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
Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a heritable neurodegenerative disease characterized by rapid respiratory failure within the first months of life and progressive muscle weakness and wasting. Although the causative gene, IGHMBP2, is well defined, information on IGHMBP2 mutations is not always sufficient to diagnose particular patients, as the gene is highly polymorphic and the pathogenicity of many gene variants is unknown. In this study, we generated a simple yeast model to establish the significance of IGHMBP2 variants for disease development, especially those that are missense mutations. We have shown that cDNA of the human gene encodes protein which is functional in yeast cells and different pathogenic mutations affect this functionality. Furthermore, there is a correlation between the phenotype estimated in in vitro studies and our results, indicating that our model may be used to quickly and simply distinguish between pathogenic and non-pathogenic mutations identified in IGHMBP2 in patients.
Assuntos
Atrofia Muscular Espinal , Doenças Neurodegenerativas , Proteínas de Ligação a DNA/genética , Humanos , Atrofia Muscular Espinal/genética , Mutação , Saccharomyces cerevisiae/genética , Fatores de Transcrição/genéticaRESUMO
Charcot-Marie-Tooth disease (CMT) is a heritable neurodegenerative disease that displays great genetic heterogeneity. The genes and mutations that underlie this heterogeneity have been extensively characterized by molecular genetics. However, the molecular pathogenesis of the vast majority of CMT subtypes remains terra incognita. Any attempts to perform experimental therapy for CMT disease are limited by a lack of understanding of the pathogenesis at a molecular level. In this study, we aim to identify the molecular pathways that are disturbed by mutations in the gene encoding GDAP1 using both yeast and human cell, based models of CMT-GDAP1 disease. We found that some mutations in GDAP1 led to a reduced expression of the GDAP1 protein and resulted in a selective disruption of the Golgi apparatus. These structural alterations are accompanied by functional disturbances within the Golgi. We screened over 1500 drugs that are available on the market using our yeast-based CMT-GDAP1 model. Drugs were identified that had both positive and negative effects on cell phenotypes. To the best of our knowledge, this study is the first report of the Golgi apparatus playing a role in the pathology of CMT disorders. The drugs we identified, using our yeast-based CMT-GDAP1 model, may be further used in translational research.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Complexo de Golgi/genética , Proteínas do Tecido Nervoso/genética , Rede trans-Golgi/genética , Doença de Charcot-Marie-Tooth/patologia , Heterogeneidade Genética , Complexo de Golgi/patologia , Células HeLa , Humanos , Modelos Genéticos , Mutação/genética , Linhagem , Relação Estrutura-Atividade , Leveduras/genéticaRESUMO
Charcot-Marie-Tooth (CMT) disease encompasses a group of rare disorders that are characterized by similar clinical manifestations and a high genetic heterogeneity. Such excessive diversity presents many problems. Firstly, it makes a proper genetic diagnosis much more difficult and, even when using the most advanced tools, does not guarantee that the cause of the disease will be revealed. Secondly, the molecular mechanisms underlying the observed symptoms are extremely diverse and are probably different for most of the disease subtypes. Finally, there is no possibility of finding one efficient cure for all, or even the majority of CMT diseases. Every subtype of CMT needs an individual approach backed up by its own research field. Thus, it is little surprise that our knowledge of CMT disease as a whole is selective and therapeutic approaches are limited. There is an urgent need to develop new CMT models to fill the gaps. In this review, we discuss the advantages and disadvantages of yeast as a model system in which to study CMT diseases. We show how this single-cell organism may be used to discriminate between pathogenic variants, to uncover the mechanism of pathogenesis, and to discover new therapies for CMT disease.
Assuntos
Doença de Charcot-Marie-Tooth/patologia , Variação Genética , Saccharomyces cerevisiae/genética , Animais , Doença de Charcot-Marie-Tooth/genética , Modelos Animais de Doenças , Predisposição Genética para Doença , Humanos , Medicina de Precisão , Saccharomyces cerevisiae/crescimento & desenvolvimentoRESUMO
Hereditary motor and sensory neuropathies (HMSN) also called as Charcot-Marie-Tooth disorders (CMT) are extremely heterogeneous group of disorders of peripheral nervous system. Over 80 genes have been reported in different types of CMT. In all CMT affected patients the main symptoms are slowly progressive wasting of the distal muscles of the lower and upper limbs. To date no efficient therapeutic approach basing upon molecular pathology of CMT has been proposed. This review presents the current state of knowledge concerning clinical, molecular pathogenesis and experimental therapy aspects in CMT disorders. Additionally the possibilities resulting from the use of the yeast model to the identification of new therapeutic substances as well as of neurotoxins are also discussed.
Assuntos
Doença de Charcot-Marie-Tooth/terapia , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/metabolismo , Doença de Charcot-Marie-Tooth/patologia , Humanos , Modelos BiológicosRESUMO
Using a combination of exome sequencing and linkage analysis, we investigated an English family with two affected siblings in their 40s with recessive Charcot-Marie Tooth disease type 2 (CMT2). Compound heterozygous mutations in the immunoglobulin-helicase-µ-binding protein 2 (IGHMBP2) gene were identified. Further sequencing revealed a total of 11 CMT2 families with recessively inherited IGHMBP2 gene mutations. IGHMBP2 mutations usually lead to spinal muscular atrophy with respiratory distress type 1 (SMARD1), where most infants die before 1 year of age. The individuals with CMT2 described here, have slowly progressive weakness, wasting and sensory loss, with an axonal neuropathy typical of CMT2, but no significant respiratory compromise. Segregating IGHMBP2 mutations in CMT2 were mainly loss-of-function nonsense in the 5' region of the gene in combination with a truncating frameshift, missense, or homozygous frameshift mutations in the last exon. Mutations in CMT2 were predicted to be less aggressive as compared to those in SMARD1, and fibroblast and lymphoblast studies indicate that the IGHMBP2 protein levels are significantly higher in CMT2 than SMARD1, but lower than controls, suggesting that the clinical phenotype differences are related to the IGHMBP2 protein levels.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Exoma/genética , Modelos Moleculares , Mutação de Sentido Incorreto/genética , Fenótipo , Adulto , Sequência de Bases , Doença de Charcot-Marie-Tooth/patologia , Mapeamento Cromossômico , Feminino , Haplótipos/genética , Humanos , Dados de Sequência Molecular , Linhagem , Mapeamento de Interação de Proteínas , Análise de Sequência de DNA , Nervo Sural/patologiaRESUMO
Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) represent the most common heritable neuromuscular disorders. Molecular diagnostics of CMT1A/HNPP diseases confirm clinical diagnosis, but their value is limited to the clinical course and prognosis. However, no biomarkers of CMT1A/HNPP have been identified. We decided to explore if the LITAF/SIMPLE gene shared a functional link to the PMP22 gene, whose duplication or deletion results in CMT1A and HNPP, respectively. By studying a large cohort of CMT1A/HNPP-affected patients, we found that the LITAF I92V sequence variant predisposes patients to an earlier age of onset of both the CMT1A and HNPP diseases. Using cell transfection experiments, we showed that the LITAF I92V sequence variant partially mislocalizes to the mitochondria in contrast to wild-type LITAF which localizes to the late endosome/lysosomes and is associated with a tendency for PMP22 to accumulate in the cells. Overall, this study shows that the I92V LITAF sequence variant would be a good candidate for a biomarker in the case of the CMT1A/HNPP disorders.
Assuntos
Artrogripose/genética , Doença de Charcot-Marie-Tooth/genética , Neuropatia Hereditária Motora e Sensorial/genética , Proteínas Nucleares/genética , Deleção de Sequência , Fatores de Transcrição/genética , Idade de Início , Animais , Artrogripose/complicações , Artrogripose/diagnóstico , Artrogripose/epidemiologia , Biomarcadores , Células Cultivadas , Doença de Charcot-Marie-Tooth/complicações , Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/epidemiologia , Chlorocebus aethiops , Feminino , Predisposição Genética para Doença , Neuropatia Hereditária Motora e Sensorial/complicações , Neuropatia Hereditária Motora e Sensorial/diagnóstico , Neuropatia Hereditária Motora e Sensorial/epidemiologia , Humanos , Masculino , Mitocôndrias/metabolismo , Proteínas da Mielina/metabolismoRESUMO
Mutations in GDAP1 lead to recessively or dominantly inherited peripheral neuropathies (Charcot-Marie-Tooth disease, CMT), indicating that GDAP1 is essential for the viability of cells in the peripheral nervous system. GDAP1 contains domains characteristic of glutathione-S-transferases (GSTs), is located in the outer mitochondrial membrane and induces fragmentation of mitochondria. We found GDAP1 upregulated in neuronal HT22 cells selected for resistance against oxidative stress. GDAP1 over-expression protected against oxidative stress caused by depletion of the intracellular antioxidant glutathione (GHS) and against effectors of GHS depletion that affect the mitochondrial membrane integrity like truncated BH3-interacting domain death agonist and 12/15-lipoxygenase. Gdap1 knockdown, in contrast, increased the susceptibility of motor neuron-like NSC34 cells against GHS depletion. Over-expression of wild-type GDAP1, but not of GDAP1 with recessively inherited mutations that cause disease and reduce fission activity, increased the total cellular GHS content and the mitochondrial membrane potential up to a level where it apparently limits mitochondrial respiration, leading to reduced mitochondrial Ca(2+) uptake and superoxide production. Fibroblasts from autosomal-recessive CMT4A patients had reduced GDAP1 levels, reduced GHS concentration and a reduced mitochondrial membrane potential. Thus, our results suggest that the potential GST GDAP1 is implicated in the control of the cellular GHS content and mitochondrial activity, suggesting an involvement of oxidative stress in the pathogenesis of CMT4A.
Assuntos
Doença de Charcot-Marie-Tooth/metabolismo , Glutationa/metabolismo , Potencial da Membrana Mitocondrial , Proteínas do Tecido Nervoso/metabolismo , Linhagem Celular , Doença de Charcot-Marie-Tooth/genética , Humanos , Mitocôndrias/metabolismo , Proteínas do Tecido Nervoso/genética , Estresse OxidativoRESUMO
We report on a patient with severe psychomotor disability, numerous dysmorphic features, and congenital malformations resulting from a complex genomic rearrangement on 16q24.1-q24.3 involving a de novo duplication-triplication pattern. To the best of our knowledge, this is the first reported patient presenting with this aberration within the distal chromosome 16q. We suggest that the clinical phenotype of our patient results from over-dosage of genes mapped to the region with duplication/triplication (five genes: FOXF1, FOXC2, ANKRD11, SPG7 and FANCA seem to play a peculiar role). Detailed molecular characterization and documentation of the complex genomic rearrangement observed in the proband and of the clinical presentation are important for accurate genotype-phenotype correlations in genetic counseling. Delineation of the gene map for the terminal region of chromosome 16q will provide insight into this chromosome 16q24.1-q24.3 contiguous gene duplication-triplication syndrome.
Assuntos
Cromossomos Humanos Par 16/genética , Tetrassomia/genética , Dosagem de Genes/genética , Duplicação Gênica/genética , Estudos de Associação Genética/métodos , Aconselhamento Genético/métodos , Humanos , Masculino , Trissomia/genéticaRESUMO
INTRODUCTION: The first episode of hereditary neuropathy with liability to pressure palsy (HNPP) in childhood is rare. METHODS: We analyzed retrospectively the data of 7 patients with a deletion in PMP22 and onset of symptoms before age 18 years. Direct sequencing of the LITAF (lipopolysaccharide-induced tumor necrosis factor) gene was performed in patients and family members. RESULTS: Clinical presentations varied from mononeuropathies to brachial plexopathy, with recurrent episodes in 4 patients. Electrophysiological abnormalities characteristic for HNNP were found in most subjects. Analysis of the LITAF gene revealed an Ile92Val polymorphism in 6 of 7 (86%) probands and 5 of 7 (83%) family members, over 4 times greater frequency than in the general population. CONCLUSIONS: Clinical suspicion of HNPP even when nerve conduction study results do not fulfill HNPP criteria should indicate genetic testing. In our patients, early-onset HNPP was associated frequently with isoleucine92valine LITAF polymorphism.
Assuntos
Artrogripose/genética , Artrogripose/fisiopatologia , Neuropatia Hereditária Motora e Sensorial/genética , Neuropatia Hereditária Motora e Sensorial/fisiopatologia , Condução Nervosa/fisiologia , Proteínas Nucleares/genética , Polimorfismo Genético/genética , Fatores de Transcrição/genética , Adolescente , Fatores Etários , Idade de Início , Artrogripose/diagnóstico , Criança , Pré-Escolar , Eletrofisiologia/métodos , Feminino , Deleção de Genes , Predisposição Genética para Doença/genética , Testes Genéticos , Neuropatia Hereditária Motora e Sensorial/diagnóstico , Humanos , Masculino , Proteínas da Mielina/genética , Estudos RetrospectivosRESUMO
Charcot-Marie-Tooth type 2A disease (CMT2A) caused by mutations in the Mitofusin 2 gene (Mfn2) has been shown to be an early-onset axonal neuropathy with severe clinical course in the majority of the patients. In this study we present a unique phenotype of CMT2A disease characterized by late-onset polyneuropathy with a very mild clinical course. This rare form of CMT2A disease is caused by a new splice-site (c.311+1G>T) mutation within the MFN2 gene. Due to disturbance of the MFN2 splicing process, this mutation generates a short transcript which encodes a very short fragment of MFN2 protein. The c.311+1G>T mutation within the MFN2 gene results in the late -onset CMT2 disease.
Assuntos
Doença de Charcot-Marie-Tooth/genética , GTP Fosfo-Hidrolases/genética , Proteínas Mitocondriais/genética , Idade de Início , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Mutação , Fenótipo , Polônia , Sítios de Splice de RNA/genéticaRESUMO
Early onset hereditary motor and sensory neuropathies are rare disorders encompassing congenital hypomyelinating neuropathy with disease onset in the direct post-natal period and Dejerine-Sottas neuropathy starting in infancy. The clinical spectrum, however, reaches beyond the boundaries of these two historically defined disease entities. De novo dominant mutations in PMP22, MPZ and EGR2 are known to be a typical cause of very early onset hereditary neuropathies. In addition, mutations in several other dominant and recessive genes for Charcot-Marie-Tooth disease may lead to similar phenotypes. To estimate mutation frequencies and to gain detailed insights into the genetic and phenotypic heterogeneity of early onset hereditary neuropathies, we selected a heterogeneous cohort of 77 unrelated patients who presented with symptoms of peripheral neuropathy within the first year of life. The majority of these patients were isolated in their family. We performed systematic mutation screening by means of direct sequencing of the coding regions of 11 genes: MFN2, PMP22, MPZ, EGR2, GDAP1, NEFL, FGD4, MTMR2, PRX, SBF2 and SH3TC2. In addition, screening for the Charcot-Marie-Tooth type 1A duplication on chromosome 17p11.2-12 was performed. In 35 patients (45%), mutations were identified. Mutations in MPZ, PMP22 and EGR2 were found most frequently in patients presenting with early hypotonia and breathing difficulties. The recessive genes FGD4, PRX, MTMR2, SBF2, SH3TC2 and GDAP1 were mutated in patients presenting with early foot deformities and variable delay in motor milestones after an uneventful neonatal period. Several patients displaying congenital foot deformities but an otherwise normal early development carried the Charcot-Marie-Tooth type 1A duplication. This study clearly illustrates the genetic heterogeneity underlying hereditary neuropathies with infantile onset.
Assuntos
Idade de Início , Neuropatia Hereditária Motora e Sensorial/genética , Adolescente , Adulto , Idoso , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Doença de Charcot-Marie-Tooth/fisiopatologia , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Neuropatia Hereditária Motora e Sensorial/patologia , Neuropatia Hereditária Motora e Sensorial/fisiopatologia , Humanos , Lactente , Pessoa de Meia-Idade , Mutação , Fenótipo , Adulto JovemRESUMO
Due to the wide use of channel strut components, manufacturing is implemented in many industrial plants. Standard technology of profiles is based on welding of two parts of the profile and requires the regalvanizing of the joint zone causes. Thus, the production is challenging to automate on a single line. The main idea of the article is to present a concept of a channel strut, a cold-formed continuous metal component with an open or closed profile section. It would serve as a cantilever support instead of a standard solution. In the article, a unique lock system combination is proposed and analyzed both numerically and experimentally to provide steadiness of the strut without welding or other joining techniques. Two main lock shapes-semicircular and triangle-were proposed with some variations in the cutting plane. Analyses were carried out for three main profile cross-sections with different dimensions, based on the current industrial applications. The semicircular type of the lock was found to be the most stable, giving optimal strength to the strut under assumed loading, comparable to traditional solutions. The commercial FEM software MSC Marc was used for the numerical analysis.
RESUMO
Charcot−Marie−Tooth disorders (CMT) represent a highly heterogeneous group of diseases of the peripheral nervous system in which more than 100 genes are involved. In some CMT patients, a few weak sequence variants toward other CMT genes are detected instead of one leading CMT mutation. Thus, the presence of a few variants in different CMT-associated genes raises the question concerning the pathogenic status of one of them. In this study, we aimed to analyze the pathogenic effect of c.664G>A, p.Glu222Lys variant in the GDAP1 gene, whose mutations are known to be causative for CMT type 4A (CMT4A). Due to low penetrance and a rare occurrence limited to five patients from two Polish families affected by the CMT phenotype, there is doubt as to whether we are dealing with real pathogenic mutation. Thus, we aimed to study the pathogenic effect of the c.664G>A, p.Glu222Lys variant in its natural environment, i.e., the neuronal SH-SY5Y cell line. Additionally, we have checked the pathogenic status of p.Glu222Lys in the broader context of the whole exome. We also have analyzed the impact of GDAP1 gene mutations on the morphology of the transfected cells. Despite the use of several tests to determine the pathogenicity of the p.Glu222Lys variant, we cannot point to one that would definitively solve the problem of pathogenicity.
Assuntos
Doença de Charcot-Marie-Tooth , Neuroblastoma , Doença de Charcot-Marie-Tooth/genética , Humanos , Mutação , Proteínas do Tecido Nervoso/genética , FenótipoRESUMO
Charcot-Marie-Tooth disease (CMT) caused by mutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene is characterized by a spectrum of phenotypes. Recurrent nonsense mutations (Q163X and S194X) showing regional distribution segregate with an early onset, severe course of recessive CMT disease with early loss of ambulancy. Missense mutations in GDAP1 have been reported in sporadic CMT cases with variable course of disease, among them the recurrent L239F missense GDAP1 mutation occurring in the European population. Finally, some GDAP1 mutations are associated with a mild form of CMT inherited as an autosomal dominant trait. In this study, we characterize the CMT phenotype in one Polish family with recessive trait of inheritance at the clinical, electrophysiological, morphological, cellular, and genetic level associated with a new Gly327Asp mutation in the GDAP1 gene. In spite of the nature of Gly327Asp mutation (missense), the CMT phenotype associated with this variant may be characterized as an early onset, severe axonal neuropathy, with severe skeletal deformities. The mutation lies within the transmembrane domain of GDAP1 and interferes with the mitochondrial targeting of the protein, similar to the loss of the domain in the previously reported Q163X and S194X mutations. We conclude that the loss of mitochondrial targeting is associated with a severe course of disease. Our study shows that clinical outcome of CMT disease caused by mutations in the GDAP1 gene cannot be predicted solely on the basis of genetic results (missense/nonsense mutations).
Assuntos
Doença de Charcot-Marie-Tooth/genética , Membranas Mitocondriais/metabolismo , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Adulto , Animais , Células COS , Doença de Charcot-Marie-Tooth/metabolismo , Chlorocebus aethiops , Aberrações Cromossômicas , Feminino , Genes Recessivos , Células HeLa , Humanos , Masculino , Mutação de Sentido Incorreto/fisiologia , Linhagem , Transporte Proteico/genética , Adulto JovemRESUMO
Some of the metabolic disorders are manifested by a predominantly expressed symptoms from the single organ, however, they display discrete symptoms from other tissues. Charcot Marie Tooth disease (CMT) divided into demyelinating (CMT1) and axonal (CMT2) subtypes is characterized by a slowly progressive wasting of distal muscles. CMT2A form diagnosis requires identification of mutation in a gene coding for mitofusin 2 (MFN2). Mitofusin 2 is a protein of an outer mitochondrial membrane encoded in the nuclear genome and characterized by numerous biochemical functions. Mfn2 is involved mainly in the fusion of mitochondria and the cooperation between endoplasmic reticulum and mitochondria. It seems probably that Mfn2 possesses also some regulatory functions and takes part in a regulation of respiratory chain activity, transcription of several proteins and in intracellular signals transduction. Mfn2-linked pathology is also observed in diabetes and heart diseases. Here, we aim to show that mitofusin 2 is a protein crucial not only for peripheral nerve disorders but is a one of the common regulator of cell metabolism.
Assuntos
Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Mutação , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/genética , Animais , Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/metabolismo , GTP Fosfo-Hidrolases , Humanos , Doenças do Sistema Nervoso Periférico/metabolismoRESUMO
Charcot-Marie-Tooth disease 2 is an inherited axonal motor and sensory neuropathy. It is very heterogenous, both clinically and genetically. Till present, 15 types of CMT2, 14 loci and 13 genes are known to be causative of CMT2. Studying mechanisms of molecular pathogenesis is very important for finding a therapy for patients but the diversity of proteins involved in pathogenesis makes this very difficult. Proteins involved in molecular pathogenesis are e.g. proteins of the mitochondrial outer membrane with opposite functions (mitofusin 2 and GDAP1) responsible for fusion and fission of the mitochondrial network. Mutations also occur in genes encoding tRNA-synthetases, neuronal cytoskeletal protein, cation channel protein and molecular chaperones. This review presents knowledge of CMT2 and possible pathogenetic mechanisms responsible for the disease.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ciclo Celular/metabolismo , Neuropatia Hereditária Motora e Sensorial/genética , Mutação , Proteínas Nucleares/metabolismo , Doença de Charcot-Marie-Tooth/genética , HumanosRESUMO
Models are practical tools with which to establish the basic aspects of a diseases. They allow systematic research into the significance of mutations, of cellular and molecular pathomechanisms, of therapeutic options and of functions of diseases associated proteins. Thus, disease models are an integral part of the study of enigmatic proteins such as immunoglobulin mu-binding protein 2 (IGHMBP2). IGHMBP2 has been well defined as a helicase, however there is little known about its role in cellular processes. Notably, it is unclear why changes in such an abundant protein lead to specific neuronal disorders including spinal muscular atrophy with respiratory distress type 1 (SMARD1) and Charcot-Marie-Tooth type 2S (CMT2S). SMARD1 is caused by a loss of motor neurons in the spinal cord that results in muscle atrophy and is accompanied by rapid respiratory failure. In contrast, CMT2S manifests as a severe neuropathy, but typically without critical breathing problems. Here, we present the clinical manifestation of IGHMBP2 mutations, function of protein and models that may be used for the study of IGHMBP2-associated disorders. We highlight the strengths and weaknesses of specific models and discuss the orthologs of IGHMBP2 that are found in different systems with regard to their similarity to human IGHMBP2.
Assuntos
Doença de Charcot-Marie-Tooth , Proteínas de Ligação a DNA/fisiologia , Modelos Animais de Doenças , Células-Tronco Pluripotentes Induzidas , Atrofia Muscular Espinal , Síndrome do Desconforto Respiratório do Recém-Nascido , Saccharomyces cerevisiae , Fatores de Transcrição/fisiologia , Animais , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/fisiopatologia , Doença de Charcot-Marie-Tooth/terapia , Proteínas de Ligação a DNA/genética , Humanos , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/fisiopatologia , Atrofia Muscular Espinal/terapia , Síndrome do Desconforto Respiratório do Recém-Nascido/genética , Síndrome do Desconforto Respiratório do Recém-Nascido/fisiopatologia , Síndrome do Desconforto Respiratório do Recém-Nascido/terapia , Fatores de Transcrição/genéticaRESUMO
Mutations in HNRNPA1 encoding heterogeneous nuclear ribonucleoprotein (hnRNP) A1 are a rare cause of amyotrophic lateral sclerosis (ALS) and multisystem proteinopathy (MSP). hnRNPA1 is part of the group of RNA-binding proteins (RBPs) that assemble with RNA to form RNPs. hnRNPs are concentrated in the nucleus and function in pre-mRNA splicing, mRNA stability, and the regulation of transcription and translation. During stress, hnRNPs, mRNA, and other RBPs condense in the cytoplasm to form stress granules (SGs). SGs are implicated in the pathogenesis of (neuro-)degenerative diseases, including ALS and inclusion body myopathy (IBM). Mutations in RBPs that affect SG biology, including FUS, TDP-43, hnRNPA1, hnRNPA2B1, and TIA1, underlie ALS, IBM, and other neurodegenerative diseases. Here, we characterize 4 potentially novel HNRNPA1 mutations (yielding 3 protein variants: *321Eext*6, *321Qext*6, and G304Nfs*3) and 2 known HNRNPA1 mutations (P288A and D262V), previously connected to ALS and MSP, in a broad spectrum of patients with hereditary motor neuropathy, ALS, and myopathy. We establish that the mutations can have different effects on hnRNPA1 fibrillization, liquid-liquid phase separation, and SG dynamics. P288A accelerated fibrillization and decelerated SG disassembly, whereas *321Eext*6 had no effect on fibrillization but decelerated SG disassembly. By contrast, G304Nfs*3 decelerated fibrillization and impaired liquid phase separation. Our findings suggest different underlying pathomechanisms for HNRNPA1 mutations with a possible link to clinical phenotypes.
Assuntos
Esclerose Lateral Amiotrófica/genética , Ribonucleoproteína Nuclear Heterogênea A1/genética , Atrofia Muscular Espinal/genética , Adolescente , Adulto , Criança , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Ribonucleoproteína Nuclear Heterogênea A1/metabolismo , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Grânulos de Estresse/metabolismo , Sequenciamento do Exoma , Adulto JovemRESUMO
Over 40 mutations in the GDAP1 gene have been shown to segregate with Charcot-Marie-Tooth disease (CMT). Among these, only two mutations, i.e., S194X and Q163X have been reported in a sufficient number of CMT families to allow for the construction of reliable phenotype-genotype correlations. Both the S194X and Q163X mutations have been shown to segregate with an early-onset and severe neuropathy resulting in loss of ambulance at the beginning of the second decade of life. In this study, we identified the L239F mutation in the GDAP1 gene in one Bulgarian and five Polish families. We hypothesized that the L239F mutation may result from a founder effect in the European population since this mutation has previously been reported in Belgian, Czech, and Polish patients. In fact, we detected a common disease-associated haplotype within the 8q13-q21 region in the Polish, German, Italian, Czech, and Bulgarian CMT families. Like the previously detected "regional" S194X and Q163X mutations, respectively present in Maghreb countries and in patients of Spanish descent, the L239F mutation seems to be the most common GDAP1 pathogenic variant in the Central and Eastern European population. Given the likely presence of a common ancestor harboring the L239F mutation, we decided to compare the phenotypes of the CMT (L239F) patients collected in this study with those of previously reported cases. In contrast to CMT4A caused by the S194X and Q163X mutations, the CMT phenotype resulting from the L239F substitution represents a milder clinical entity with a long-preserved period of ambulance at least until the end of the second decade of life.