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1.
medRxiv ; 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-39006432

RESUMO

Defects in mitochondrial dynamics are a common cause of Charcot-Marie-Tooth disease (CMT), while primary deficiencies in the mitochondrial respiratory chain (MRC) are rare and atypical for this etiology. This study aims to report COX18 as a novel CMT-causing gene. This gene encodes an assembly factor of mitochondrial Complex IV (CIV) that translocates the C-terminal tail of MTCO2 across the mitochondrial inner membrane. Exome sequencing was performed in four affected individuals. The patients and available family members underwent thorough neurological and electrophysiological assessment. The impact of one of the identified variants on splicing, protein levels, and mitochondrial bioenergetics was investigated in patient-derived lymphoblasts. The functionality of the mutant protein was assessed using a Proteinase K protection assay and immunoblotting. Neuronal relevance of COX18 was assessed in a Drosophila melanogaster knockdown model. Exome sequencing coupled with homozygosity mapping revealed a homozygous splice variant c.435-6A>G in COX18 in two siblings with early-onset progressive axonal sensory-motor peripheral neuropathy. By querying external databases, we identified two additional families with rare deleterious biallelic variants in COX18 . All affected individuals presented with axonal CMT and some patients also exhibited central nervous system symptoms, such as dystonia and spasticity. Functional characterization of the c.435-6A>G variant demonstrated that it leads to the expression of an alternative transcript that lacks exon 2, resulting in a stable but defective COX18 isoform. The mutant protein impairs CIV assembly and activity, leading to a reduction in mitochondrial membrane potential. Downregulation of the COX18 homolog in Drosophila melanogaster displayed signs of neurodegeneration, including locomotor deficit and progressive axonal degeneration of sensory neurons. Our study presents genetic and functional evidence that supports COX18 as a newly identified gene candidate for autosomal recessive axonal CMT with or without central nervous system involvement. These findings emphasize the significance of peripheral neuropathy within the spectrum of primary mitochondrial disorders and the role of mitochondrial CIV in the development of CMT. Our research has important implications for the diagnostic workup of CMT patients.

2.
J Neuromuscul Dis ; 4(4): 293-306, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29125504

RESUMO

BACKGROUND: Recent short-term clinical trials in patients with Duchenne Muscular Dystrophy (DMD) have indicated greater disease variability in terms of progression than expected. In addition, as average life-expectancy increases, reliable data is required on clinical progression in the older DMD population. OBJECTIVE: To determine the effects of corticosteroids on major clinical outcomes of DMD in a large multinational cohort of genetically confirmed DMD patients. METHODS: In this cross-sectional study we analysed clinical data from 5345 genetically confirmed DMD patients from 31 countries held within the TREAT-NMD global DMD database. For analysis patients were categorised by corticosteroid background and further stratified by age. RESULTS: Loss of ambulation in non-steroid treated patients was 10 years and in corticosteroid treated patients 13 years old (p = 0.0001). Corticosteroid treated patients were less likely to need scoliosis surgery (p < 0.001) or ventilatory support (p < 0.001) and there was a mild cardioprotective effect of corticosteroids in the patient population aged 20 years and older (p = 0.0035). Patients with a single deletion of exon 45 showed an increased survival in contrast to other single exon deletions. CONCLUSIONS: This study provides data on clinical outcomes of DMD across many healthcare settings and including a sizeable cohort of older patients. Our data confirm the benefits of corticosteroid treatment on ambulation, need for scoliosis surgery, ventilation and, to a lesser extent, cardiomyopathy. This study underlines the importance of data collection via patient registries and the critical role of multi-centre collaboration in the rare disease field.


Assuntos
Distrofia Muscular de Duchenne/epidemiologia , Distrofia Muscular de Duchenne/terapia , Adolescente , Corticosteroides/uso terapêutico , Adulto , Criança , Pré-Escolar , Estudos Transversais , Bases de Dados como Assunto , Humanos , Lactente , Recém-Nascido , Masculino , Distrofia Muscular de Duchenne/genética , Resultado do Tratamento , Adulto Jovem
3.
Parkinsonism Relat Disord ; 45: 81-84, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28958832

RESUMO

BACKGROUND: GTP cyclohydrolase 1-deficient DOPA-responsive dystonia, caused by autosomal dominant mutation in the gene coding for GTP cyclohydrolase 1, is a rare disorder with a reported prevalence of 0.5 per million. A correct diagnosis of DRD is crucial, given that this is an exquisitely treatable neurogenetic disorder. Although genetic testing is now widely available, we hypothesize that DRD is still underdiagnosed and its prevalence underestimated. METHODS: Molecular genetic analysis of the GCH1 gene was performed in a representative cohort of 47 Serbian patients with clinical features of DRD and in their 16 available relatives. The DRD prevalence rate in Serbia was estimated based on population size, catchment area, and the centralized Serbian referral system for rare diseases. RESULTS: We identified 9 different GCH1 mutations in 23 individuals from 11 families, 5 of which are novel. Patients displayed a broad range of clinical phenotypes. The estimated prevalence of GCH1-related DOPA-responsive dystonia in Serbia was 2.96 per million individuals and there was no evidence for a common founder. CONCLUSIONS: Our data expand the genotypic spectrum of GCH1 and confirm the broad phenotypic spectrum of DRD in the Serbian population. The number of detected mutation carriers in this sample implies that the frequency of DRD in the Serbian population is considerably higher than expected based on published prevalence rates, suggesting that the prevalence of this treatable disease should be revisited also in other populations.


Assuntos
Distúrbios Distônicos/epidemiologia , Distúrbios Distônicos/genética , GTP Cicloidrolase/genética , Fenilcetonúrias/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Prevalência , Sérvia/epidemiologia , Adulto Jovem
4.
Eur J Hum Genet ; 25(5): 572-581, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28295036

RESUMO

Variants in the TTN gene have been associated with distal myopathies and other distinctive phenotypes involving skeletal and cardiac muscle. Through whole-exome sequencing we identified a novel stop-gain variant (c.107635C>T, p.(Gln35879Ter)) in the TTN gene, coding a part of the M-line of titin, in 14 patients with autosomal recessive distal myopathy and Serbian ancestry. All patients share a common 1 Mb core haplotype associated with c.107635C>T, suggesting a founder variant. In compound heterozygotes, nine other TTN variants were identified: four stop-gain, three frameshift, one missense and one splice donor variant. Patients homozygous for the common variant did not show significant clinical differences to the compound heterozygous patients. The clinical presentation of all patients was an adult onset distal myopathy with predominant lower limb involvement. In addition, most patients had normal to mildly elevated serum creatine kinase levels, myopathic electromyograms, normal cardiologic and respiratory tests and muscle pathology consistent with a dystrophic process. In this study, we describe a distinct phenotype for patients with distal myopathy associated with novel recessive TTN variants including a Serbian founder variant. Our results expand the phenotypic and genetic spectrum of titinopathies and will facilitate the diagnosis of this condition in patients of Serbian origin.


Assuntos
Conectina/genética , Miopatias Distais/genética , Efeito Fundador , Distrofias Musculares/genética , Mutação de Sentido Incorreto , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Creatina Quinase/sangue , Miopatias Distais/diagnóstico , Feminino , Frequência do Gene , Genes Recessivos , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Distrofias Musculares/diagnóstico , Fenótipo , Sérvia , Síndrome
5.
Hum Mutat ; 36(4): 395-402, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25604253

RESUMO

Analyzing the type and frequency of patient-specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning, and improved clinical care. Locus-specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations).


Assuntos
Bases de Dados Genéticas , Distrofina/genética , Distrofia Muscular de Duchenne/genética , Mutação , Humanos , Sistema de Registros
6.
Am J Hum Genet ; 95(5): 590-601, 2014 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-25439726

RESUMO

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/patologia
7.
J Neurol ; 261(11): 2192-8, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25182700

RESUMO

Inherited ataxias are heterogeneous disorders affecting both children and adults, with over 40 different causative genes, making molecular genetic diagnosis challenging. Although recent advances in next-generation sequencing have significantly improved mutation detection, few treatments exist for patients with inherited ataxia. In two patients with adult-onset cerebellar ataxia and coenzyme Q10 (CoQ10) deficiency in muscle, whole exome sequencing revealed mutations in ANO10, which encodes anoctamin 10, a member of a family of putative calcium-activated chloride channels, and the causative gene for autosomal recessive spinocerebellar ataxia-10 (SCAR10). Both patients presented with slowly progressive ataxia and dysarthria leading to severe disability in the sixth decade. Epilepsy and learning difficulties were also present in one patient, while retinal degeneration and cataract were present in the other. The detection of mutations in ANO10 in our patients indicate that ANO10 defects cause secondary low CoQ10 and SCAR10 patients may benefit from CoQ10 supplementation.


Assuntos
Ataxia/diagnóstico , Ataxia/genética , Proteínas de Membrana/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Debilidade Muscular/diagnóstico , Debilidade Muscular/genética , Mutação/genética , Ubiquinona/deficiência , Adolescente , Adulto , Anoctaminas , Criança , Feminino , Humanos , Pessoa de Meia-Idade , Ubiquinona/genética , Adulto Jovem
8.
J Neurol ; 261(1): 152-63, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24162038

RESUMO

Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder characterised by the degeneration of motor neurons and progressive muscle weakness. It is caused by homozygous deletions in the survival motor neuron gene on chromosome 5. SMA shows a wide range of clinical severity, with SMA type I patients often dying before 2 years of age, whereas type III patients experience less severe clinical manifestations and can have a normal life span. Here, we describe the design, setup and utilisation of the TREAT-NMD national SMA patient registries characterised by a small, but fully standardised set of registry items and by genetic confirmation in all patients. We analyse a selection of clinical items from the SMA registries in order to provide a snapshot of the clinical data stratified by SMA subtype, and compare these results with published recommendations on standards of care. Our study included 5,068 SMA patients in 25 countries. A total of 615 patients were ventilated, either invasively (178) or non-invasively (437), 439 received tube feeding and 455 had had scoliosis surgery. Some of these interventions were not available to patients in all countries, but differences were also noted among high-income countries with comparable wealth and health care systems. This study provides the basis for further research, such as quality of life in ventilated SMA patients, and will inform clinical trial planning.


Assuntos
Cooperação Internacional , Atrofia Muscular Espinal/epidemiologia , Sistema de Registros/estatística & dados numéricos , Adolescente , Adulto , Fatores Etários , Idoso , Australásia/epidemiologia , Criança , Pré-Escolar , Europa (Continente)/epidemiologia , Feminino , Inquéritos Epidemiológicos , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Atrofia Muscular Espinal/fisiopatologia , América do Norte/epidemiologia , Adulto Jovem
9.
Hum Mutat ; 34(11): 1449-57, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23913485

RESUMO

Duchenne muscular dystrophy (DMD) is an X-linked genetic disease, caused by the absence of the dystrophin protein. Although many novel therapies are under development for DMD, there is currently no cure and affected individuals are often confined to a wheelchair by their teens and die in their twenties/thirties. DMD is a rare disease (prevalence <5/10,000). Even the largest countries do not have enough affected patients to rigorously assess novel therapies, unravel genetic complexities, and determine patient outcomes. TREAT-NMD is a worldwide network for neuromuscular diseases that provides an infrastructure to support the delivery of promising new therapies for patients. The harmonized implementation of national and ultimately global patient registries has been central to the success of TREAT-NMD. For the DMD registries within TREAT-NMD, individual countries have chosen to collect patient information in the form of standardized patient registries to increase the overall patient population on which clinical outcomes and new technologies can be assessed. The registries comprise more than 13,500 patients from 31 different countries. Here, we describe how the TREAT-NMD national patient registries for DMD were established. We look at their continued growth and assess how successful they have been at fostering collaboration between academia, patient organizations, and industry.


Assuntos
Bases de Dados Factuais , Distrofia Muscular de Duchenne , Sistema de Registros , Bases de Dados Factuais/economia , Geografia Médica , Saúde Global , Humanos , Distrofia Muscular de Duchenne/economia , Distrofia Muscular de Duchenne/epidemiologia
10.
Nat Genet ; 44(10): 1080-3, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22961002

RESUMO

Inherited peripheral neuropathies are frequent neuromuscular disorders known for their clinical and genetic heterogeneity. In 33 families, we identified 8 mutations in HINT1 (encoding histidine triad nucleotide-binding protein 1) by combining linkage analyses with next-generation sequencing and subsequent cohort screening of affected individuals. Our study provides evidence that loss of functional HINT1 protein results in a distinct phenotype of autosomal recessive axonal neuropathy with neuromyotonia.


Assuntos
Anormalidades Múltiplas/genética , Neuropatia Hereditária Motora e Sensorial/genética , Mutação de Sentido Incorreto , Miotonia/genética , Proteínas do Tecido Nervoso/genética , Anormalidades Múltiplas/enzimologia , Sequência de Aminoácidos , Animais , Sequência Conservada , Análise Mutacional de DNA , Expressão Gênica , Genes Recessivos , Estudos de Associação Genética , Teste de Complementação Genética , Neuropatia Hereditária Motora e Sensorial/enzimologia , Humanos , Camundongos , Miotonia/enzimologia , Proteínas do Tecido Nervoso/metabolismo , Saccharomyces cerevisiae/enzimologia , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Síndrome
11.
Muscle Nerve ; 46(2): 246-56, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22806374

RESUMO

INTRODUCTION: Giant axonal neuropathy (GAN) is a progressive hereditary disease that affects the peripheral and central nervous systems. It is characterized morphologically by aggregates of intermediate filaments in different tissues. Mutations have been reported in the gene that codes for gigaxonin. Nevertheless, the underlying molecular mechanism remains obscure. METHODS: Cell lines from 4 GAN patients and 4 controls were analyzed by iTRAQ. RESULTS: Among the dysregulated proteins were ribosomal protein L29, ribosomal protein L37, galectin-1, glia-derived nexin, and aminopeptidase N. Also, nuclear proteins linked to formin-binding proteins were found to be dysregulated. Although the major role of gigaxonin is reported to be degradation of cytoskeleton-associated proteins, the amount of 76 structural cytoskeletal proteins was unaltered. CONCLUSIONS: Several of the dysregulated proteins play a role in cytoskeletal reorganization. Based on these findings, we speculate that disturbed cytoskeletal regulation is responsible for formation of aggregates of intermediate filaments.


Assuntos
Axônios/metabolismo , Neuropatia Axonal Gigante/metabolismo , Antígenos CD13/metabolismo , Feminino , Fibroblastos/metabolismo , Galectina 1/metabolismo , Humanos , Masculino , Proteômica , Proteínas Ribossômicas/metabolismo , Serpina E2/metabolismo
12.
Brain ; 131(Pt 5): 1217-27, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18325928

RESUMO

Distal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal alpha-motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; glycyl-tRNA synthetase (GARS), dynactin 1 (DCTN1), small heat shock 27 kDa protein 1 (HSPB1), small heat shock 22 kDa protein 8 (HSPB8), Berardinelli-Seip congenital lipodystrophy (BSCL2) and senataxin (SETX). In addition a mutation in the (VAMP)-associated protein B and C (VAPB) was found in several Brazilian families with complex and atypical forms of autosomal dominantly inherited motor neuron disease. We have investigated the distribution of mutations in these seven genes in a cohort of 112 familial and isolated patients with a diagnosis of distal motor neuropathy and found nine different disease-causing mutations in HSPB8, HSPB1, BSCL2 and SETX in 17 patients of whom 10 have been previously reported. No mutations were found in GARS, DCTN1 and VAPB. The phenotypic features of patients with mutations in HSPB8, HSPB1, BSCL2 and SETX fit within the distal HMN classification, with only one exception; a C-terminal HSPB1-mutation was associated with upper motor neuron signs. Furthermore, we provide evidence for a genetic mosaicism in transmitting an HSPB1 mutation. This study, performed in a large cohort of familial and isolated distal HMN patients, clearly confirms the genetic and phenotypic heterogeneity of distal HMN and provides a basis for the development of algorithms for diagnostic mutation screening in this group of disorders.


Assuntos
Neuropatia Hereditária Motora e Sensorial/genética , Mutação de Sentido Incorreto , Sequência de Bases , Cromossomos Humanos Par 11/genética , DNA Helicases , Eletrofisiologia , Feminino , Subunidades gama da Proteína de Ligação ao GTP/genética , Genótipo , Proteínas de Choque Térmico HSP27 , Haplótipos , Proteínas de Choque Térmico/genética , Neuropatia Hereditária Motora e Sensorial/fisiopatologia , Humanos , Masculino , Chaperonas Moleculares , Mosaicismo , Enzimas Multifuncionais , Proteínas de Neoplasias/genética , Linhagem , Fenótipo , Proteínas Serina-Treonina Quinases/genética , RNA Helicases/genética
13.
Brain ; 131(Pt 3): 747-59, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18180250

RESUMO

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous inherited disorders characterized by impaired neuromuscular transmission. Mutations in the acetylcholinesterase (AChE) collagen-like tail subunit gene (COLQ) cause synaptic basal-lamina associated CMS with end-plate AChE deficiency. Here we present the clinical and molecular genetic findings of 22 COLQ-mutant CMS patients, carrying a total of 20 different COLQ mutations, 11 of them had not previously been reported. Typically, patients with esterase deficiency suffer from a severe, progressive weakness with onset at birth or in early infancy. In addition, patients with a late onset showing a mild course of disease are described. AChE inhibitor therapy, beneficial for other forms of CMS, is of no effect in cases of esterase deficiency. The large cohort of COLQ patients studied here enabled us to define additional clinical presentations associated with COLQ mutations that differ from the 'classical' phenotypes: several patients with disease onset at birth or in early infancy presented an unexpected, mild disease course without significant progression of weakness. Moreover, many patients had clinical features reminiscent of limb-girdle CMS with mutations in the recently discovered DOK7 gene, including sparing of eye movements and a predominantly proximal muscle weakness. There was no long-term objective benefit from esterase inhibitors treatment in COLQ patients. Surprisingly, a short-term beneficial effect was observed in four patients and a Tensilon test was positive in two. Treatment with ephedrine was efficient in all five cases where it was administered. The variability of phenotypes caused by COLQ mutations, the divergence from the previously published classical clinical features and an initial positive response to esterase inhibitors in some patients may obscure AChE deficiency as the molecular cause of the disease and delay the start of appropriate therapy. Moreover, overlap with other CMS subtypes and potentially absence of a repetitive compound muscle action potential should be considered in the diagnosis of COLQ-mutated patients.


Assuntos
Acetilcolinesterase/genética , Colágeno/genética , Proteínas Musculares/genética , Mutação , Síndromes Miastênicas Congênitas/genética , Acetilcolinesterase/deficiência , Potenciais de Ação , Adolescente , Idade de Início , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Biópsia , Criança , Pré-Escolar , Estimulação Elétrica , Movimentos Oculares , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Músculo Esquelético/patologia , Síndromes Miastênicas Congênitas/tratamento farmacológico , Síndromes Miastênicas Congênitas/patologia , Síndromes Miastênicas Congênitas/fisiopatologia , Fenótipo , Resultado do Tratamento
14.
Neuromuscul Disord ; 17(8): 624-30, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17587580

RESUMO

Giant axonal neuropathy (GAN, MIM: 256850) is a devastating autosomal recessive disorder characterized by an early onset severe peripheral neuropathy, varying central nervous system involvement and strikingly frizzly hair. Giant axonal neuropathy is usually caused by mutations in the gigaxonin gene (GAN) but genetic heterogeneity has been demonstrated for a milder variant of this disease. Here, we report ten patients referred to us for molecular genetic diagnosis. All patients had typical clinical signs suggestive of giant axonal neuropathy. In seven affected individuals, we found disease causing mutations in the gigaxonin gene affecting both alleles: two splice-site and four missense mutations, not reported previously. Gigaxonin binds N-terminally to ubiquitin activating enzyme E1 and C-terminally to various microtubule associated proteins causing their ubiquitin mediated degradation. It was shown for a number of gigaxonin mutations that they impede this process leading to accumulation of microtubule associated proteins and there by impairing cellular functions.


Assuntos
Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/patologia , Adolescente , Adulto , Criança , Análise Mutacional de DNA , Éxons/genética , Feminino , Genótipo , Humanos , Imageamento por Ressonância Magnética , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Doenças do Sistema Nervoso Periférico/metabolismo , Fenótipo , Regiões Promotoras Genéticas/genética , Ubiquitina/metabolismo
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