < 0.05). Furthermore, in patients with Charcot-Marie-Tooth type 1A, the fraction of denervated Merkel cells was highly increased and correlated with age (P < 0.05, R = 0.37). Analysis of nodes of Ranvier revealed shortened paranodes and a reduced fraction of long nodes in patients compared with healthy controls (both P < 0.001). Langerhans cell density was increased in chronic inflammatory demyelinating polyneuropathy, but not different in Charcot-Marie-Tooth type 1A compared with healthy controls. Our data suggest that intraepidermal nerve fibre density might be used as an outcome measure in Charcot-Marie-Tooth type 1A disease, as it correlates with disease severity. The densities of Meissner corpuscles and Merkel cells might be an additional tool for the evaluation of the disease progression. Analysis of follow-up biopsies will clarify the effects of Charcot-Marie-Tooth type 1A disease progression on cutaneous innervation. PMID: 32954280 [PubMed] PubMed:32954280 Hartmannsberger B, Doppler K, Stauber J, Schlotter-Weigel B, Young P, Sereda MW, Sommer C

https://www.ncbi.nlm.nih.gov/pubmed/31899213?dopt=Abstract

https://www.sciencedirect.com/science/article/abs/pii/S0006899319306791?via%3Dihub

Are we prepared for clinical trials in Charcot-Marie-Tooth disease?

Are we prepared for clinical trials in Charcot-Marie-Tooth disease?

Brain Res. 2019 Dec 30;:146625

Authors: Rossor AM, Shy ME, Reilly MM

Abstract

There has been considerable progress in developing treatments for Charcot-Marie-Tooth disease with a number of therapies either completing or nearing clinical trials. In the case of CMT1A, the commonest subtype of CMT, there have been more than five randomised, double blind placebo-controlled trials. Although these trials were negative for the primary outcome measure, considerable lessons have been learnt leading to the collection of large prospective natural history data sets with which to inform future trial design as well as the development of new and sensitive outcome measures. In this review we summarise the difficulties of conducting clinical trials in a slowly progressive disease such as CMT1A and the requirement for sensitive, reproducible and clinically relevant outcome measures. We summarise the current array of CMT specific outcome measures subdivided into clinical outcome measures, functional outcome measures, patient reported outcome measures, biomarkers of disease burden and treatment specific biomarkers of target engagement. Although there is now an array of CMT specific outcome measures, which collectively incorporate clinically relevant, sensitive and reproducible outputs, a single outcome measure incorporating all three qualities remains elusive.

PMID: 31899213 [PubMed – as supplied by publisher]

PubMed:31899213

Rossor AM, Shy ME, Reilly MM

https://pubs.acs.org/doi/10.1021/acschemneuro.9b00338

https://www.ncbi.nlm.nih.gov/pubmed/31845794?dopt=Abstract

Novel HDAC6 inhibitors increase tubulin acetylation and rescue axonal transport of mitochondria in a model of Charcot-Marie-Tooth Type 2F.

Novel HDAC6 inhibitors increase tubulin acetylation and rescue axonal transport of mitochondria in a model of Charcot-Marie-Tooth Type 2F.

ACS Chem Neurosci. 2019 Dec 17;:

Authors: Adalbert R, Kaieda A, Antoniou C, Loreto A, Yang X, Gilley J, Hoshino T, Uga K, Makhija MT, Coleman MP

Abstract

Disruption of axonal transport causes a number of rare, inherited axonopathies and is heavily implicated in a wide range of more common neurodegenerative disorders, many of them age-related. Acetylation of α-tubulin is one important regulatory mechanism, influencing microtubule stability and motor protein attachment. Of several strategies so far used to enhance axonal transport, increasing microtubule acetylation through inhibition of the deacetylase enzyme HDAC6 has been one of the most effective. Several inhibitors have been developed and tested in animal and cellular models but better drug candidates are still needed. Here we report the development and characterisation of two highly potent HDAC6 inhibitors, which show low toxicity, promising pharmacokinetic properties, and enhance microtubule acetylation in the nanomolar range. We demonstrate their capacity to rescue axonal transport of mitochondria in a primary neuronal culture model of the inherited axonopathy Charcot-Marie-Tooth Type 2F, caused by a dominantly acting mutation in heat shock protein beta 1.

PMID: 31845794 [PubMed – as supplied by publisher]

PubMed:31845794

Adalbert R, Kaieda A, Antoniou C, Loreto A, Yang X, Gilley J, Hoshino T, Uga K, Makhija MT, Coleman MP

https://n.neurology.org/content/94/1/e51

https://www.ncbi.nlm.nih.gov/pubmed/31827005?dopt=Abstract

Targeted next-generation sequencing panels in the diagnosis of Charcot-Marie-Tooth disease.

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Targeted next-generation sequencing panels in the diagnosis of Charcot-Marie-Tooth disease.

Neurology. 2019 Dec 11;:

Authors: Cortese A, Wilcox JE, Polke JM, Poh R, Skorupinska M, Rossor AM, Laura M, Tomaselli PJ, Houlden H, Shy ME, Reilly MM

Abstract

OBJECTIVE: To investigate the effectiveness of targeted next-generation sequencing (NGS) panels in achieving a molecular diagnosis in Charcot-Marie-Tooth disease (CMT) and related disorders in a clinical setting.

METHODS: We prospectively enrolled 220 patients from 2 tertiary referral centers, one in London, United Kingdom (n = 120), and one in Iowa (n = 100), in whom a targeted CMT NGS panel had been requested as a diagnostic test. PMP22 duplication/deletion was previously excluded in demyelinating cases. We reviewed the genetic and clinical data upon completion of the diagnostic process.

RESULTS: After targeted NGS sequencing, a definite molecular diagnosis, defined as a pathogenic or likely pathogenic variant, was reached in 30% of cases (n = 67). The diagnostic rate was similar in London (32%) and Iowa (29%). Variants of unknown significance were found in an additional 33% of cases. Mutations in GJB1, MFN2, and MPZ accounted for 39% of cases that received genetic confirmation, while the remainder of positive cases had mutations in diverse genes, including SH3TC2, GDAP1, IGHMBP2, LRSAM1, FDG4, and GARS, and another 12 less common genes. Copy number changes in PMP22, MPZ, MFN2, SH3TC2, and FDG4 were also accurately detected. A definite genetic diagnosis was more likely in cases with an early onset, a positive family history of neuropathy or consanguinity, and a demyelinating neuropathy.

CONCLUSIONS: NGS panels are effective tools in the diagnosis of CMT, leading to genetic confirmation in one-third of cases negative for PMP22 duplication/deletion, thus highlighting how rarer and previously undiagnosed subtypes represent a relevant part of the genetic landscape of CMT.

PMID: 31827005 [PubMed – as supplied by publisher]

PubMed:31827005

Cortese A, Wilcox JE, Polke JM, Poh R, Skorupinska M, Rossor AM, Laura M, Tomaselli PJ, Houlden H, Shy ME, Reilly MM

https://link.springer.com/chapter/10.1007%2F978-981-32-9636-7_19

https://www.ncbi.nlm.nih.gov/pubmed/31760652?dopt=Abstract

Schwann Cell and the Pathogenesis of Charcot-Marie-Tooth Disease.

Schwann Cell and the Pathogenesis of Charcot-Marie-Tooth Disease.

Adv Exp Med Biol. 2019;1190:301-321

Authors: Murakami T, Sunada Y

Abstract

Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuropathy and genetically heterogeneous. CMT1 and CMTX are autosomal dominant and X-linked demyelinating neuropathies, respectively. CMT1A, CMT1B, and CMTX1 are the common forms of CMT, which are attributed to the genes encoding the myelin or gap junction proteins expressed in the myelinating Schwann cells. CMT4 is a rare autosomal recessive demyelinating neuropathy that usually shows an early-onset severe phenotype. Twelve genes have been described as CMT4, which encodes many kinds of proteins including mitochondrial proteins, phosphatases in the endosomal pathway, endocytic recycling proteins, and trafficking proteins. The genes responsible for CMT4 are expressed in Schwan cells and necessary for the development and maintenance in the peripheral nervous system. However, CMT1, CMT4, and CMTX1 are primarily demyelinating neuropathies, axonal degeneration is necessary for symptoms to develop. Schwann cell-axon interactions are impaired in the pathogenesis of demyelinating CMT.

PMID: 31760652 [PubMed – in process]

PubMed:31760652

Murakami T, Sunada Y

https://peerj.com/articles/7983/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6875392/

https://www.ncbi.nlm.nih.gov/pubmed/31772832?dopt=Abstract

Charcot-Marie-Tooth type 4B2 demyelinating neuropathy in miniature Schnauzer dogs caused by a novel splicing SBF2 (MTMR13) genetic variant: a new spontaneous clinical model.

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Charcot-Marie-Tooth type 4B2 demyelinating neuropathy in miniature Schnauzer dogs caused by a novel splicing SBF2 (MTMR13) genetic variant: a new spontaneous clinical model.

PeerJ. 2019;7:e7983

Authors: Granger N, Luján Feliu-Pascual A, Spicer C, Ricketts S, Hitti R, Forman O, Hersheson J, Houlden H

Abstract

Background: Charcot-Marie-Tooth (CMT) disease is the most common neuromuscular disorder in humans affecting 40 out of 100,000 individuals. In 2008, we described the clinical, electrophysiological and pathological findings of a demyelinating motor and sensory neuropathy in Miniature Schnauzer dogs, with a suspected autosomal recessive mode of inheritance based on pedigree analysis. The discovery of additional cases has followed this work and led to a genome-wide association mapping approach to search for the underlying genetic cause of the disease.

Methods: For genome wide association screening, genomic DNA samples from affected and unaffected dogs were genotyped using the Illumina CanineHD SNP genotyping array. SBF2 and its variant were sequenced using primers and PCRs. RNA was extracted from muscle of an unaffected and an affected dog and RT-PCR performed. Immunohistochemistry for myelin basic protein was performed on peripheral nerve section specimens.

Results: The genome-wide association study gave an indicative signal on canine chromosome 21. Although the signal was not of genome-wide significance due to the small number of cases, the SBF2 (also known as MTMR13) gene within the region of shared case homozygosity was a strong positional candidate, as 22 genetic variants in the gene have been associated with demyelinating forms of Charcot-Marie-Tooth disease in humans. Sequencing of SBF2 in cases revealed a splice donor site genetic variant, resulting in cryptic splicing and predicted early termination of the protein based on RNA sequencing results.

Conclusions: This study reports the first genetic variant in Miniature Schnauzer dogs responsible for the occurrence of a demyelinating peripheral neuropathy with abnormally folded myelin. This discovery establishes a genotype/phenotype correlation in affected Miniature Schnauzers that can be used for the diagnosis of these dogs. It further supports the dog as a natural model of a human disease; in this instance, Charcot-Marie-Tooth disease. It opens avenues to search the biological mechanisms responsible for the disease and to test new therapies in a non-rodent large animal model. In particular, recent gene editing methods that led to the restoration of dystrophin expression in a canine model of muscular dystrophy could be applied to other canine models such as this before translation to humans.

PMID: 31772832 [PubMed]

PubMed:31772832

Granger N, Luján Feliu-Pascual A, Spicer C, Ricketts S, Hitti R, Forman O, Hersheson J, Houlden H

https://www.nature.com/articles/s41467-019-12909-9

Transcriptional dysregulation by a nucleus-localized aminoacyl-tRNA synthetase associated with Charcot-Marie-Tooth neuropathy

These data highlight that this translation factor may contribute to transcriptional regulation in neurons, and suggest a therapeutic strategy for CMT

https://www.sciencedirect.com/science/article/abs/pii/S0006899319305931?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/31689415?dopt=Abstract

Targeting the Programmed Axon Degeneration Pathway as a Potential Therapeutic for Charcot-Marie-Tooth Disease.

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Targeting the Programmed Axon Degeneration Pathway as a Potential Therapeutic for Charcot-Marie-Tooth Disease.

Brain Res. 2019 Nov 02;:146539

Authors: Moss KR, Höke A

Abstract

The programmed axon degeneration pathway has emerged as an important process contributing to the pathogenesis of several neurological diseases. The most crucial events in this pathway include activation of the central executioner SARM1 and NAD+ depletion, which leads to an energetic failure and ultimately axon destruction. Given the prevalence of this pathway, it is not surprising that inhibitory therapies are currently being developed in order to treat multiple neurological diseases with the same therapy. Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of neurological diseases that may also benefit from this therapeutic approach. To evaluate the appropriateness of this strategy, the contribution of the programmed axon degeneration pathway to the pathogenesis of different CMT subtypes is being actively investigated. The subtypes CMT1A, CMT1B and CMT2D are the first to have been examined. Based on the results from these studies and advances in developing therapies to block the programmed axon degeneration pathway, promising therapeutics for CMT are now on the horizon.

PMID: 31689415 [PubMed – as supplied by publisher]

PubMed:31689415

Moss KR, Höke A

https://www.pnas.org/content/early/2019/09/06/1908288116

https://www.ncbi.nlm.nih.gov/pubmed/31501329?dopt=Abstract

CMT disease severity correlates with mutation-induced open conformation of histidyl-tRNA synthetase, not aminoacylation loss, in patient cells.

Related Articles

CMT disease severity correlates with mutation-induced open conformation of histidyl-tRNA synthetase, not aminoacylation loss, in patient cells.

Proc Natl Acad Sci U S A. 2019 Sep 09;:

Authors: Blocquel D, Sun L, Matuszek Z, Li S, Weber T, Kuhle B, Kooi G, Wei N, Baets J, Pan T, Schimmel P, Yang XL

Abstract

Aminoacyl-transfer RNA (tRNA) synthetases (aaRSs) are the largest protein family causatively linked to neurodegenerative Charcot-Marie-Tooth (CMT) disease. Dominant mutations cause the disease, and studies of CMT disease-causing mutant glycyl-tRNA synthetase (GlyRS) and tyrosyl-tRNA synthetase (TyrRS) showed their mutations create neomorphic structures consistent with a gain-of-function mechanism. In contrast, based on a haploid yeast model, loss of aminoacylation function was reported for CMT disease mutants in histidyl-tRNA synthetase (HisRS). However, neither that nor prior work of any CMT disease-causing aaRS investigated the aminoacylation status of tRNAs in the cellular milieu of actual patients. Using an assay that interrogated aminoacylation levels in patient cells, we investigated a HisRS-linked CMT disease family with the most severe disease phenotype. Strikingly, no difference in charged tRNA levels between normal and diseased family members was found. In confirmation, recombinant versions of 4 other HisRS CMT disease-causing mutants showed no correlation between activity loss in vitro and severity of phenotype in vivo. Indeed, a mutation having the most detrimental impact on activity was associated with a mild disease phenotype. In further work, using 3 independent biophysical analyses, structural opening (relaxation) of mutant HisRSs at the dimer interface best correlated with disease severity. In fact, the HisRS mutation in the severely afflicted patient family caused the largest degree of structural relaxation. These data suggest that HisRS-linked CMT disease arises from open conformation-induced mechanisms distinct from loss of aminoacylation.

PMID: 31501329 [PubMed – as supplied by publisher]

PubMed:31501329

Blocquel D, Sun L, Matuszek Z, Li S, Weber T, Kuhle B, Kooi G, Wei N, Baets J, Pan T, Schimmel P, Yang XL

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425404/

https://www.ncbi.nlm.nih.gov/pubmed/32954258?dopt=Abstract

Recessive Charcot-Marie-Tooth and multiple sclerosis associated with a variant in MCM3AP.

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Recessive Charcot-Marie-Tooth and multiple sclerosis associated with a variant in MCM3AP.

Brain Commun. 2019;1(1):fcz011

Authors: Sedghi M, Moslemi AR, Cabrera-Serrano M, Ansari B, Ghasemi M, Baktashian M, Fattahpour A, Tajsharghi H

Abstract

Variants in MCM3AP, encoding the germinal-centre associated nuclear protein, have been associated with progressive polyneuropathy with or without intellectual disability and ptosis in some cases, and with a complex phenotype with immunodeficiency, skin changes and myelodysplasia. MCM3AP encoded protein functions as an acetyltransferase that acetylates the replication protein, MCM3, and plays a key role in the regulation of DNA replication. In this study, we report a novel variant in MCM3AP (p.Ile954Thr), in a family including three affected individuals with characteristic features of Charcot-Marie-Tooth neuropathy and multiple sclerosis, an inflammatory condition of the central nervous system without known genetic cause. The affected individuals were homozygous for a missense MCM3AP variant, located at the Sac3 domain, which was predicted to affect conserved amino acid likely important for the function of the germinal-centre associated nuclear protein. Our data support further expansion of the clinical spectrum linked to MCM3AP variant and highlight that MCM3AP should be considered in patients with accompaniment of recessive motor axonal Charcot-Marie-Tooth neuropathy and multiple sclerosis.

PMID: 32954258 [PubMed]

PubMed:32954258

Sedghi M, Moslemi AR, Cabrera-Serrano M, Ansari B, Ghasemi M, Baktashian M, Fattahpour A, Tajsharghi H

https://onlinelibrary.wiley.com/doi/abs/10.1002/mus.26688

https://www.ncbi.nlm.nih.gov/pubmed/31469427?dopt=Abstract

Nerve size correlates with clinical severity in CMT1A.

Nerve size correlates with clinical severity in CMT1A.

Muscle Nerve. 2019 Aug 30;:

Authors: Zanette G, Tamburin S, Taioli F, Lauriola MF, Badari A, Ferrarini M, Cavallaro T, Fabrizi GM

Abstract

INTRODUCTION: Nerve cross sectional area (CSA) is larger than normal in Charcot-Marie-Tooth disease 1A (CMT1A), although to a variable extent. We explored whether CSA is correlated with CMT clinical severity measured with neuropathy score version 2 (CMTNS2) and its examination subscore (CMTES2) in CMT1A.

METHODS: We assessed 56 CMT1A patients (42 families). They underwent nerve conduction study (NCS) and nerve high-resolution ultrasound (HRUS) of the left median, ulnar and fibular nerves.

RESULTS: Univariate analysis showed NCS and HRUS variables to be significantly correlated with CMTNS2 and CMTES2 and with each other. Multivariate analysis showed ulnar motor nerve conduction velocity (β: -0.19) and fibular compound muscle action potential amplitude (-1.50) to significantly influence CMTNS2 and median forearm CSA to significantly influence CMTNS2 (β: 5.29) and CMTES2 (4.28).

DISCUSSION: Nerve size is significantly associated with clinical scores in CMT1A, suggesting it might represent a potential biomarker of CMT damage and progression. This article is protected by copyright. All rights reserved.

PMID: 31469427 [PubMed – as supplied by publisher]

PubMed:31469427

Zanette G, Tamburin S, Taioli F, Lauriola MF, Badari A, Ferrarini M, Cavallaro T, Fabrizi GM

https://www.nature.com/articles/s41434-019-0098-z

https://www.ncbi.nlm.nih.gov/pubmed/31455873?dopt=Abstract

miR-29a and/or PMP22-targeting siRNAs as therapeutic agents for correcting the aberrant expression of PMP22 in Charcot-Marie-Tooth disease patients

Downregulation of the human peripheral myelin protein 22 gene by miR-29a in cellular models of Charcot-Marie-Tooth disease.

Related Articles

Downregulation of the human peripheral myelin protein 22 gene by miR-29a in cellular models of Charcot-Marie-Tooth disease.

Gene Ther. 2019 Aug 27;:

Authors: Serfecz J, Bazick H, Al Salihi MO, Turner P, Fields C, Cruz P, Renne R, Notterpek L

Abstract

The majority of hereditary neuropathies are caused by duplication of the peripheral myelin protein 22 (PMP22) gene. Therefore, mechanisms to suppress the expression of the PMP22 gene have high therapeutic significance. Here we asked whether the human PMP22 gene is a target for regulation by microRNA 29a (miR-29a). Using bioinformatics, we determined that the human PMP22 gene contains the conserved seed sequence of the miR-29a binding site and this regulatory motif is included in the duplicated region in neuropathic patients. Using luciferase reporter assays in HEK293 cells, we demonstrated that transient transfection of a miR-29a mimic is associated with reduction in PMP22 3’UTR reporter activity. Transfecting normal and humanized transgenic neuropathic mouse Schwann cells with a miR-29a expression plasmid effectively lowered both the endogenous mouse and the transgenic human PMP22 transcripts compared with control vector. In dermal fibroblasts derived from neuropathic patients, ectopic expression of miR-29a led to ~50% reduction in PMP22 mRNA, which corresponded to ~20% decrease in PMP22 protein levels. Significantly, miR-29a-mediated reduction in PMP22 mitigated the reduced mitotic capacity of the neuropathic cells. Together, these results support further testing of miR-29a and/or PMP22-targeting siRNAs as therapeutic agents for correcting the aberrant expression of PMP22 in neuropathic patients.

PMID: 31455873 [PubMed – as supplied by publisher]

PubMed:31455873

Serfecz J, Bazick H, Al Salihi MO, Turner P, Fields C, Cruz P, Renne R, Notterpek L

https://www.ncbi.nlm.nih.gov/pubmed/31426691?dopt=Abstract

Novel mutation in the periaxin gene causal to Charcot-Marie-Tooth disease type 4F.

Related Articles

Novel mutation in the periaxin gene causal to Charcot-Marie-Tooth disease type 4F.

J Int Med Res. 2019 Aug 20;:300060519862064

Authors: Chen YH, Zhang H, Meng LB, Tang XY, Gong T, Yin J

PMID: 31426691 [PubMed – as supplied by publisher]

PubMed:31426691

Chen YH, Zhang H, Meng LB, Tang XY, Gong T, Yin J

https://www.ncbi.nlm.nih.gov/pubmed/31412900?dopt=Abstract

Peripheral myelin protein 2 – a novel cluster of mutations causing Charcot-Marie-Tooth neuropathy.

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Peripheral myelin protein 2 – a novel cluster of mutations causing Charcot-Marie-Tooth neuropathy.

Orphanet J Rare Dis. 2019 Aug 14;14(1):197

Authors: Palaima P, Chamova T, Jander S, Mitev V, Van Broeckhoven C, Tournev I, Peeters K, Jordanova A

Abstract

BACKGROUND: Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder characterized by wide clinical, genetic and pathomechanistic heterogeneity. Recently, the gene encoding peripheral myelin protein 2 (PMP2) was identified as a novel cause for CMT neuropathy with three mutations that structurally cluster together (p.Ile43Asn, p.Thr51Pro, p.Ile52Thr) reported in five families.

RESULTS: Using whole exome sequencing and cohort screening we identified two novel missense substitutions in PMP2 in Bulgarian (p.Met114Thr, c.341C > T) and German (p.Val115Ala, c.344 T > C) families. The mutations affect adjacent and highly conserved amino acid residues outside of the known mutation-rich region in the protein. Crystal structure analysis positions the affected residues within a cluster of highly conserved fatty acid coordinating residues implying their functional significance. The clinical, electrophysiological and imaging features in both families were consistent with a childhood onset polyneuropathy with variable patterns of demyelination, slow to very slow progression, and most severe involvement of the peroneal muscles.

CONCLUSIONS: We expand the genetic and phenotypic spectrum of PMP2-related peripheral neuropathy. Our findings reveal a second mutational cluster in the protein.

PMID: 31412900 [PubMed – in process]

PubMed:31412900

Palaima P, Chamova T, Jander S, Mitev V, Van Broeckhoven C, Tournev I, Peeters K, Jordanova A

https://www.msard-journal.com/article/S2211-0348(19)30308-6/fulltext

https://www.ncbi.nlm.nih.gov/pubmed/31352181?dopt=Abstract

A special association between Charcot-Marie-Tooth type 1A disease and relapsing remitting multiple sclerosis.

A special association between Charcot-Marie-Tooth type 1A disease and relapsing remitting multiple sclerosis.

Mult Scler Relat Disord. 2019 Jul 22;35:83-85

Authors: Doğan Y, Gül Ş, Ceylan AC, Kutsal YG

Abstract

BACKGROUND: Central nervous system involvement has been reported in different subtypes of Charcot-Marie-Tooth (CMT) diseases. The increasing number of cases with CMT and MS may provide further information about the common pathway of demyelination and MS pathogenesis.

CASE PRESENTATION: We report the case of a 21-year-old woman with CMT1A and MS. Bilateral rest and intention tremor, steroid associated psychotic episodes, and severe disability at an early age were unexpected aspects of this case.

CONCLUSION: PMP22, the target protein in CMT1A, shares partial homology with other CNS proteins. PMP22 gene might be relevant to a common pathway of the demyelinating process.

PMID: 31352181 [PubMed – as supplied by publisher]

PubMed:31352181

Doğan Y, Gül Ş, Ceylan AC, Kutsal YG

https://www.mdpi.com/1422-0067/20/14/3419

https://www.ncbi.nlm.nih.gov/pubmed/31336816?dopt=Abstract

Charcot-Marie-Tooth: From Molecules to Therapy.

Related Articles

Charcot-Marie-Tooth: From Molecules to Therapy.

Int J Mol Sci. 2019 Jul 12;20(14):

Authors: Morena J, Gupta A, Hoyle JC

Abstract

Charcot-Marie-Tooth (CMT) is the most prevalent category of inherited neuropathy. The most common inheritance pattern is autosomal dominant, though there also are X-linked and autosomal recessive subtypes. In addition to a variety of inheritance patterns, there are a myriad of genes associated with CMT, reflecting the heterogeneity of this disorder. Next generation sequencing (NGS) has expanded and simplified the diagnostic yield of genes/molecules underlying and/or associated with CMT, which is of paramount importance in providing a substrate for current and future targeted disease-modifying treatment options. Considerable research attention for disease-modifying therapy has been geared towards the most commonly encountered genetic mutations (PMP22, GJB1, MPZ, and MFN2). In this review, we highlight the clinical background, molecular understanding, and therapeutic investigations of these CMT subtypes, while also discussing therapeutic research pertinent to the remaining less common CMT subtypes.

PMID: 31336816 [PubMed – in process]

PubMed:31336816

Morena J, Gupta A, Hoyle JC