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Heterogeneous Clinical Phenotypes of dHMN Caused by Mutation in HSPB1 Gene: A Case Series. Biomolecules 2022; 12:biom12101382. [PMID: 36291591 PMCID: PMC9599773 DOI: 10.3390/biom12101382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 09/07/2022] [Accepted: 09/22/2022] [Indexed: 11/21/2022] Open
Abstract
Mutations in HSPB1 are known to cause Charcot-Marie-Tooth disease type 2F (CMT2F) and distal hereditary motor neuropathy (dHMN). In this study, we presented three patients with mutation in HSPB1 who were diagnosed with dHMN. Proband 1 was a 14-year-old male with progressive bilateral lower limb weakness and walking difficulty for four years. Proband 2 was a 65-year-old male with chronic lower limb weakness and restless legs syndrome from the age of 51. Proband 3 was a 50-year-old female with progressive weakness, lower limbs atrophy from the age of 44. The nerve conduction studies (NCS) suggested axonal degeneration of the peripheral motor nerves and needle electromyography (EMG) revealed chronic neurogenic changes in probands. Open sural nerve biopsy for proband 2 and the mother of proband 1 showed mild to moderate loss of myelinated nerve fibers with some nerve fiber regeneration. A novel p.V97L in HSPB1 was identified in proband 3, the other two variants (p.P182A and p.R127W) in HSPB1 have been reported previously. The functional studies showed that expressing mutant p.V97L HSPB1 in SH-SY5Y cells displayed a decreased cell activity and increased apoptosis under stress condition. Our study expands the clinical phenotypic spectrum and etiological spectrum of HSPB1 mutation.
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Lu S, Hu J, Arogundade OA, Goginashvili A, Vazquez-Sanchez S, Diedrich JK, Gu J, Blum J, Oung S, Ye Q, Yu H, Ravits J, Liu C, Yates JR, Cleveland DW. Heat-shock chaperone HSPB1 regulates cytoplasmic TDP-43 phase separation and liquid-to-gel transition. Nat Cell Biol 2022; 24:1378-1393. [PMID: 36075972 PMCID: PMC9872726 DOI: 10.1038/s41556-022-00988-8] [Citation(s) in RCA: 73] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 07/28/2022] [Indexed: 01/27/2023]
Abstract
While acetylated, RNA-binding-deficient TDP-43 reversibly phase separates within nuclei into complex droplets (anisosomes) comprised of TDP-43-containing liquid outer shells and liquid centres of HSP70-family chaperones, cytoplasmic aggregates of TDP-43 are hallmarks of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here we show that transient oxidative stress, proteasome inhibition or inhibition of the ATP-dependent chaperone activity of HSP70 provokes reversible cytoplasmic TDP-43 de-mixing and transition from liquid to gel/solid, independently of RNA binding or stress granules. Isotope labelling mass spectrometry was used to identify that phase-separated cytoplasmic TDP-43 is bound by the small heat-shock protein HSPB1. Binding is direct, mediated through TDP-43's RNA binding and low-complexity domains. HSPB1 partitions into TDP-43 droplets, inhibits TDP-43 assembly into fibrils, and is essential for disassembly of stress-induced TDP-43 droplets. A decrease in HSPB1 promotes cytoplasmic TDP-43 de-mixing and mislocalization. HSPB1 depletion was identified in spinal motor neurons of patients with ALS containing aggregated TDP-43. These findings identify HSPB1 to be a regulator of cytoplasmic TDP-43 phase separation and aggregation.
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Affiliation(s)
- Shan Lu
- Department of Cellular and Molecular Medicine, University of California, San Diego, CA, USA
- Ludwig Institute for Cancer Research, San Diego, CA, USA
| | - Jiaojiao Hu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | | | - Alexander Goginashvili
- Department of Cellular and Molecular Medicine, University of California, San Diego, CA, USA
- Ludwig Institute for Cancer Research, San Diego, CA, USA
| | - Sonia Vazquez-Sanchez
- Department of Cellular and Molecular Medicine, University of California, San Diego, CA, USA
- Ludwig Institute for Cancer Research, San Diego, CA, USA
| | | | - Jinge Gu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Jacob Blum
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Spencer Oung
- Department of Cellular and Molecular Medicine, University of California, San Diego, CA, USA
- Ludwig Institute for Cancer Research, San Diego, CA, USA
| | - Qiaozhen Ye
- Department of Cellular and Molecular Medicine, University of California, San Diego, CA, USA
| | - Haiyang Yu
- Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Peter O'Donnell Jr Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - John Ravits
- Department of Neurosciences, University of California, San Diego, CA, USA
| | - Cong Liu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - John R Yates
- The Scripps Research Institute, La Jolla, CA, USA
| | - Don W Cleveland
- Department of Cellular and Molecular Medicine, University of California, San Diego, CA, USA.
- Ludwig Institute for Cancer Research, San Diego, CA, USA.
- Department of Neurosciences, University of California, San Diego, CA, USA.
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Holguin BA, Hildenbrand ZL, Bernal RA. Insights Into the Role of Heat Shock Protein 27 in the Development of Neurodegeneration. Front Mol Neurosci 2022; 15:868089. [PMID: 35431800 PMCID: PMC9005852 DOI: 10.3389/fnmol.2022.868089] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 03/09/2022] [Indexed: 12/11/2022] Open
Abstract
Small heat shock protein 27 is a critically important chaperone, that plays a key role in several essential and varied physiological processes. These include thermotolerance, apoptosis, cytoskeletal dynamics, cell differentiation, protein folding, among others. Despite its relatively small size and intrinsically disordered termini, it forms large and polydisperse oligomers that are in equilibrium with dimers. This equilibrium is driven by transient interactions between the N-terminal region, the α-crystallin domain, and the C-terminal region. The continuous redistribution of binding partners results in a conformationally dynamic protein that allows it to adapt to different functions where substrate capture is required. However, the intrinsic disorder of the amino and carboxy terminal regions and subsequent conformational variability has made structural investigations challenging. Because heat shock protein 27 is critical for so many key cellular functions, it is not surprising that it also has been linked to human disease. Charcot-Marie-Tooth and distal hereditary motor neuropathy are examples of neurodegenerative disorders that arise from single point mutations in heat shock protein 27. The development of possible treatments, however, depends on our understanding of its normal function at the molecular level so we might be able to understand how mutations manifest as disease. This review will summarize recent reports describing investigations into the structurally elusive regions of Hsp27. Recent insights begin to provide the required context to explain the relationship between a mutation and the resulting loss or gain of function that leads to Charcot-Marie Tooth disease and distal hereditary motor neuropathy.
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Gonçalves CC, Sharon I, Schmeing TM, Ramos CHI, Young JC. The chaperone HSPB1 prepares protein aggregates for resolubilization by HSP70. Sci Rep 2021; 11:17139. [PMID: 34429462 PMCID: PMC8384840 DOI: 10.1038/s41598-021-96518-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Accepted: 08/11/2021] [Indexed: 01/22/2023] Open
Abstract
In human cells under stress conditions, misfolded polypeptides can form potentially cytotoxic insoluble aggregates. To eliminate aggregates, the HSP70 chaperone machinery extracts and resolubilizes polypeptides for triage to refolding or degradation. Yeast and bacterial chaperones of the small heat-shock protein (sHSP) family can bind substrates at early stages of misfolding, during the aggregation process. The co-aggregated sHSPs then facilitate downstream disaggregation by HSP70. Because it is unknown whether a human sHSP has this activity, we investigated the disaggregation role of human HSPB1. HSPB1 co-aggregated with unfolded protein substrates, firefly luciferase and mammalian lactate dehydrogenase. The co-aggregates formed with HSPB1 were smaller and more regularly shaped than those formed in its absence. Importantly, co-aggregation promoted the efficient disaggregation and refolding of the substrates, led by HSP70. HSPB1 itself was also extracted during disaggregation, and its homo-oligomerization ability was not required. Therefore, we propose that a human sHSP is an integral part of the chaperone network for protein disaggregation.
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Affiliation(s)
- Conrado C Gonçalves
- Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Room 900, Montreal, QC, H3G 1Y6, Canada
| | - Itai Sharon
- Department of Biochemistry, McGill University, 3649 Promenade Sir William Osler, Room 457, Montreal, QC, H3G 0B1, Canada
| | - T Martin Schmeing
- Department of Biochemistry, McGill University, 3649 Promenade Sir William Osler, Room 457, Montreal, QC, H3G 0B1, Canada
| | - Carlos H I Ramos
- Institute of Chemistry, University of Campinas (UNICAMP), Campinas, SP, 13083-970, Brazil
| | - Jason C Young
- Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Room 900, Montreal, QC, H3G 1Y6, Canada.
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Tejero S, Chans-Veres J, Carranza-Bencano A, Galhoum AE, Poggio D, Valderrábano V, Herrera-Pérez M. Functional results and quality of life after joint preserving or sacrificing surgery in Charcot-Marie-Tooth foot deformities. INTERNATIONAL ORTHOPAEDICS 2021; 45:2569-2578. [PMID: 33611670 DOI: 10.1007/s00264-021-04978-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 02/02/2021] [Indexed: 04/01/2025]
Abstract
INTRODUCTION The purpose of this study was to assess the functional results, quality of life, and complications in two groups of Charcot-Marie-Tooth (CMT) patients according to the type of surgical operations, joint preserving, or joint sacrificing surgery. METHODS Fifty-two feet in forty-six patients with CMT who had undergone surgical deformity correction were divided into two groups based on the main surgical procedure for the correction: Class I (joint preserving surgery) and class II (joint sacrificing surgery). Foot ankle disability index (FADI) and short form 12 version 2 (SF12V2) were documented pre-operative and 12 months post-operative. The complications of both groups were monitored with a mean follow-up time of 20.5 months (range, 13-71.5). RESULTS After surgical treatment, FADI scores showed differences (p=0.005) between both groups. The functional improvement was 29 (20-46; p<0.001) in class I and 10 (2-36; p=0.001) in class II. The patients in both groups acquired a better quality of life as demonstrated in physical component summary of SF12 but without statistically difference. Three feet needed reintervention in class I (two for cavovarus recurrence and one for hallux flexus) at the end of follow-up. In contrast, five feet needed a new operation for cavovarus recurrence, claw toes recurrence, and ankle osteoarthritis after the progression of the condition. DISCUSSION An early surgical intervention to neutralize the deforming forces in CMT patients could be a useful strategy to delay or prevent the need for extensive reconstruction and potential future complications. CONCLUSION Based on the type of surgical intervention in CMT patients, the joint preserving surgery in addition to soft tissue balancing procedures obtained better functional outcomes and lower rate of complications when compared to the group of joint sacrificing surgery.
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Affiliation(s)
- Sergio Tejero
- Foot Ankle Unit, University Hospital Virgen del Rocío, Seville, Spain. .,University of Seville, Seville, Spain.
| | | | | | | | | | - Victor Valderrábano
- Schmerzklinik Basel, Genolier Swiss Medical Network GSMN, Basel, Switzerland
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The Neurochaperonopathies: Anomalies of the Chaperone System with Pathogenic Effects in Neurodegenerative and Neuromuscular Disorders. APPLIED SCIENCES-BASEL 2021. [DOI: 10.3390/app11030898] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The chaperone (or chaperoning) system (CS) constitutes molecular chaperones, co-chaperones, and chaperone co-factors, interactors and receptors, and its canonical role is protein quality control. A malfunction of the CS may cause diseases, known as the chaperonopathies. These are caused by qualitatively and/or quantitatively abnormal molecular chaperones. Since the CS is ubiquitous, chaperonopathies are systemic, affecting various tissues and organs, playing an etiologic-pathogenic role in diverse conditions. In this review, we focus on chaperonopathies involved in the pathogenic mechanisms of diseases of the central and peripheral nervous systems: the neurochaperonopathies (NCPs). Genetic NCPs are linked to pathogenic variants of chaperone genes encoding, for example, the small Hsp, Hsp10, Hsp40, Hsp60, and CCT-BBS (chaperonin-containing TCP-1- Bardet–Biedl syndrome) chaperones. Instead, the acquired NCPs are associated with malfunctional chaperones, such as Hsp70, Hsp90, and VCP/p97 with aberrant post-translational modifications. Awareness of the chaperonopathies as the underlying primary or secondary causes of disease will improve diagnosis and patient management and open the possibility of investigating and developing chaperonotherapy, namely treatment with the abnormal chaperone as the main target. Positive chaperonotherapy would apply in chaperonopathies by defect, i.e., chaperone insufficiency, and consist of chaperone replacement or boosting, whereas negative chaperonotherapy would be pertinent when a chaperone actively participates in the initiation and progression of the disease and must be blocked and eliminated.
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Taga A, Cornblath DR. A novel HSPB1 mutation associated with a late onset CMT2 phenotype: Case presentation and systematic review of the literature. J Peripher Nerv Syst 2020; 25:223-229. [PMID: 32639100 DOI: 10.1111/jns.12395] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 05/20/2020] [Accepted: 05/21/2020] [Indexed: 02/06/2023]
Abstract
Mutations in the HSPB1 gene are associated with Charcot-Marie-Tooth (CMT) disease type 2F (CMT2F) and distal hereditary motor neuropathy type 2 (dHMN2). More than 18 pathogenic mutations spanning across the whole HSPB1 gene have been reported. Three family members with a novel p.P57S (c.169C>T) HSPB1 mutation resulting in a late onset axonal neuropathy with heterogeneous clinical and electrophysiological features are detailed. We systematically reviewed published case reports and case series on HSPB1 mutations. While a genotype-phenotype correlation was not obvious, we identified a common phenotype, which included adult onset, male predominance, motor more frequently than sensory involvement, distal and symmetric distribution with preferential involvement of plantar flexors, and a motor and axonal electrophysiological picture.
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Affiliation(s)
- Arens Taga
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - David R Cornblath
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Adalbert R, Kaieda A, Antoniou C, Loreto A, Yang X, Gilley J, Hoshino T, Uga K, Makhija MT, Coleman MP. Novel HDAC6 Inhibitors Increase Tubulin Acetylation and Rescue Axonal Transport of Mitochondria in a Model of Charcot-Marie-Tooth Type 2F. ACS Chem Neurosci 2020; 11:258-267. [PMID: 31845794 DOI: 10.1021/acschemneuro.9b00338] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
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 histone deacetylase 6 (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 characterization 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.
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Affiliation(s)
- Robert Adalbert
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site Robinson Way, Cambridge CB2 0PY, United Kingdom
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Szeged, Szeged H-6724, Hungary
| | - Akira Kaieda
- Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Christina Antoniou
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site Robinson Way, Cambridge CB2 0PY, United Kingdom
| | - Andrea Loreto
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site Robinson Way, Cambridge CB2 0PY, United Kingdom
| | - Xiuna Yang
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site Robinson Way, Cambridge CB2 0PY, United Kingdom
| | - Jonathan Gilley
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site Robinson Way, Cambridge CB2 0PY, United Kingdom
| | - Takashi Hoshino
- Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Keiko Uga
- Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Mahindra T. Makhija
- Takeda Development Centre Europe Ltd., 61 Aldwych, London WC2B 4AE, United Kingdom
| | - Michael P. Coleman
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site Robinson Way, Cambridge CB2 0PY, United Kingdom
- Babraham Institute, Babraham, Cambridge CB22 3AT, United Kingdom
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Charcot-Marie-Tooth 2F (Hsp27 mutations): A review. Neurobiol Dis 2019; 130:104505. [PMID: 31212070 DOI: 10.1016/j.nbd.2019.104505] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 06/11/2019] [Accepted: 06/13/2019] [Indexed: 12/13/2022] Open
Abstract
Charcot-Marie-Tooth disease is a commonly inherited form of neuropathy. Although named over 100 years ago, identification of subtypes of Charcot-Marie-Tooth has rapidly expanded in the preceding decades with the advancement of genetic sequencing, including type 2F (CMT2F), due to mutations in heat shock protein 27 (Hsp27). However, despite CMT being one of the most common inherited neurological diseases, definitive mechanistic models of pathology and effective treatments for CMT2F are lacking. This review extensively profiles the published literature on CMT2F and distal hereditary motor neuropathy II (dHMN II), a similar neuropathy with exclusively motor symptoms that is also due to mutations in Hsp27. This includes a review of case reports and sequencing studies detailing disease course. Included are tables listing of all known published mutations of Hsp27 that cause symptoms of CMT2F and dHMN II. Furthermore, pathological mechanisms are assessed. While many groups have established pathologies relating to defective chaperone function, cellular neurofilament and microtubule structure and function, and mitochondrial and metabolic dysfunction, there are still discrepancies in results between different model systems. Moreover, initial mouse models have also produced promising results with similar phenotypes to humans, however discrepancies still exist. Both patient-focused and scientific studies have demonstrated variability in phenotypes even considering specific mutations. Given the clinical heterogeneity in presentation, CMT2F and dHMN II likely result from similar pathological mechanisms of the same general disease process that may present distinctly due to other genetic and environment influences. Determining how these influences exert their effects to produce pathology contributing to the disease phenotype will be a major future challenge ahead in the field.
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Genetics of Charcot-Marie-Tooth (CMT) Disease within the Frame of the Human Genome Project Success. Genes (Basel) 2014; 5:13-32. [PMID: 24705285 PMCID: PMC3978509 DOI: 10.3390/genes5010013] [Citation(s) in RCA: 188] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2013] [Revised: 01/08/2014] [Accepted: 01/10/2014] [Indexed: 02/06/2023] Open
Abstract
Charcot-Marie-Tooth (CMT) neuropathies comprise a group of monogenic disorders affecting the peripheral nervous system. CMT is characterized by a clinically and genetically heterogeneous group of neuropathies, involving all types of Mendelian inheritance patterns. Over 1,000 different mutations have been discovered in 80 disease-associated genes. Genetic research of CMT has pioneered the discovery of genomic disorders and aided in understanding the effects of copy number variation and the mechanisms of genomic rearrangements. CMT genetic study also unraveled common pathomechanisms for peripheral nerve degeneration, elucidated gene networks, and initiated the development of therapeutic approaches. The reference genome, which became available thanks to the Human Genome Project, and the development of next generation sequencing tools, considerably accelerated gene and mutation discoveries. In fact, the first clinical whole genome sequence was reported in a patient with CMT. Here we review the history of CMT gene discoveries, starting with technologies from the early days in human genetics through the high-throughput application of modern DNA analyses. We highlight the most relevant examples of CMT genes and mutation mechanisms, some of which provide promising treatment strategies. Finally, we propose future initiatives to accelerate diagnosis of CMT patients through new ways of sharing large datasets and genetic variants, and at ever diminishing costs.
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Nicolaou P, Christodoulou K. Advances in the molecular diagnosis of Charcot-Marie-Tooth disease. World J Neurol 2013; 3:42-55. [DOI: 10.5316/wjn.v3.i3.42] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2013] [Revised: 07/23/2013] [Accepted: 08/16/2013] [Indexed: 02/06/2023] Open
Abstract
Charcot-Marie-Tooth (CMT) disease or hereditary motor and sensory neuropathy is the most common inherited neuromuscular disorder affecting at least 1 in 2500. CMT disease is pathologically and genetically heterogeneous and is characterized by a variable age of onset, slowly progressive weakness and muscle atrophy, starting in the lower limbs and subsequently affecting the upper extremities. Symptoms are usually slowly progressive, especially for the classic and late-onset phenotypes, but can be rather severe in early-onset forms. CMT is grouped into demyelinating, axonal and intermediate forms, based on electrophysiological and pathological findings. The demyelinating types are characterized by severely reduced motor nerve conduction velocities (MNCVs) and mainly by myelin abnormalities. The axonal types are characterized by normal or slightly reduced MNCVs and mainly axonal abnormalities. The intermediate types are characterized by MNCVs between 25 m/s and 45 m/s and they have features of both demyelination and axonopathy. Inheritance can be autosomal dominant, X-linked, or autosomal recessive. Mutations in more than 30 genes have been associated with the different forms of CMT, leading to major advancements in molecular diagnostics of the disease, as well as in the understanding of pathogenetic mechanisms. This editorial aims to provide an account that is practicable and efficient on the current molecular diagnostic procedures for CMT, in correlation with the clinical, pathological and electrophysiological findings. The most frequent causative mutations of CMT will also be outlined.
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Abstract
The inherited neuropathies are a clinically and genetically heterogeneous group of disorders in which there have been rapid advances in the last two decades. Molecular genetic testing is now an integral part of the evaluation of patients with inherited neuropathies. In this chapter we describe the genes responsible for the primary inherited neuropathies. We briefly discuss the clinical phenotype of each of the known inherited neuropathy subgroups, describe algorithms for molecular genetic testing of affected patients and discuss genetic counseling. The basic principles of careful phenotyping, documenting an accurate family history, and testing the available genes in an appropriate manner should identify the vast majority of individuals with CMT1 and many of those with CMT2. In this chapter we also describe the current methods of genetic testing. As advances are made in molecular genetic technologies and improvements are made in bioinformatics, it is likely that the current time-consuming methods of DNA sequencing will give way to quicker and more efficient high-throughput methods, which are briefly discussed here.
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Gaeta M, Mileto A, Mazzeo A, Minutoli F, Di Leo R, Settineri N, Donato R, Ascenti G, Blandino A. MRI findings, patterns of disease distribution, and muscle fat fraction calculation in five patients with Charcot-Marie-Tooth type 2 F disease. Skeletal Radiol 2012; 41:515-24. [PMID: 21611841 DOI: 10.1007/s00256-011-1199-y] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2011] [Revised: 04/12/2011] [Accepted: 05/02/2011] [Indexed: 02/02/2023]
Abstract
PURPOSE To describe the magnetic resonance imaging (MRI) pattern of muscle involvement and disease progression in five patients with late-onset Charcot-Marie-Tooth (CMT) disease type 2 F, due to a previously unknown mutation. MATERIALS AND METHODS Five patients (three males, two females) underwent MRI of the lower limbs to define the pattern of muscle involvement and evaluate the muscle fat fraction (MFF) of residual thigh muscle with gradient-echo (GRE) dual-echo dual-flip angle technique. Evaluation of fatty infiltration both by visual inspection and MFF calculation was performed. RESULTS A proximal-to-distal gradient of muscle involvement was depicted in male patients with extensive muscle wasting of lower legs, less severe impairment of distal thigh muscles, and sparing of proximal thigh muscles. A peculiar phenotype finding was that no or only slight muscle abnormalities could be found in the two female patients. CONCLUSION We described the pattern of muscle involvement and disease progression in a family with CMT disease type 2 F. GRE dual-echo dual-flip angle MRI technique is a valuable technique to obtain a rapid quantification of MFF.
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Affiliation(s)
- Michele Gaeta
- Dipartimento di Scienze Radiologiche, Policlinico G. Martino, Via Consolare Valeria 1, 98125 Messina, Italy
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Charcot–Marie–Tooth diseases. Neurogenetics 2012. [DOI: 10.1017/cbo9781139087711.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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d'Ydewalle C, Krishnan J, Chiheb DM, Van Damme P, Irobi J, Kozikowski AP, Vanden Berghe P, Timmerman V, Robberecht W, Van Den Bosch L. HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease. Nat Med 2011; 17:968-74. [PMID: 21785432 DOI: 10.1038/nm.2396] [Citation(s) in RCA: 364] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2011] [Accepted: 05/10/2011] [Indexed: 12/20/2022]
Abstract
Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system. Mutations in the 27-kDa small heat-shock protein gene (HSPB1) cause axonal CMT or distal hereditary motor neuropathy (distal HMN). We developed and characterized transgenic mice expressing two different HSPB1 mutations (S135F and P182L) in neurons only. These mice showed all features of CMT or distal HMN dependent on the mutation. Expression of mutant HSPB1 decreased acetylated α-tubulin abundance and induced severe axonal transport deficits. An increase of α-tubulin acetylation induced by pharmacological inhibition of histone deacetylase 6 (HDAC6) corrected the axonal transport defects caused by HSPB1 mutations and rescued the CMT phenotype of symptomatic mutant HSPB1 mice. Our findings demonstrate the pathogenic role of α-tubulin deacetylation in mutant HSPB1-induced neuropathies and offer perspectives for using HDAC6 inhibitors as a therapeutic strategy for hereditary axonopathies.
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Recent Advances in the Genetics of Hereditary Axonal Sensory-Motor Neuropathies Type 2. Curr Neurol Neurosci Rep 2011; 11:262-73. [DOI: 10.1007/s11910-011-0185-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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Ikeda Y, Abe A, Ishida C, Takahashi K, Hayasaka K, Yamada M. A clinical phenotype of distal hereditary motor neuronopathy type II with a novel HSPB1 mutation. J Neurol Sci 2009; 277:9-12. [DOI: 10.1016/j.jns.2008.09.031] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2008] [Revised: 09/19/2008] [Accepted: 09/23/2008] [Indexed: 11/24/2022]
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18
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Barisic N, Claeys KG, Sirotković-Skerlev M, Löfgren A, Nelis E, De Jonghe P, Timmerman V. Charcot-Marie-Tooth disease: a clinico-genetic confrontation. Ann Hum Genet 2008; 72:416-41. [PMID: 18215208 DOI: 10.1111/j.1469-1809.2007.00412.x] [Citation(s) in RCA: 115] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Charcot-Marie-Tooth disease (CMT) is the most common neuromuscular disorder. It represents a group of clinically and genetically heterogeneous inherited neuropathies. Here, we review the results of molecular genetic investigations and the clinical and neurophysiological features of the different CMT subtypes. The products of genes associated with CMT phenotypes are important for the neuronal structure maintenance, axonal transport, nerve signal transduction and functions related to the cellular integrity. Identifying the molecular basis of CMT and studying the relevant genes and their functions is important to understand the pathophysiological mechanisms of these neurodegenerative disorders, and the processes involved in the normal development and function of the peripheral nervous system. The results of molecular genetic investigations have impact on the appropriate diagnosis, genetic counselling and possible new therapeutic options for CMT patients.
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Affiliation(s)
- N Barisic
- Department of Pediatrics, Zagreb University Medical School, Zagreb, Croatia.
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19
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Cho HJ, Sung DH, Kim BJ, Ki CS. Mitochondrial GTPase mitofusin 2 mutations in Korean patients with Charcot-Marie-Tooth neuropathy type 2. Clin Genet 2007; 71:267-72. [PMID: 17309650 DOI: 10.1111/j.1399-0004.2007.00763.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Charcot-Marie-Tooth disease (CMT) is classified into two types, the demyelinating (CMT1) and axonal forms (CMT2). CMT2 is further subdivided by linkage analysis into eight subgroups. Recently, mutations in the MFN2 gene, which encodes the mitochondrial GTPase mitofusin 2 (Mfn2) that regulates the mitochondrial network architecture by fusing the mitochondria, were identified in CMT2A patients. This study carried out mutation analysis of the MFN2 gene in 12 unrelated Korean patients suspected of having CMT2 and identified four mutations (Arg94Trp, His165Arg, Ser263Pro, and Ser350Pro). Three mutations were found within the highly conserved GTPase domain that is essential for the function of Mfn2, and one mutation (Ser350Pro) was observed between the GTPase domain and the downstream coiled-coil domain. This suggests that mutations in the MFN2 gene are an important causative gene underlying Korean patients with CMT2, and screening for a mutation in the MFN2 gene is strongly recommended for making a molecular diagnosis of CMT2.
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Affiliation(s)
- H-J Cho
- Department of Laboratory Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-Gu, Seoul, Korea
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20
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Züchner S, Vance JM. Molecular genetics of autosomal-dominant axonal Charcot-Marie-Tooth disease. Neuromolecular Med 2007; 8:63-74. [PMID: 16775367 DOI: 10.1385/nmm:8:1-2:63] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2005] [Revised: 11/18/2005] [Accepted: 11/30/2005] [Indexed: 01/22/2023]
Abstract
The autosomal-dominant axonal peripheral neuropathies comprise a genetically heterogeneous group of disorders that are clinically subsumed under Charcot-Marie-Tooth disease type 2 (CMT2). A significant increase in the number of genes underlying major forms of CMT2 has improved the classification of specific CMT phenotypes. The molecular dissection of cellular functions of the related gene products has only begun and detailed pathophysiological models are still missing, but already the biological scope of genes linked to CMT2 is more diversified than CMT1. The known CMT2 genes present key players in these pathways and will likely prove as powerful tools in identifying eventual future targets for therapeutic intervention.
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Affiliation(s)
- Stephan Züchner
- Center for Human Genetics, Duke University Medical Center, 595 LaSalle Street, Box 3445 DUMC, Durham, NC 27710, USA.
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21
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James PA, Talbot K. The molecular genetics of non-ALS motor neuron diseases. Biochim Biophys Acta Mol Basis Dis 2006; 1762:986-1000. [PMID: 16765570 DOI: 10.1016/j.bbadis.2006.04.003] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2006] [Revised: 03/23/2006] [Accepted: 04/11/2006] [Indexed: 12/11/2022]
Abstract
Hereditary disorders of voluntary motor neurons are individually relatively uncommon, but have the potential to provide significant insights into motor neuron function in general and into the mechanisms underlying the more common form of sporadic Amyotrophic Lateral Sclerosis. Recently, mutations in a number of novel genes have been associated with Lower Motor Neuron (HSPB1, HSPB8, GARS, Dynactin), Upper Motor Neuron (Spastin, Atlastin, Paraplegin, HSP60, KIF5A, NIPA1) or mixed ALS-like phenotypes (Alsin, Senataxin, VAPB, BSCL2). In comparison to sporadic ALS these conditions are usually associated with slow progression, but as experience increases, a wide variation in clinical phenotype has become apparent. At the molecular level common themes are emerging that point to areas of specific vulnerability for motor neurons such as axonal transport, endosomal trafficking and RNA processing. We review the clinical and molecular features of this diverse group of genetically determined conditions and consider the implications for the broad group of motor neuron diseases in general.
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Affiliation(s)
- Paul A James
- Department of Physiology, Anatomy and Genetics, Oxford University, Oxford, UK
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22
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Kijima K, Numakura C, Goto T, Takahashi T, Otagiri T, Umetsu K, Hayasaka K. Small heat shock protein 27 mutation in a Japanese patient with distal hereditary motor neuropathy. J Hum Genet 2005; 50:473-476. [PMID: 16155736 DOI: 10.1007/s10038-005-0280-6] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2005] [Accepted: 07/13/2005] [Indexed: 10/25/2022]
Abstract
Heat shock protein 27 (HSP27) belongs to a family of small heat shock proteins that play significant roles in the cellular stress response and are also involved in the control of protein-protein interactions as chaperons. Mutation in HSP27 has been identified as the cause of axonal Charcot-Marie-Tooth disease (CMT) and distal hereditary motor neuropathy (HMN). Heat shock protein 22 (HSP22) is a molecular counterpart of HSP27, and its mutation is another cause of distal HMN. We screened the mutation of HSP27 and HSP22 in 68 Japanese patients with axonal CMT or unclassified CMT and six Japanese patients with distal HMN. We detected a heterozygous P182S mutation of HSP27 in a patient with distal HMN, but we found no mutations in HSP22. Mutation in HSP27 may impair the formation of the stable neurofilament network that is indispensable for the maintenance of peripheral nerves.
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Affiliation(s)
- Kazuki Kijima
- Department of Pediatrics, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan
| | - Chikahiko Numakura
- Department of Pediatrics, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan
| | - Tomohide Goto
- Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
| | - Takao Takahashi
- Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
| | - Tesshu Otagiri
- Department of Pediatrics, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan
| | - Kazuo Umetsu
- Department of Forensic Medicine, Yamagata University School of Medicine, Yamagata, Japan
| | - Kiyoshi Hayasaka
- Department of Pediatrics, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan.
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Shy ME, Krajewski KM. GENETICS OF NEUROPATHY. Continuum (Minneap Minn) 2005. [DOI: 10.1212/01.con.0000293698.08217.89] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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24
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25
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Greenberg SA, Walsh RJ. Molecular diagnosis of inheritable neuromuscular disorders. Part I: Genetic determinants of inherited disease and their laboratory detection. Muscle Nerve 2005; 31:418-30. [PMID: 15704142 DOI: 10.1002/mus.20278] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Understanding of the genetic basis of inheritable neuromuscular disorders has grown rapidly over the last decade, resulting in improved classification and understanding of their pathogenesis. A consequence of these advances has been the development of genetic tests of blood specimens for the diagnosis of many of these diseases. For many patients, these blood tests have eliminated the need for other more invasive diagnostic tests such as muscle or nerve biopsy, and for some patients, reduced exposure to immunosuppressive medication and its complications. The first part of this review focuses on the nature of genetic disorders, the laboratory methods used in the performance of genetic tests, and general practical aspects of their use and interpretation. The second part discusses the applicability of these tests to the range of neuromuscular disorders.
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Affiliation(s)
- Steven A Greenberg
- Department of Neurology, Division of Neuromuscular Disease, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA.
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27
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Kijima K, Numakura C, Izumino H, Umetsu K, Nezu A, Shiiki T, Ogawa M, Ishizaki Y, Kitamura T, Shozawa Y, Hayasaka K. Mitochondrial GTPase mitofusin 2 mutation in Charcot?Marie?Tooth neuropathy type 2A. Hum Genet 2004; 116:23-7. [PMID: 15549395 DOI: 10.1007/s00439-004-1199-2] [Citation(s) in RCA: 191] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2004] [Accepted: 09/07/2004] [Indexed: 12/31/2022]
Abstract
Charcot-Marie-Tooth disease (CMT) has been classified into two types, CMT1 and CMT2, demyelinating and axonal forms, respectively. CMT2 has been further subdivided into eight groups by linkage studies. CMT2A is linked to chromosome 1p35-p36 and mutation in the kinesin family member 1B-beta (KIF1B) gene had been reported in one pedigree. However, no mutation in KIF1B was detected in other pedigrees with CMT2A and the mutations in the mitochondrial fusion protein mitofusin 2 (MFN2) gene were recently detected in those pedigrees. MFN2, a mitochondrial transmembrane GTPase, regulates the mitochondrial network architecture by fusion of mitochondria. We studied MFN2 in 81 Japanese patients with axonal or unclassified CMT and detected seven mutations in seven unrelated patients. Six of them were novel and one of them was a de novo mutation. Most mutations locate within or immediately upstream of the GTPase domain or within two coiled-coil domains, which are critical for the functioning or mitochondrial targeting of MFN2. Formation of a mitochondrial network would be required to maintain the functional peripheral nerve axon.
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Affiliation(s)
- Kazuki Kijima
- Department of Pediatrics, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan
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28
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Bissar-Tadmouri N, Nelis E, Züchner S, Parman Y, Deymeer F, Serdaroglu P, De Jonghe P, Van Gerwen V, Timmerman V, Schröder JM, Battaloglu E. Absence of KIF1B mutation in a large Turkish CMT2A family suggests involvement of a second gene. Neurology 2004; 62:1522-5. [PMID: 15136675 DOI: 10.1212/01.wnl.0000123253.57555.3a] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Charcot-Marie-Tooth disease type 2A (CMT2A) was assigned to a 19.3-cM region on chromosome 1p35-36. A missense mutation in the kinesin family member 1B gene (KIF1B) was reported in a single CMT2A family. OBJECTIVE To report the clinical and genetic data of a Turkish family with CMT2A. METHODS Linkage to CMT2 loci was investigated in the family. Haplotype analysis of the CMT2A region was completed using additional single-nucleotide polymorphism and short tandem repeat markers. The KIF1B gene was sequenced on genomic DNA and cDNA in two patients. RESULTS A recombination event narrowed the CMT2A locus to a 9.3-cM region flanked by D1S160 and D1S434. No mutation in KIF1B was found. CONCLUSION The exclusion of KIF1B gene mutations in this family suggests the involvement of another CMT2A gene in the linked region.
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Affiliation(s)
- N Bissar-Tadmouri
- Department of Molecular Biology and Genetics, Bogazici University, Istanbul, Turkey
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29
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30
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Evgrafov OV, Mersiyanova I, Irobi J, Van Den Bosch L, Dierick I, Leung CL, Schagina O, Verpoorten N, Van Impe K, Fedotov V, Dadali E, Auer-Grumbach M, Windpassinger C, Wagner K, Mitrovic Z, Hilton-Jones D, Talbot K, Martin JJ, Vasserman N, Tverskaya S, Polyakov A, Liem RKH, Gettemans J, Robberecht W, De Jonghe P, Timmerman V. Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. Nat Genet 2004; 36:602-6. [PMID: 15122254 DOI: 10.1038/ng1354] [Citation(s) in RCA: 442] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2004] [Accepted: 04/12/2004] [Indexed: 01/30/2023]
Abstract
Charcot-Marie-Tooth disease (CMT) is the most common inherited neuromuscular disease and is characterized by considerable clinical and genetic heterogeneity. We previously reported a Russian family with autosomal dominant axonal CMT and assigned the locus underlying the disease (CMT2F; OMIM 606595) to chromosome 7q11-q21 (ref. 2). Here we report a missense mutation in the gene encoding 27-kDa small heat-shock protein B1 (HSPB1, also called HSP27) that segregates in the family with CMT2F. Screening for mutations in HSPB1 in 301 individuals with CMT and 115 individuals with distal hereditary motor neuropathies (distal HMNs) confirmed the previously observed mutation and identified four additional missense mutations. We observed the additional HSPB1 mutations in four families with distal HMN and in one individual with CMT neuropathy. Four mutations are located in the Hsp20-alpha-crystallin domain, and one mutation is in the C-terminal part of the HSP27 protein. Neuronal cells transfected with mutated HSPB1 were less viable than cells expressing the wild-type protein. Cotransfection of neurofilament light chain (NEFL) and mutant HSPB1 resulted in altered neurofilament assembly in cells devoid of cytoplasmic intermediate filaments.
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Affiliation(s)
- Oleg V Evgrafov
- Department of Psychiatry, New York State Psychiatric Institute/Research Foundation for Mental Hygiene, Unit 28, 1051 Riverside Drive, New York, New York 10032, USA.
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31
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Tang BS, Luo W, Xia K, Xiao JF, Jiang H, Shen L, Tang JG, Zhao GH, Cai F, Pan Q, Dai HP, Yang QD, Xia JH, Evgrafov OV. A new locus for autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2L) maps to chromosome 12q24. Hum Genet 2004; 114:527-33. [PMID: 15021985 DOI: 10.1007/s00439-004-1102-1] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2003] [Accepted: 02/02/2004] [Indexed: 01/08/2023]
Abstract
Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neurological disorders with a prevalence estimated at 1/2500. The axonal form of this disorder is referred to as Charcot-Marie-Tooth type 2 disease (CMT2). Recently, a large Chinese family with CMT2 was found in the Hunan and Hubei provinces of China. The known loci for CMT1A, CMT2D, CMT1B (the same locus is also responsible for CMT2I and CMT2J), CMT2A, CMT2E, and CMT2F were excluded in this family by linkage analysis. A genome-wide screening was then carried out, and the results revealed linkage of CMT2 to a locus at chromosome 12q24. Haplotype construction and analyses localized this novel locus to a 6.8-cM interval between microsatellite markers D12S366 and D12S1611. The maximal two-point LOD score of 6.35 and multipoint LOD score of 8.08 for marker D12S76 at a recombination fraction (theta) of 0 strongly supported linkage to this locus. Thus, CMT2 neuropathy in this family represents a novel genetic entity that we have designated as CMT2L.
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Affiliation(s)
- Bei-Sha Tang
- National Laboratory of Medical Genetics of China, Central South University, 410078 Changsha, Hunan, People's Republic of China.
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32
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Züchner S, Vorgerd M, Sindern E, Schröder JM. The novel neurofilament light (NEFL) mutation Glu397Lys is associated with a clinically and morphologically heterogeneous type of Charcot-Marie-Tooth neuropathy. Neuromuscul Disord 2004; 14:147-57. [PMID: 14733962 DOI: 10.1016/j.nmd.2003.10.003] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Charcot-Marie-Tooth disease comprises a heterogeneous group of hereditary neuropathies which fall into two main groups: demyelinating CMT1 with reduced nerve conduction velocity and axonal CMT2 with normal nerve conduction velocity. The neuropathological features correspond in most cases to this classification. Four genes were recently identified to cause autosomal dominant CMT2, including the neurofilament light gene. Thus far, only few mutations have been reported in neurofilament light involving eight amino acids of the gene. We identified a novel mutation, Glu397Lys, in a conserved motive signaling the end of the rod domain. The affected family members from three generations showed strikingly different clinical phenotypes, including weakness of the lower extremities, foot deformities, and deafness. The mutation was associated with nerve conduction velocities ranging from 27 m/s in a 25-year-old female to 43 m/s in an 82-year-old male in the lower extremity motor nerves. Sural nerve biopsies of two affected subjects were analyzed by light and electron microscopy. The pathological changes consisted of a reduction of predominantly large myelinated nerve fibers and various stages of onion bulb formation as typically seen in CMT1. This correlative study further confirms that neurofilament light gene mutations cause a wide clinical spectrum. Thus, analysis of the neurofilament light gene should not be restricted to pure axonal neuropathies.
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Affiliation(s)
- Stephan Züchner
- Institut für Neuropathologie, Universitätsklinikum der RWTH Aachen, Pauwelsstrasse 32, 52074 Aachen, Germany
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33
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Jordanova A, Thomas FP, Guergueltcheva V, Tournev I, Gondim FAA, Ishpekova B, De Vriendt E, Jacobs A, Litvinenko I, Ivanova N, Buzhov B, De Jonghe P, Kremensky I, Timmerman V. Dominant intermediate Charcot-Marie-Tooth type C maps to chromosome 1p34-p35. Am J Hum Genet 2003; 73:1423-30. [PMID: 14606043 PMCID: PMC1180404 DOI: 10.1086/379792] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2003] [Accepted: 09/10/2003] [Indexed: 01/18/2023] Open
Abstract
Dominant intermediate Charcot-Marie-Tooth (DI-CMT) neuropathy is a genetic and phenotypic variant of classical CMT, characterized by intermediate nerve conduction velocities and histological evidence of both axonal and demyelinating features. We report two unrelated families with intermediate CMT linked to a novel locus on chromosome 1p34-p35 (DI-CMTC). The combined haplotype analysis in both families localized the DI-CMTC gene within a 6.3-cM linkage interval flanked by markers D1S2787 and D1S2830. The functional and positional candidate genes, Syndecan 3 (SDC3), and lysosomal-associated multispanning membrane protein 5 (LAPTM5) were excluded for pathogenic mutations.
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Affiliation(s)
- Albena Jordanova
- Molecular Genetics Department, Flanders Interuniversity Institute for Biotechnology, and Division of Neurology, University Hospital of Antwerp, Antwerp; Laboratory of Molecular Pathology and Departments of Neurology and Pediatrics, Sofia Medical University, Sofia; Department of Molecular Microbiology and Immunology, Institute for Molecular Virology, St. Louis VA Medical Center, and Department of Neurology, Saint Louis University, St. Louis
| | - Florian P. Thomas
- Molecular Genetics Department, Flanders Interuniversity Institute for Biotechnology, and Division of Neurology, University Hospital of Antwerp, Antwerp; Laboratory of Molecular Pathology and Departments of Neurology and Pediatrics, Sofia Medical University, Sofia; Department of Molecular Microbiology and Immunology, Institute for Molecular Virology, St. Louis VA Medical Center, and Department of Neurology, Saint Louis University, St. Louis
| | - Velina Guergueltcheva
- Molecular Genetics Department, Flanders Interuniversity Institute for Biotechnology, and Division of Neurology, University Hospital of Antwerp, Antwerp; Laboratory of Molecular Pathology and Departments of Neurology and Pediatrics, Sofia Medical University, Sofia; Department of Molecular Microbiology and Immunology, Institute for Molecular Virology, St. Louis VA Medical Center, and Department of Neurology, Saint Louis University, St. Louis
| | - Ivailo Tournev
- Molecular Genetics Department, Flanders Interuniversity Institute for Biotechnology, and Division of Neurology, University Hospital of Antwerp, Antwerp; Laboratory of Molecular Pathology and Departments of Neurology and Pediatrics, Sofia Medical University, Sofia; Department of Molecular Microbiology and Immunology, Institute for Molecular Virology, St. Louis VA Medical Center, and Department of Neurology, Saint Louis University, St. Louis
| | - Francisco A. A. Gondim
- Molecular Genetics Department, Flanders Interuniversity Institute for Biotechnology, and Division of Neurology, University Hospital of Antwerp, Antwerp; Laboratory of Molecular Pathology and Departments of Neurology and Pediatrics, Sofia Medical University, Sofia; Department of Molecular Microbiology and Immunology, Institute for Molecular Virology, St. Louis VA Medical Center, and Department of Neurology, Saint Louis University, St. Louis
| | - Borjana Ishpekova
- Molecular Genetics Department, Flanders Interuniversity Institute for Biotechnology, and Division of Neurology, University Hospital of Antwerp, Antwerp; Laboratory of Molecular Pathology and Departments of Neurology and Pediatrics, Sofia Medical University, Sofia; Department of Molecular Microbiology and Immunology, Institute for Molecular Virology, St. Louis VA Medical Center, and Department of Neurology, Saint Louis University, St. Louis
| | - Els De Vriendt
- Molecular Genetics Department, Flanders Interuniversity Institute for Biotechnology, and Division of Neurology, University Hospital of Antwerp, Antwerp; Laboratory of Molecular Pathology and Departments of Neurology and Pediatrics, Sofia Medical University, Sofia; Department of Molecular Microbiology and Immunology, Institute for Molecular Virology, St. Louis VA Medical Center, and Department of Neurology, Saint Louis University, St. Louis
| | - An Jacobs
- Molecular Genetics Department, Flanders Interuniversity Institute for Biotechnology, and Division of Neurology, University Hospital of Antwerp, Antwerp; Laboratory of Molecular Pathology and Departments of Neurology and Pediatrics, Sofia Medical University, Sofia; Department of Molecular Microbiology and Immunology, Institute for Molecular Virology, St. Louis VA Medical Center, and Department of Neurology, Saint Louis University, St. Louis
| | - Ivan Litvinenko
- Molecular Genetics Department, Flanders Interuniversity Institute for Biotechnology, and Division of Neurology, University Hospital of Antwerp, Antwerp; Laboratory of Molecular Pathology and Departments of Neurology and Pediatrics, Sofia Medical University, Sofia; Department of Molecular Microbiology and Immunology, Institute for Molecular Virology, St. Louis VA Medical Center, and Department of Neurology, Saint Louis University, St. Louis
| | - Neviana Ivanova
- Molecular Genetics Department, Flanders Interuniversity Institute for Biotechnology, and Division of Neurology, University Hospital of Antwerp, Antwerp; Laboratory of Molecular Pathology and Departments of Neurology and Pediatrics, Sofia Medical University, Sofia; Department of Molecular Microbiology and Immunology, Institute for Molecular Virology, St. Louis VA Medical Center, and Department of Neurology, Saint Louis University, St. Louis
| | - Borjan Buzhov
- Molecular Genetics Department, Flanders Interuniversity Institute for Biotechnology, and Division of Neurology, University Hospital of Antwerp, Antwerp; Laboratory of Molecular Pathology and Departments of Neurology and Pediatrics, Sofia Medical University, Sofia; Department of Molecular Microbiology and Immunology, Institute for Molecular Virology, St. Louis VA Medical Center, and Department of Neurology, Saint Louis University, St. Louis
| | - Peter De Jonghe
- Molecular Genetics Department, Flanders Interuniversity Institute for Biotechnology, and Division of Neurology, University Hospital of Antwerp, Antwerp; Laboratory of Molecular Pathology and Departments of Neurology and Pediatrics, Sofia Medical University, Sofia; Department of Molecular Microbiology and Immunology, Institute for Molecular Virology, St. Louis VA Medical Center, and Department of Neurology, Saint Louis University, St. Louis
| | - Ivo Kremensky
- Molecular Genetics Department, Flanders Interuniversity Institute for Biotechnology, and Division of Neurology, University Hospital of Antwerp, Antwerp; Laboratory of Molecular Pathology and Departments of Neurology and Pediatrics, Sofia Medical University, Sofia; Department of Molecular Microbiology and Immunology, Institute for Molecular Virology, St. Louis VA Medical Center, and Department of Neurology, Saint Louis University, St. Louis
| | - Vincent Timmerman
- Molecular Genetics Department, Flanders Interuniversity Institute for Biotechnology, and Division of Neurology, University Hospital of Antwerp, Antwerp; Laboratory of Molecular Pathology and Departments of Neurology and Pediatrics, Sofia Medical University, Sofia; Department of Molecular Microbiology and Immunology, Institute for Molecular Virology, St. Louis VA Medical Center, and Department of Neurology, Saint Louis University, St. Louis
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34
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Jordanova A, Thomas FP, Guergueltcheva V, Tournev I, Gondim FAA, Ishpekova B, De Vriendt E, Jacobs A, Litvinenko I, Ivanova N, Buzhov B, De Jonghe P, Kremensky I, Timmerman V. Dominant intermediate Charcot-Marie-Tooth type C maps to chromosome 1p34-p35. Am J Hum Genet 2003. [PMID: 14606043 DOI: 10.1086/379792/s0002-9297(07)63991-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Dominant intermediate Charcot-Marie-Tooth (DI-CMT) neuropathy is a genetic and phenotypic variant of classical CMT, characterized by intermediate nerve conduction velocities and histological evidence of both axonal and demyelinating features. We report two unrelated families with intermediate CMT linked to a novel locus on chromosome 1p34-p35 (DI-CMTC). The combined haplotype analysis in both families localized the DI-CMTC gene within a 6.3-cM linkage interval flanked by markers D1S2787 and D1S2830. The functional and positional candidate genes, Syndecan 3 (SDC3), and lysosomal-associated multispanning membrane protein 5 (LAPTM5) were excluded for pathogenic mutations.
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Affiliation(s)
- Albena Jordanova
- Molecular Genetics Department, Flanders Interuniversity Institute for Biotechnology, Antwerp, Belgium
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Kok C, Kennerson ML, Spring PJ, Ing AJ, Pollard JD, Nicholson GA. A locus for hereditary sensory neuropathy with cough and gastroesophageal reflux on chromosome 3p22-p24. Am J Hum Genet 2003; 73:632-7. [PMID: 12870133 PMCID: PMC1180687 DOI: 10.1086/377591] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2003] [Accepted: 06/10/2003] [Indexed: 11/03/2022] Open
Abstract
Hereditary sensory neuropathy type I (HSN I) is a group of dominantly inherited degenerative disorders of peripheral nerve in which sensory features are more prominent than motor involvement. We have described a new form of HSN I that is associated with cough and gastroesophageal reflux. To map the chromosomal location of the gene causing the disorder, a 10-cM genome screen was undertaken in a large Australian family. Two-point analysis showed linkage to chromosome 3p22-p24 (Zmax=3.51 at recombination fraction (theta) 0.0 for marker D3S2338). A second family with a similar phenotype shares a different disease haplotype but segregates at the same locus. Extended haplotype analysis has refined the region to a 3.42-cM interval, flanked by markers D3S2336 and D3S1266.
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Affiliation(s)
- C Kok
- Neurobiology Laboratory, ANZAC Research Institute, University of Sydney, Sydney, Australia.
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Abstract
Since 1886, the year that Charcot and Marie and Tooth described a genetic "peroneal muscular atrophy syndrome," electrophysiological and histological studies of the peripheral nervous system have greatly aided the characterization of this syndrome, which falls among the hereditary sensory-motor neuropathies. Two principal forms of Charcot-Marie-Tooth (CMT) disease have been distinguished: CMT 1, corresponding to a demyelinating type, and CMT 2, corresponding to an axonal type. The modes of transmission of these types are variable, recessive or dominant, autosomal, or X-linked. Our discussion here is confined to the dominant forms. In recent years, advances in molecular biology have greatly modified the approach to CMT disease and related neuropathies (such as hereditary neuropathy with liability to pressure palsies). With increased knowledge of responsible gene mutations and several other loci identified by linkage studies, our understanding of the pathophysiology of these neuropathies is increasing; however, with greater understanding, the classification of these disorders is becoming more complex. In this review we present and discuss the currently characterized subtypes, with emphasis on their known histological aspects. While nerve biopsy has lost its diagnostic importance in certain forms of the disease, such as CMT 1A, CMT 1B, and X-linked CMT (CMT X), it remains important for better characterizing the lesions of CMT 2 and forms of genetic peroneal atrophy in which DNA study is unrevealing.
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Gilbert F. Chromosome 7. GENETIC TESTING 2003; 6:141-61. [PMID: 12215256 DOI: 10.1089/10906570260199429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Affiliation(s)
- Fred Gilbert
- Genetics/Box 93, Weill Medical College of Cornell University, New York, NY 10021, USA.
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Abstract
Inherited neuropathies are common and are usually caused by mutations in genes that are expressed by myelinating Schwann cells or neurons, which is the biological basis for long-standing distinction between primary demyelinating and axonal neuropathies. Neuropathies can be isolated, the primary manifestation of a more complex syndrome, or overshadowed by other aspects of the inherited disease. Increasing knowledge of the molecular-genetic causes of inherited neuropathies facilitates faster, more accurate diagnosis, and sets the stage for development of specific therapeutic interventions.
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Affiliation(s)
- Kleopas A Kleopa
- University of Pennsylvania Medical Center, 3400 Spruce Street, 3 West Gates, Philadelphia, PA 19104, USA.
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Santoro L, Manganelli F, Di Maio L, Barbieri F, Carella M, D'Adamo P, Casari G. Charcot-Marie-Tooth disease type 2C: a distinct genetic entity. Clinical and molecular characterization of the first European family. Neuromuscul Disord 2002; 12:399-404. [PMID: 12062259 DOI: 10.1016/s0960-8966(01)00305-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Charcot- Marie-Tooth disease type 2 is clinically and genetically heterogeneous. A particular clinical subtype of autosomal dominant Charcot-Marie-Tooth disease type 2, characterized by diaphragm and vocal cord paralysis, is labelled Charcot-Marie-Tooth disease type 2C but no genetic locus has been mapped for this form. We describe the first European family affected by Charcot-Marie-Tooth disease type 2C. Genetic analysis excluded linkage to locus of Charcot-Marie-Tooth disease type 2A, B, D, E and F, and to locus of distal hereditary motor neuronopathy type VII. In this family the disease has high penetrance, variable severity and apparently the most severe limb muscle involvement in the youngest generation. Vocal cord paralysis is unrelated to the degree of muscular weakness and patients with the most severe muscle involvement have absent or minimal respiratory symptoms. Charcot-Marie-Tooth disease type 2C is clinically and genetically different from Charcot-Marie-Tooth disease type 2A, B, D, E and F, and is not allelic with distal hereditary motor neuronopathy type VII.
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Affiliation(s)
- L Santoro
- Department of Neurological Sciences, Servizio di Neurofisiopatologia, University of Naples "Federico II", via Sergio Pansini 5, 80131, Naples, Italy.
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