RESUMO
Immunoglobulin Mu-binding protein 2 (IGHMBP2) pathogenic variants result in the fatal, neurodegenerative disease spinal muscular atrophy with respiratory distress type 1 (SMARD1) and the milder, Charcot-Marie-Tooth (CMT) type 2S (CMT2S) neuropathy. More than 20 years after the link between IGHMBP2 and SMARD1 was revealed, and 10 years after the discovery of the association between IGHMBP2 and CMT2S, the pathogenic mechanism of these diseases is still not well defined. The discovery that IGHMBP2 functions as an RNA/DNA helicase was an important step, but it did not reveal the pathogenic mechanism. Helicases are enzymes that use ATP hydrolysis to catalyse the separation of nucleic acid strands. They are involved in numerous cellular processes, including DNA repair and transcription; RNA splicing, transport, editing and degradation; ribosome biogenesis; translation; telomere maintenance; and homologous recombination. IGHMBP2 appears to be a multifunctional factor involved in several cellular processes that regulate gene expression. It is difficult to determine which processes, when dysregulated, lead to pathology. Here, we summarise our current knowledge of the clinical presentation of IGHMBP2-related diseases. We also overview the available models, including yeast, mice and cells, which are used to study the function of IGHMBP2 and the pathogenesis of the related diseases. Further, we discuss the structure of the IGHMBP2 protein and its postulated roles in cellular functioning. Finally, we present potential anomalies that may result in the neurodegeneration observed in IGHMBP2-related disease and highlight the most prominent ones.
Assuntos
Proteínas de Ligação a DNA , Atrofia Muscular Espinal , Fatores de Transcrição , Humanos , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Animais , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/patologia , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Síndrome do Desconforto Respiratório do Recém-Nascido/genéticaRESUMO
Charcot-Marie-Tooth type 2A (CMT2A) is an inherited sensorimotor neuropathy associated with mutations within the Mitofusin 2 (MFN2) gene. These mutations impair normal mitochondrial functioning via different mechanisms, disturbing the equilibrium between mitochondrial fusion and fission, of mitophagy and mitochondrial axonal transport. Although CMT2A disease causes a significant disability, no resolutive treatment for CMT2A patients to date. In this context, reliable experimental models are essential to precisely dissect the molecular mechanisms of disease and to devise effective therapeutic strategies. The most commonly used models are either in vitro or in vivo, and among the latter murine models are by far the most versatile and popular. Here, we critically revised the most relevant literature focused on the experimental models, providing an update on the mammalian models of CMT2A developed to date. We highlighted the different phenotypic, histopathological and molecular characteristics, and their use in translational studies for bringing potential therapies from the bench to the bedside. In addition, we discussed limitations of these models and perspectives for future improvement.
Assuntos
Doença de Charcot-Marie-Tooth , Modelos Animais de Doenças , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Doença de Charcot-Marie-Tooth/terapia , Doença de Charcot-Marie-Tooth/metabolismo , Animais , Humanos , Mutação , Mitocôndrias/metabolismo , Mitocôndrias/genética , Mitocôndrias/patologia , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Camundongos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Dinâmica Mitocondrial/genéticaRESUMO
PAR3/INSC/LGN form an evolutionarily conserved complex required for asymmetric cell division in the developing brain, but its post-developmental function and disease relevance in the peripheral nervous system (PNS) remains unknown. We mapped a new locus for axonal Charcot-Marie-Tooth disease (CMT2) and identified a missense mutation c.209 T > G (p.Met70Arg) in the INSC gene. Modeling the INSCM70R variant in Drosophila, we showed that it caused proprioceptive defects in adult flies, leading to gait defects resembling those in CMT2 patients. Cellularly, PAR3/INSC/LGN dysfunction caused tubulin aggregation and necrotic neurodegeneration, with microtubule-stabilizing agents rescuing both morphological and functional defects of the INSCM70R mutation in the PNS. Our findings underscore the critical role of the PAR3/INSC/LGN machinery in the adult PNS and highlight a potential therapeutic target for INSC-associated CMT2.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Doença de Charcot-Marie-Tooth , Proteínas do Citoesqueleto , Mutação de Sentido Incorreto , Animais , Humanos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Modelos Animais de Doenças , Drosophila/genética , Proteínas Nucleares , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/patologia , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismoRESUMO
OBJECTIVE: To explore the clinical manifestations and genetic basis for a Chinese pedigree affected with atypical Charcot-Marie-Tooth disease type 1 A (CMT1A). METHODS: A patient admitted to the Department of Neurology, Xijing Hospital Affiliated to Air Force Medical University in June 2022 was selected as the study subject. Clinical data of the patient was collected, and 17 family members from four generations of this pedigree were traced based on pes arcuatus and atypical clinical symptoms. Neuroultrasound and genetic testing were carried out on available family members. Whole exome sequencing and multiple ligation-dependent probe amplification assay were carried out for the proband and some of the affected members of the pedigree. RESULTS: The proband, a 15-year-old male, had presented with paroxystic limb pain with weakness, accompanied by pes cavus and hypertrophy of gastrocnemius muscles, without stork leg sign caused by muscles atrophy in the distal lower extremities. MRI has revealed no sign of fat infiltration in the muscles of both legs. Nerve conduction examination had indicated damages of the sensory and motor nerves of the limbs, mainly with demyelinating changes. Seven members of the pedigree had pes arcuatus, including 5 presenting with paroxysmal neuropathic pain and myasthenia in the limbs, whilst 2 were without any clinical symptoms. Neurosonography of the proband, his brother, father and aunt showed thickened peripheral nerves of the extremities with unclear bundle structure. Genetic analysis revealed a large repeat encompassing exons 1 to 5 of the PMP22 gene and flanking regions (chr17: 15133768_15502298) in some of the affected members, which was predicted to be pathogenic. CONCLUSION: The duplication of PMP22 gene was considered to be pathogenic for this CMT1A pedigree.
Assuntos
Doença de Charcot-Marie-Tooth , Masculino , Humanos , Adolescente , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Linhagem , Proteínas da Mielina/genética , Músculo Esquelético , China , Duplicação GênicaRESUMO
PURPOSE: We describe 3 families with Charcot-Marie-Tooth neuropathy (CMT), harboring a homozygous NDUFS6 NM_004553.6:c.309+5G>A variant previously linked to fatal Leigh syndrome. We aimed to characterize clinically and molecularly the newly identified patients and understand the mechanism underlying their milder phenotype. METHODS: The patients underwent extensive clinical examinations. Exome sequencing was done in 4 affected individuals. The functional effect of the c.309+5G>A variant was investigated in patient-derived EBV-transformed lymphoblasts at the complementary DNA, protein, and mitochondrial level. Alternative splicing was evaluated using complementary DNA long-read sequencing. RESULTS: All patients presented with early-onset, slowly progressive axonal CMT, and nystagmus; some exhibited additional central nervous system symptoms. The c.309+5G>A substitution caused the expression of aberrantly spliced transcripts and negligible levels of the canonical transcript. Immunoblotting showed reduced levels of mutant isoforms. No detectable defects in mitochondrial complex stability or bioenergetics were found. CONCLUSION: We expand the clinical spectrum of NDUFS6-related mitochondrial disorders to include axonal CMT, emphasizing the clinical and pathophysiologic overlap between these 2 clinical entities. This work demonstrates the critical role that alternative splicing may play in modulating the severity of a genetic disorder, emphasizing the need for careful consideration when interpreting splice variants and their implications on disease prognosis.
Assuntos
Processamento Alternativo , Doença de Charcot-Marie-Tooth , Doenças Mitocondriais , Humanos , Processamento Alternativo/genética , Masculino , Feminino , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Doenças Mitocondriais/genética , Doenças Mitocondriais/patologia , Criança , NADH Desidrogenase/genética , Linhagem , Mutação/genética , Fenótipo , Sequenciamento do Exoma , Doença de Leigh/genética , Doença de Leigh/patologia , Mitocôndrias/genética , Mitocôndrias/patologia , Complexo I de Transporte de Elétrons/genética , Adulto , Pré-Escolar , AdolescenteRESUMO
The CMT1A variant accounts for over 60% of cases of Charcot-Marie-Tooth disease (CMT), one of the most common human neuropathies. The cause of CMT1A has been identified as the duplication of PMP22, a myelin protein expressed in Schwann cells. Yet, the pathological mechanisms have not been elucidated, and no treatment is currently available. In our study, we established an iPS cell line from a CMT1A patient with PMP22 duplication. The generated iPSCs maintain pluripotency and in vitro differentiation potency.
Assuntos
Doença de Charcot-Marie-Tooth , Células-Tronco Pluripotentes Induzidas , Proteínas da Mielina , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Proteínas da Mielina/genética , Proteínas da Mielina/metabolismo , Linhagem Celular , Diferenciação Celular , Duplicação Gênica , MasculinoRESUMO
BACKGROUND AND OBJECTIVES: Germline truncating variants in the DRP2 gene (encoding dystrophin-related protein 2) cause the disruption of the periaxin-DRP2-dystroglycan complex and have been linked to Charcot-Marie-Tooth disease. However, the causality and the underlying phenotype of the genetic alterations are not clearly defined. METHODS: This cross-sectional retrospective observational study includes 9 patients with Charcot-Marie-Tooth disease (CMT) with DRP2 germline variants evaluated at 6 centers throughout Spain. RESULTS: We identified 7 Spanish families with 4 different DRP2 likely pathogenic germline variants. In agreement with an X-linked inheritance, men harboring hemizygous DRP2 variants presented with an intermediate form of CMT, whereas heterozygous women were asymptomatic. Symptom onset was variable (36.6 ± 16 years), with lower limb weakness and multimodal sensory loss producing a mild-to-moderate functional impairment. Nerve echography revealed an increase in the cross-sectional area of nerve roots and proximal nerves. Lower limb muscle magnetic resonance imaging confirmed the presence of a length-dependent fatty infiltration. Immunostaining in intradermal nerve fibers demonstrated the absence of DRP2 and electron microscopy revealed abnormal myelin thickness that was also detectable in the sural nerve sections. DISCUSSION: Our findings support the causality of DRP2 pathogenic germline variants in CMT and further define the phenotype as a late-onset sensory and motor length-dependent neuropathy, with intermediate velocities and thickening of proximal nerve segments.
Assuntos
Doença de Charcot-Marie-Tooth , Mutação em Linhagem Germinativa , Feminino , Humanos , Masculino , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Bainha de Mielina/patologia , Nervos Periféricos/diagnóstico por imagem , Fenótipo , Estudos Transversais , Estudos Retrospectivos , Linhagem , Adulto Jovem , Pessoa de Meia-Idade , IdosoRESUMO
Haplo-insufficiency of the gene encoding the myelin protein PMP22 leads to focal myelin overgrowth in the peripheral nervous system and hereditary neuropathy with liability to pressure palsies (HNPP). Conversely, duplication of PMP22 causes Charcot-Marie-Tooth disease type 1A (CMT1A), characterized by hypomyelination of medium to large caliber axons. The molecular mechanisms of abnormal myelin growth regulation by PMP22 have remained obscure. Here, we show in rodent models of HNPP and CMT1A that the PI3K/Akt/mTOR-pathway inhibiting phosphatase PTEN is correlated in abundance with PMP22 in peripheral nerves, without evidence for direct protein interactions. Indeed, treating DRG neuron/Schwann cell co-cultures from HNPP mice with PI3K/Akt/mTOR pathway inhibitors reduced focal hypermyelination. When we treated HNPP mice in vivo with the mTOR inhibitor Rapamycin, motor functions were improved, compound muscle amplitudes were increased and pathological tomacula in sciatic nerves were reduced. In contrast, we found Schwann cell dedifferentiation in CMT1A uncoupled from PI3K/Akt/mTOR, leaving partial PTEN ablation insufficient for disease amelioration. For HNPP, the development of PI3K/Akt/mTOR pathway inhibitors may be considered as the first treatment option for pressure palsies.
Assuntos
Artrogripose , Doença de Charcot-Marie-Tooth , Neuropatia Hereditária Motora e Sensorial , Fosfatidilinositol 3-Quinases , Camundongos , Animais , Proteínas Proto-Oncogênicas c-akt , Roedores/metabolismo , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Proteínas da Mielina/genética , Proteínas da Mielina/metabolismo , Serina-Treonina Quinases TORRESUMO
Mutations in Mitofusin2 (MFN2) associated with the pathology of the debilitating neuropathy Charcot-Marie-Tooth type 2A (CMT2A) are known to alter mitochondrial morphology. Previously, such mutations have been shown to elicit two diametrically opposite phenotypes - while some mutations have been causally linked to enhanced mitochondrial fragmentation, others have been shown to induce hyperfusion. Our study identifies one such MFN2 mutant, T206I that causes mitochondrial hyperfusion. Cells expressing this MFN2 mutant have elongated and interconnected mitochondria. T206I-MFN2 mutation in the GTPase domain increases MFN2 stability and renders cells susceptible to stress. We show that cells expressing T206I-MFN2 have a higher predisposition towards mitophagy under conditions of serum starvation. We also detect increased DRP1 recruitment onto the outer mitochondrial membrane, though the total DRP1 protein level remains unchanged. Here we have characterized a lesser studied CMT2A-linked MFN2 mutant to show that its presence affects mitochondrial morphology and homeostasis.
Assuntos
Doença de Charcot-Marie-Tooth , Mitofagia , Humanos , Dinâmica Mitocondrial , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Mitocôndrias/metabolismo , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/metabolismo , Doença de Charcot-Marie-Tooth/patologia , Mutação , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismoRESUMO
Charcot-Marie-Tooth disease 4H(CMT4H) is an autosomal recessive demyelinating form of CMT caused by FGD4/FRABIN mutations. CMT4H is characterized by early onset and slowly progressing motor and sensory deficits in the distal extremities, along with foot deformities. We describe a patient with CMT4H who presented with rapidly progressing flaccid quadriparesis during the postpartum period, which improved significantly with steroid therapy. Magnetic resonance imaging and ultrasonography demonstrated considerable nerve thickening with increased cross-sectional area in the peripheral nerves. A nerve biopsy revealed significant demyelination and myelin outfolding. This is the first report of an Indian patient with a novel homozygous nonsense c.1672C>T (p.Arg558Ter) mutation in the FGD4 gene, expanding the mutational and phenotypic spectrum of this disease.
Assuntos
Doença de Charcot-Marie-Tooth , Feminino , Humanos , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Proteínas dos Microfilamentos/genética , Linhagem , Mutação , Fenótipo , Fatores de Troca do Nucleotídeo Guanina/genéticaRESUMO
Myelin protein zero (MPZ/P0) is a major structural protein of peripheral nerve myelin. Disease-associated variants in the MPZ gene cause a wide phenotypic spectrum of inherited peripheral neuropathies. Previous nerve biopsy studies showed evidence for subtype-specific morphological features. Here, we aimed at enhancing the understanding of these subtype-specific features and pathophysiological aspects of MPZ neuropathies. We examined archival material from two Central European centers and systematically determined genetic, clinical, and neuropathological features of 21 patients with MPZ mutations compared to 16 controls. Cases were grouped based on nerve conduction data into congenital hypomyelinating neuropathy (CHN; n = 2), demyelinating Charcot-Marie-Tooth (CMT type 1; n = 11), intermediate (CMTi; n = 3), and axonal CMT (type 2; n = 5). Six cases had combined muscle and nerve biopsies and one underwent autopsy. We detected four MPZ gene variants not previously described in patients with neuropathy. Light and electron microscopy of nerve biopsies confirmed fewer myelinated fibers, more onion bulbs and reduced regeneration in demyelinating CMT1 compared to CMT2/CMTi. In addition, we observed significantly more denervated Schwann cells, more collagen pockets, fewer unmyelinated axons per Schwann cell unit and a higher density of Schwann cell nuclei in CMT1 compared to CMT2/CMTi. CHN was characterized by basal lamina onion bulb formation, a further increase in Schwann cell density and hypomyelination. Most late onset axonal neuropathy patients showed microangiopathy. In the autopsy case, we observed prominent neuromatous hyperinnervation of the spinal meninges. In four of the six muscle biopsies, we found marked structural mitochondrial abnormalities. These results show that MPZ alterations not only affect myelinated nerve fibers, leading to either primarily demyelinating or axonal changes, but also affect non-myelinated nerve fibers. The autopsy case offers insight into spinal nerve root pathology in MPZ neuropathy. Finally, our data suggest a peculiar association of MPZ mutations with mitochondrial alterations in muscle.
Assuntos
Doença de Charcot-Marie-Tooth , Proteína P0 da Mielina , Humanos , Proteína P0 da Mielina/genética , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Mutação/genética , Proteínas/genética , BiópsiaRESUMO
BACKGROUND The anesthetic management of patients with Charcot-Marie-Tooth disease (CMT) requires special deliberation. Previous literature has suggested that patients with CMT may have increased sensitivity to non-depolarizing neuromuscular blocking agents, and hyperkalemia associated with the administration of succinylcholine has been reported. The potential risk of malignant hyperthermia and underlying cardiopulmonary abnormalities, such as pre-existing arrhythmias, cardiomyopathy, or respiratory muscle weakness, must also be considered in patients with CMT. CASE REPORT We describe a case of a patient with a history of CMT and multivessel coronary artery disease who underwent coronary artery bypass grafting (CABG). Careful consideration was given to the anesthetic plan, which consisted of thorough pre- and perioperative evaluation of cardiac function, total intravenous anesthesia with propofol and remifentanil infusions, the use of a non-depolarizing neuromuscular blocking agent, and utilization of a malignant hyperthermia protocol with avoidance of volatile anesthetics to decrease the possible risk of malignant hyperthermia. Following a 3-vessel CABG, no anesthetic or surgical complications were noted and the patient was discharged on postoperative day 6 after an uneventful hospital course. CONCLUSIONS Exacerbation of underlying cardiac and pulmonary abnormalities associated with the pathophysiology of CMT, as well as patient response to neuromuscular blocking and volatile agents, should be of concern for the anesthesiologist when anesthetizing a patient with CMT. Therefore, CMT patients undergoing surgery require special consideration of their anesthetic management plan in order to ensure patient safety and optimize perioperative outcomes.
Assuntos
Anestésicos , Doença de Charcot-Marie-Tooth , Doença da Artéria Coronariana , Hipertermia Maligna , Humanos , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/cirurgia , Doença de Charcot-Marie-Tooth/complicações , Doença de Charcot-Marie-Tooth/patologia , Hipertermia Maligna/complicações , Ponte de Artéria CoronáriaRESUMO
The neurofilament (NF) cytoskeleton is critical for neuronal morphology and function. In particular, the neurofilament-light (NF-L) subunit is required for NF assembly in vivo and is mutated in subtypes of Charcot-Marie-Tooth (CMT) disease. NFs are highly dynamic, and the regulation of NF assembly state is incompletely understood. Here, we demonstrate that human NF-L is modified in a nutrient-sensitive manner by O-linked-ß-N-acetylglucosamine (O-GlcNAc), a ubiquitous form of intracellular glycosylation. We identify five NF-L O-GlcNAc sites and show that they regulate NF assembly state. NF-L engages in O-GlcNAc-mediated protein-protein interactions with itself and with the NF component α-internexin, implying that O-GlcNAc may be a general regulator of NF architecture. We further show that NF-L O-GlcNAcylation is required for normal organelle trafficking in primary neurons. Finally, several CMT-causative NF-L mutants exhibit perturbed O-GlcNAc levels and resist the effects of O-GlcNAcylation on NF assembly state, suggesting a potential link between dysregulated O-GlcNAcylation and pathological NF aggregation. Our results demonstrate that site-specific glycosylation regulates NF-L assembly and function, and aberrant NF O-GlcNAcylation may contribute to CMT and other neurodegenerative disorders.
Assuntos
Doença de Charcot-Marie-Tooth , Humanos , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Filamentos Intermediários , Mutação , Glicosilação , Acetilglucosamina , Processamento de Proteína Pós-TraducionalRESUMO
BACKGROUND AND AIMS: Neuronal intranuclear inclusion disease (NIID) is a rare progressive neurodegenerative disorder mainly caused by abnormally expanded GGC repeats within the NOTCH2NLC gene. Most patients with NIID show polyneuropathy. Here, we aim to investigate diagnostic electrophysiological markers of NIID. METHODS: In this retrospective dual-center study, we reviewed 96 patients with NOTCH2NLC-related NIID, 94 patients with genetically confirmed Charcot-Marie-Tooth (CMT) disease, and 62 control participants without history of peripheral neuropathy, who underwent nerve conduction studies between 2018 and 2022. RESULTS: Peripheral nerve symptoms were presented by 53.1% of patients with NIID, whereas 97.9% of them showed peripheral neuropathy according to electrophysiological examinations. Patients with NIID were characterized by slight demyelinating sensorimotor polyneuropathy; some patients also showed mild axonal lesions. Motor nerve conduction velocity (MCV) of the median nerve usually exceeded 35 m/s, and were found to be negatively correlated with the GGC repeat sizes. Regarding the electrophysiological differences between muscle weakness type (n = 27) and non-muscle weakness type (n = 69) of NIID, nerve conduction abnormalities were more severe in the muscle weakness type involving both demyelination and axonal impairment. Notably, specific DWI subcortical lace sign was presented in only 33.3% of muscle weakness type, thus it was difficult to differentiate them from CMT. Combining age of onset, distal motor latency, and compound muscle action potential of the median nerve showed the optimal diagnostic performance to distinguish NIID from major CMT (AUC = 0.989, sensitivity = 92.6%, specificity = 97.4%). INTERPRETATION: Peripheral polyneuropathy is common in NIID. Our study suggest that nerve conduction study is useful to discriminate NIID.
Assuntos
Doença de Charcot-Marie-Tooth , Doenças Neurodegenerativas , Humanos , Estudos de Condução Nervosa , Estudos Retrospectivos , Doenças Neurodegenerativas/diagnóstico , Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Debilidade MuscularRESUMO
Type 1 Charcot-Marie-Tooth disease (CMT1) is the most common demyelinating peripheral neuropathy. Patients suffer from progressive muscle weakness and sensory problems. The underlying disease mechanisms of CMT1 are still unclear and no therapy is currently available, hence patients completely rely on supportive care. Balancing protein levels is a complex multistep process fundamental to maintain cells in their healthy state and a disrupted proteostasis is a hallmark of several neurodegenerative diseases. When protein misfolding occurs, protein quality control systems are activated such as chaperones, the lysosomal-autophagy system and proteasomal degradation to ensure proper degradation. However, in pathological circumstances, these mechanisms are overloaded and thereby become inefficient to clear the load of misfolded proteins. Recent evidence strongly indicates that a disbalance in proteostasis plays an important role in several forms of CMT1. In this review, we present an overview of the protein quality control systems, their role in CMT1, and potential treatment strategies to restore proteostasis.
Assuntos
Doença de Charcot-Marie-Tooth , Humanos , Doença de Charcot-Marie-Tooth/metabolismo , Doença de Charcot-Marie-Tooth/patologia , ProteostaseRESUMO
Charcot-Marie-Tooth Disease (CMT) is a commonly inherited peripheral polyneuropathy. Clinical manifestations for this disease include symmetrical distal polyneuropathy, altered deep tendon reflexes, distal sensory loss, foot deformities, and gait abnormalities. Genetic mutations in heat shock proteins have been linked to CMT2. Specifically, mutations in the heat shock protein B1 (HSPB1) gene encoding for heat shock protein 27 (Hsp27) have been linked to CMT2F and distal hereditary motor and sensory neuropathy type 2B (dHMSN2B) subtype. The goal of the study was to examine the role of an endogenous mutation in HSPB1 in vivo and to define the effects of this mutation on motor function and pathology in a novel animal model. As sphingolipids have been implicated in hereditary and sensory neuropathies, we examined sphingolipid metabolism in central and peripheral nervous tissues in 3-month-old HspS139F mice. Though sphingolipid levels were not altered in sciatic nerves from HspS139F mice, ceramides and deoxyceramides, as well as sphingomyelins (SMs) were elevated in brain tissues from HspS139F mice. Histology was utilized to further characterize HspS139F mice. HspS139F mice exhibited no alterations to the expression and phosphorylation of neurofilaments, or in the expression of acetylated α-tubulin in the brain or sciatic nerve. Interestingly, HspS139F mice demonstrated cerebellar demyelination. Locomotor function, grip strength and gait were examined to define the role of HspS139F in the clinical phenotypes associated with CMT2F. Gait analysis revealed no differences between HspWT and HspS139F mice. However, both coordination and grip strength were decreased in 3-month-old HspS139F mice. Together these data suggest that the endogenous S139F mutation in HSPB1 may serve as a mouse model for hereditary and sensory neuropathies such as CMT2F.
Assuntos
Doença de Charcot-Marie-Tooth , Camundongos , Animais , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Proteínas de Choque Térmico/genética , Mutação/genética , Modelos Animais de Doenças , EsfingolipídeosRESUMO
Dominant genetic variants in the mitofusin 2 (MFN2) gene lead to Charcot-Marie-Tooth type 2A (CMT2A), a neurodegenerative disease caused by genetic defects that directly damage axons. In this study, we reported a proband with a pathogenic variant in the GTPase domain of MFN2, c.494A > G (p.His165Arg). To date, at least 184 distinct MFN2 variants identified in 944 independent probands have been reported in 131 references. However, the field of medical genetics has long been challenged by how genetic variation in the MFN2 gene is associated with disease phenotypes. Here, by collating the MFN2 variant data and patient clinical information from Leiden Open Variant Database 3.0, NCBI clinvar database, and available related references in PubMed, we determined the mutation frequency, age of onset, sex ratio, and geographical distribution. Furthermore, the results of an analysis examining the relationship between variants and phenotypes from multiple genetic perspectives indicated that insertion and deletions (indels), copy number variants (CNVs), duplication variants, and nonsense mutations in single nucleotide variants (SNVs) tend to be pathogenic, and the results emphasized the importance of the GTPase domain to the structure and function of MFN2. Overall, three reliable classification methods of MFN2 genotype-phenotype associations provide insights into the prediction of CMT2A disease severity. Of course, there are still many MFN2 variants that have not been given clear clinical significance, which requires clinicians to make more accurate clinical diagnoses.
Assuntos
Doença de Charcot-Marie-Tooth , Doenças Neurodegenerativas , Humanos , Mutação , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , GTP Fosfo-Hidrolases/genética , Estudos de Associação Genética , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/químicaRESUMO
Congenital hypomyelinating polyneuropathy (HPN) restricted to the peripheral nervous system was reported in 1989 in two Golden Retriever (GR) littermates. Recently, four additional cases of congenital HPN in young, unrelated GRs were diagnosed via neurological examination, electrodiagnostic evaluation, and peripheral nerve pathology. Whole-genome sequencing was performed on all four GRs, and variants from each dog were compared to variants found across >1,000 other dogs, all presumably unaffected with HPN. Likely causative variants were identified for each HPN-affected GR. Two cases shared a homozygous splice donor site variant in MTMR2, with a stop codon introduced within six codons following the inclusion of the intron. One case had a heterozygous MPZ isoleucine to threonine substitution. The last case had a homozygous SH3TC2 nonsense variant predicted to truncate approximately one-half of the protein. Haplotype analysis using 524 GR established the novelty of the identified variants. Each variant occurs within genes that are associated with the human Charcot-Marie-Tooth (CMT) group of heterogeneous diseases, affecting the peripheral nervous system. Testing a large GR population (n = >200) did not identify any dogs with these variants. Although these variants are rare within the general GR population, breeders should be cautious to avoid propagating these alleles.
Assuntos
Doença de Charcot-Marie-Tooth , Polineuropatias , Humanos , Animais , Cães , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/veterinária , Doença de Charcot-Marie-Tooth/patologia , Proteínas/genética , Heterozigoto , Polineuropatias/genética , Polineuropatias/veterinária , Alelos , Mutação , Proteínas Tirosina Fosfatases não Receptoras/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteína P0 da Mielina/genéticaRESUMO
Charcot-Marie-Tooth disease (CMT) due to GJB1 variants (CMTX1) is the second most common form of CMT. It is an X-linked disorder characterized by progressive sensory and motor neuropathy with males affected more severely than females. Many reported GJB1 variants remain classified as variants of uncertain significance (VUS). In this large, international, multicentre study we prospectively collected demographic, clinical and genetic data on patients with CMT associated with GJB1 variants. Pathogenicity for each variant was defined using adapted American College of Medical Genetics criteria. Baseline and longitudinal analyses were conducted to study genotype-phenotype correlations, to calculate longitudinal change using the CMT Examination Score (CMTES), to compare males versus females, and pathogenic/likely pathogenic (P/LP) variants versus VUS. We present 387 patients from 295 families harbouring 154 variants in GJB1. Of these, 319 patients (82.4%) were deemed to have P/LP variants, 65 had VUS (16.8%) and three benign variants (0.8%; excluded from analysis); an increased proportion of patients with P/LP variants compared with using ClinVar's classification (74.6%). Male patients (166/319, 52.0%, P/LP only) were more severely affected at baseline. Baseline measures in patients with P/LP variants and VUS showed no significant differences, and regression analysis suggested the disease groups were near identical at baseline. Genotype-phenotype analysis suggested c.-17G>A produces the most severe phenotype of the five most common variants, and missense variants in the intracellular domain are less severe than other domains. Progression of disease was seen with increasing CMTES over time up to 8 years follow-up. Standard response mean (SRM), a measure of outcome responsiveness, peaked at 3 years with moderate responsiveness [change in CMTES (ΔCMTES) = 1.3 ± 2.6, P = 0.00016, SRM = 0.50]. Males and females progressed similarly up to 8 years, but baseline regression analysis suggested that over a longer period, females progress more slowly. Progression was most pronounced for mild phenotypes (CMTES = 0-7; 3-year ΔCMTES = 2.3 ± 2.5, P = 0.001, SRM = 0.90). Enhanced variant interpretation has yielded an increased proportion of GJB1 variants classified as P/LP and will aid future variant interpretation in this gene. Baseline and longitudinal analysis of this large cohort of CMTX1 patients describes the natural history of the disease including the rate of progression; CMTES showed moderate responsiveness for the whole group at 3 years and higher responsiveness for the mild group at 3, 4 and 5 years. These results have implications for patient selection for upcoming clinical trials.