Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 540
Filtrar
2.
Pesqui. bras. odontopediatria clín. integr ; 19(1): 4709, 01 Fevereiro 2019. ilus
Artigo em Inglês | LILACS (Américas), BBO | ID: biblio-998221

RESUMO

Objective: To determine the DUSP6 gene mutation in three generations of Malaysian Malay subjects having Class III malocclusion. Material and Methods: Genetic analyses of DUSP6 gene were carried out in 30 subjects by selecting three individuals representing three generations, respectively, from ten Malaysian Malay families having Class III malocclusion and 30 healthy controls. They were submitted Clinical Evaluation to clinical examination, lateral cephalometric radiographs, dental casts, and/ or facial and intra-oral photographs. Buccal cell was taken from each participant of Class III malocclusion and control groups. DNA extractions from buccal cell were carried out using Gentra puregene buccal cell kit. Bio Edit Sequence Alignment Editor software was used to see the sequencing result. Results: A heterozygous missense mutation c.1094C>T (p. Thr 365 Ile) was identified in DUSP6 gene in three members of one family with Class III malocclusion, whereas no mutation was found in the control group. Conclusion: Current study successfully identified a missense mutation in DUSP6 gene among one Malaysian Malay family affected by Class III malocclusion. The outcome of this study broadened the mutation spectrum of Class III malocclusion and the importance of DUSP6 gene in skeletal functions.


Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto , Variação Genética/genética , Cefalometria/métodos , Mutação de Sentido Incorreto , Má Oclusão , Arábia , Estudos de Casos e Controles , Fotografia Dentária/instrumentação
3.
Artigo em Inglês | WPRIM (Pacífico Ocidental) | ID: wprim-763180

RESUMO

PURPOSE: Partner and localizer of BRCA2 (PALB2) is a breast cancer susceptibility gene that plays an important role in DNA repair. This is the first study assessing the prevalence of PALB2 mutations in early-onset and familial breast/ovarian cancer patients from Pakistan. MATERIALS AND METHODS: PALB2 mutation screening was performed in 370 Pakistani patients with early-onset and familial breast/ovarian cancer, who were negative for BRCA1, BRCA2, TP53, CHEK2, and RAD51C mutations, using denaturing high-performance liquid chromatography analysis. Mutations were confirmed by DNA sequencing. Novel PALB2 alterations were analyzed for their potential effect on protein function or splicing using various in silico prediction tools. Three-hundred and seventy-two healthy controls were screened for the presence of the identified (potentially) functional mutations. RESULTS: A novel nonsense mutation, p.Y743*, was identified in one familial breast cancer patient (1/127, 0.8%). Besides, four in silico-predicted potentially functional mutations including three missense mutations and one 5' untranslated region mutation were identified: p.D498Y, novel p.G644R, novel p.E744K, and novel c.-134_-133delTCinsGGGT. The mutations p.Y743* and p.D498Y were identified in two familial patients diagnosed with unilateral or synchronous bilateral breast cancer at the ages of 29 and 39, respectively. The other mutations were identified in an early-onset (≤ 30 years of age) breast cancer patient each. All five mutations were absent in 372 healthy controls suggesting that they are disease associated. CONCLUSION: Our findings show that PALB2 mutations account for a small proportion of early-onset and hereditary breast/ovarian cancer cases in Pakistan.


Assuntos
Regiões 5' não Traduzidas , Neoplasias da Mama , Cromatografia Líquida , Códon sem Sentido , Simulação por Computador , Reparo do DNA , Mutação em Linhagem Germinativa , Humanos , Programas de Rastreamento , Mutação de Sentido Incorreto , Paquistão , Prevalência , Análise de Sequência de DNA
4.
Artigo | WPRIM (Pacífico Ocidental) | ID: wprim-785404

RESUMO

Tatton-Brown-Rahman Syndrome (TBRS), an overgrowth syndrome caused by heterozygous mutation of DNMT3A, first was described in 2014. Approximately 60 DNMT3A variants, including 32 missense variants, have been reported, with most missense mutations located on the DNMT3A functional domains. Autosomal dominant inheritance by germ-line mutation of DNMT3A has been reported, but vertical transmission within a family is extremely rare. Herein, we report the first Korean family with maternally inherited TBRS due to the novel heterozygous DNMT3A variant c.118G>C p.(Glu40Gln), located outside the main functional domain and identified by multigene panel sequencing. The patient and her mother had typical clinical features, including tall stature during childhood, macrocephaly, intellectual disability, and characteristic facial appearance. TBRS shows milder dysmorphic features than other overgrowth syndromes, potentially leading to underdiagnosis and underestimated prevalence; thus, targeted multigene panel sequencing including DNMT3A will be a useful tool in cases of overgrowth and unexplained mild intellectual disability for early diagnosis and genetic counseling.


Assuntos
Diagnóstico Precoce , Aconselhamento Genético , Mutação em Linhagem Germinativa , Transtornos do Crescimento , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Deficiência Intelectual , Megalencefalia , Mães , Mutação de Sentido Incorreto , Prevalência , Análise de Sequência de DNA , Testamentos
5.
Artigo | WPRIM (Pacífico Ocidental) | ID: wprim-785402

RESUMO

Maturity Onset Diabetes of the Young (MODY) includes a clinically and genetically heterogeneous group of diabetes subtypes with MODY-2 being the second most prevalent form. We report 2 cases of MODY-2 identified during the investigation of asymptomatic hyperglycemia. A 12-year-old girl with a familiar history of diabetes (mother, maternal aunt, and maternal grandfather) was referred due to hypercholesterolemia, abnormal fasting glucose (114 mg/dL), and increased levels of glycated haemoglobin (HbA(1c)) (6%) presenting with negative β-cell antibodies. A glucokinase (GCK) heterozygous missense mutation c.364C>T (p.Leu122Phe) in exon 4 was identified in the index patient and in the 3 family members. An obese 9-year-old boy was investigated for elevated fasting glycemic levels (99–126 mg/dL), HbA(1c) rise (6.6%–7.6%), and negative β-cell antibodies. The patient's father, paternal aunt, and paternal grandfather had a history of diabetes during their childhood. A GCK heterozygous missense mutation c.698G>A (p.Cys233Tyr) in exon 7 was identified in the index patient. This variant was only described in another family strongly affected by both MODY and classic autoimmune mediated diabetes, contrary to our case. MODY-2 should be suspected in the presence of early onset of persistent mild fasting hyperglycemia and negative β-cell antibodies associated with a positive family history of diabetes. These cases illustrate the challenging aspects of MODY diagnosis due to possible phenotypic overlap with other types of diabetes. The diagnosis requires a high level of suspicion and GCK genetic screening should be performed in the presence of compatible features. An early diagnosis allows for appropriate management, genetic counselling, and the identification of affected family members.


Assuntos
Anticorpos , Criança , Diabetes Mellitus Tipo 2 , Diagnóstico , Diagnóstico Precoce , Éxons , Jejum , Pai , Feminino , Testes Genéticos , Glucoquinase , Glucose , Avós , Humanos , Hipercolesterolemia , Hiperglicemia , Masculino , Mutação de Sentido Incorreto
6.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wprim-776813

RESUMO

OBJECTIVE@#To identify pathogenic variations of EXT1 and EXT2 genes in two Chinese pedigrees affected with hereditary multiple exostosis (HME).@*METHODS@#Genomic DNA was extracted from peripheral blood samples using a phenol-chloroform method. PCR and Sanger sequencing was conducted to amplify the exons and the flanking intronic regions of the EXT1 and EXT2 genes.@*RESULTS@#DNA sequencing has revealed a heterozygous missense variation c.812A>G (p.Tyr271Cys) in the exon 1 of EXT1 in pedigree 1, and a heterozygous frameshift variation c.1431dup (p.Ser478Leufs*43) in the exon 6 of EXT1 in the proband from pedigree 2. Both variations have co-segregated with the disease phenotype, which was also consistent with previous report.@*CONCLUSION@#Two heterozygous pathogenic variations underlying HME have been identified. The result has facilitated genetic counseling and prenatal diagnosis for the affected pedigrees.


Assuntos
Grupo com Ancestrais do Continente Asiático , Sequência de Bases , Análise Mutacional de DNA , Exostose Múltipla Hereditária , Genética , Patologia , Mutação da Fase de Leitura , Humanos , Mutação de Sentido Incorreto , N-Acetilglucosaminiltransferases , Genética , Linhagem
7.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wprim-776804

RESUMO

OBJECTIVE@#To explore the molecular basis for a pedigree affected with Darier-White disease.@*METHODS@#Genomic DNA was isolated from 3 patients and 1 unaffected member from the pedigree, as well as 80 healthy controls. Targeted sequence capture and next-generation sequencing were used to screen mutations of skin disease-related genes. Candidate mutations were verified by Sanger sequencing, and co-segregation analysis was carried out to confirm the pathogenicity of mutation. Conservation analysis and protein structure and function were also predicted with Bioinformatic tools.@*RESULTS@#A heterozygous mutation c.2246G>T (p.G749V) was identified in exon 15 of ATP2A2 gene in all 3 patients from the pedigree, but not in the unaffected member or 80 healthy controls. The corresponding amino acid was highly conserved, and mutation of which can lead to structural and functional changes of the protein.@*CONCLUSION@#The c.2246G>T missense mutation of the ATP2A2 gene probably underlies the Darier-White disease in this pedigree by causing damages to the structure and function of sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2).


Assuntos
Doença de Darier , Genética , Heterozigoto , Humanos , Mutação de Sentido Incorreto , Linhagem , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático , Genética
8.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wprim-776768

RESUMO

OBJECTIVE@#To explore the genetic basis of a patient with early-onset Parkinson disease from a consanguineous family.@*METHODS@#Homozygosity mapping and Sanger sequencing of cDNA were used to identify the causative mutation.@*RESULTS@#A homozygous missense variation (c.56C>G, p.Thr19Arg) in the PARK7 gene was identified in the patient. In silico analysis suggested the c.56C>G variation to be pathogenic.@*CONCLUSION@#Homozygous c.56C>G variation of the PARK7 gene was the disease-causing variation in this family.


Assuntos
Consanguinidade , Homozigoto , Humanos , Mutação de Sentido Incorreto , Doença de Parkinson , Genética , Linhagem , Proteína Desglicase DJ-1 , Genética
9.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wprim-776735

RESUMO

OBJECTIVE@#To explore the genetic basis for a pedigree affected with Marfan syndrome (MFS).@*METHODS@#Clinical data of the patients was collected. With genomic DNA extracted from peripheral blood samples, potential mutation was detected by targeted exome sequencing. Candidate variants were validated by Sanger sequencing and bioinformatic analysis.@*RESULTS@#Targeted exome sequencing and Sanger sequencing revealed a missense c.649T to C(p.Trp217Arg) variant in the exon 7 of FBN1 gene, which was unreported previously. Bioinformatics analysis suggested that the variant can cause amino acid replacement and affect the structure and function of fibrillin-1.@*CONCLUSION@#A novel missense variant of the FBN1 gene was identified, which probably underlies the autosomal dominant MFS in this pedigree.


Assuntos
Análise Mutacional de DNA , Éxons , Fibrilina-1 , Genética , Fibrilinas , Humanos , Síndrome de Marfan , Genética , Mutação , Mutação de Sentido Incorreto , Linhagem
10.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wprim-775761

RESUMO

OBJECTIVE@#To identify the pathogenic mutation underlying retinitis pigmentosa in a large pedigree.@*METHODS@#The pedigree has included three generations showing an autosomal dominant transmission of retinitis pigmentosa. Potential mutations were screened using a retinitis pigmentosa gene panel and an Ion PGM platform. Suspected mutation was verified by Sanger sequencing.@*RESULTS@#A novel heterozygous missense mutation, c.251T>C(p.Leu84Pro), was identified in the RHO gene. The mutation has co-segregated with the retinitis pigmentosa phenotype among all family members and was not found in public databases ExAC, 1000G and dbSNP or 831 healthy controls. The mutation was predicted to be damaging by three major protein-predicting software.@*CONCLUSION@#The c.251T>C (p.Leu84Pro) mutation of the RHO gene is a novel pathogenic mutation underlying the retinitis pigmentosa phenotype in this pedigree. Above findings have enabled prenatal diagnosis for the pedigree.


Assuntos
Análise Mutacional de DNA , Proteínas do Olho , Humanos , Mutação , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Retinite Pigmentosa , Genética
11.
Artigo em Coreano | WPRIM (Pacífico Ocidental) | ID: wprim-766770

RESUMO

Congenital fiber type disproportion (CFTD) has been related with mutations in ACTA1, SEPN1, RYR1 and tropomyosin 3 (TPM3) genes. Particularly, TPM3 mutation was identified as one of the most frequent cause of CFTD and was also detected in cap myopathy and nemaline myopathy. Herein we report patients of autosomal dominant TPM3 missense mutations with CFTD in a Korean family over twogenerations. Two of our patients, who developed mild muscle weakness in infancy, presented with altered mentality and respiratory distress despite relatively mild limb weakness.


Assuntos
Extremidades , Humanos , Debilidade Muscular , Doenças Musculares , Mutação de Sentido Incorreto , Miopatias da Nemalina , Miopatias Congênitas Estruturais , Insuficiência Respiratória , Canal de Liberação de Cálcio do Receptor de Rianodina , Tropomiosina
12.
Artigo em Inglês | WPRIM (Pacífico Ocidental) | ID: wprim-761870

RESUMO

Concomitant Loeys-Dietz syndrome (LDS) and hematologic malignancies are exceptionally rare. This is the first report of a patient operated on for aortic root dilation who had been previously diagnosed with LDS and B-cell-lymphoma. After completion of chemotherapy and complete remission, an elective valve-sparing aortic root replacement (using the David-V method) was performed. Due to the positive family history, pre-operative genetic counseling was conducted, and revealed LDS with a TGFBR1 (transforming growth factor beta receptor type I) mutation in 6 probands of the family, albeit in 1 of them posthumously. This missense mutation has been previously described in relation to aortic dissection, but a causative relationship to malignancy has so far neither been proposed nor proven.


Assuntos
Aneurisma da Aorta Torácica , Tratamento Farmacológico , Aconselhamento Genético , Neoplasias Hematológicas , Humanos , Síndrome de Loeys-Dietz , Linfoma de Células B , Mutação de Sentido Incorreto
13.
Artigo em Inglês | WPRIM (Pacífico Ocidental) | ID: wprim-766018

RESUMO

BACKGROUND: Most triple-negative breast cancers (TNBCs) have a high histologic grade, are associated with high endoplasmic stress, and possess a high frequency of TP53 mutations. TP53 missense mutations lead to the production of mutant p53 protein and usually show high levels of p53 protein expression. Tumor-infiltrating lymphocytes (TILs) accumulate as part of the anti-tumor immune response and have a strong prognostic and predictive significance in TNBC. We aimed to elucidate the association between p53 expression and the amount of TILs in TNBC. METHODS: In 678 TNBC patients, we evaluated TIL levels and expression of endoplasmic stress molecules. Immunohistochemical examination of p53 protein expression was categorized into three groups: no, low, and high expression. RESULTS: No, low, and high p53 expression was identified in 44.1% (n = 299), 20.1% (n = 136), and 35.8% (n = 243) of patients, respectively. Patients with high p53 expression showed high histologic grade (p < .001), high TIL levels (p = .009), and high expression of endoplasmic reticulum stress-associated molecules (p-eIF2a, p = .013; XBP1, p = .007), compared to patients with low p53 expression. There was no significant difference in disease-free (p = .406) or overall survival rates (p = .444) among the three p53 expression groups. CONCLUSIONS: High p53 expression is associated with increased expression of endoplasmic reticulum stress molecules and TIL influx.


Assuntos
Neoplasias da Mama , Retículo Endoplasmático , Estresse do Retículo Endoplasmático , Humanos , Linfócitos do Interstício Tumoral , Mutação de Sentido Incorreto , Taxa de Sobrevida , Neoplasias de Mama Triplo Negativas
14.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wprim-772120

RESUMO

OBJECTIVE@#To investigate the molecular genetic mechanism of Charcot- Marie-Tooth (CMT) disease in a pedigree.@*METHODS@#Genomic DNA was extracted from the peripheral blood of the family members of a pedigree with autosomal dominant CMT disease, and 65 candidate genes of the proband were screened using target exon capture and the next generation sequencing, and the suspicious genes were verified using Sanger sequencing. PolyPhen-2, PROVEAN and SIFT software were used to predict the function of the mutant genes, and PyMOL-1 software was used to simulate the mutant protein structure.@*RESULTS@#A heterozygous missense mutation [c.371A>G (p.Y124C)] was detected in exon 3 of gene of the proband. This heterozygous mutation was also detected in both the proband's mother and her brother, but not in her father. Multiple sequence alignment analysis showed that tyrosine at codon 124 of GDAP1 protein was highly conserved. All the 3 prediction software predicted that the mutation was harmful. Molecular structure simulation showed a weakened interaction force between the amino acid residues at codon 124 and the surrounding amino acid residues to affect the overall stability of the protein.@*CONCLUSIONS@#The mutation of gene may be related to the pathogenesis of autosomal dominant AD-CMT in this pedigree. The newly discovered c.371A>G mutation (p.Y124C) expands the mutation spectrum of gene, but further study is needed to clarify the underlying pathogenesis.


Assuntos
Aminoácidos , Doença de Charcot-Marie-Tooth , Genética , Feminino , Genes Dominantes , Genética , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Métodos , Humanos , Masculino , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso , Genética , Linhagem , Software
15.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wprim-771991

RESUMO

OBJECTIVE@#To report on the clinical pictures of 7 patients from a pedigree affected with X-linked adrenal hypoplasia congenita (XL-AHC) and hypogonadotropic hypogonadism (HH) and the underlying mutations.@*METHODS@#Seven patients were identified from a four-generation pedigree affected with XL-AHC and HH. Their clinical features, endocrinological changes, treatment and drug response were recorded. The patients were subjected to next-generation sequencing, and the result was verified by Sanger sequencing. PolyPhen-2 was used for predicting the influence of the mutation on protein production.@*RESULTS@#Three deceased patients had manifested adrenal insufficiency (AI) within one year after birth. Two died at 6 and one died at 12. The four survivors presented with salient clinical and endocrinological features of AHC and HH, adrenal and testicular atrophy, and renin-angiotensin compensation. Two adult patients had testicular micro-stone detected by ultrasound.One of them also had remarkable seminiferous tubule degeneration by biopsy. The patients were followed up for 0.5 to 10 years. All required hyper-physiological dose of hydrocortisone to stabilize their clinical condition. In three patients, gonadotropic or androgen replacement induced cardinal masculine development but with unsatisfactory testis growth and sperm production.Genetic analysis revealed a novel missense c.827A>C (p.Q276P) mutation in a hotspot region within a highly conserved domain. PolyPhen-2 predicted the mutation to be highly hazardous.@*CONCLUSION@#The novel p.Q276P mutation of the DAX1 gene probably underlies the XL-AHC and HH in this pedigree with variable clinical presentations in the patients.


Assuntos
Insuficiência Adrenal , Receptor Nuclear Órfão DAX-1 , Genética , Humanos , Hipoadrenocorticismo Familiar , Genética , Masculino , Mutação , Mutação de Sentido Incorreto , Linhagem , Proteínas Repressoras
16.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wprim-775836

RESUMO

OBJECTIVE@#To explore the characteristics of PAH gene variants among 113 phenylketonuria patients from Henan Province.@*METHODS@#The 13 exons of the PAH gene were subjected to PCR amplification and direct sequencing. Large fragment deletion and duplication of the PAH gene were detected with a multiple ligation-dependent probe amplification (MLPA) assay.@*RESULTS@#In total 195 point variants and 3 large fragment deletions were detected among the 226 alleles, with the detection rates being 86.28% and 1.33%, respectively. Variants of p.Arg243Gln (18.14%), p.Arg111X (6.19%), p.Arg53His (5.31%), EX6-96A>G (5.31%), p.Tyr356X (4.87%) and p.Val399Val (4.42%) were relatively common. Most of the variants were located in exons 7, 11, 3 and 6. Missense variations were most common. Four novel variations were detected, which included c.1016C>A (p.Ser339Tyr), c.1000T>C (p.Cys334Arg), c.1110G>T (p.Glu370Asp), and IVS6+1G>T.@*CONCLUSION@#The PAH gene variations in Henan Province have featured extensive allelic heterogeneity and variety.


Assuntos
China , Éxons , Humanos , Mutação de Sentido Incorreto , Fenilalanina Hidroxilase , Genética , Fenilcetonúrias , Genética , Mutação Puntual , Deleção de Sequência
17.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wprim-775825

RESUMO

OBJECTIVE@#To carry out variant analysis for a Chinese boy featuring dyshormonogenesis due to congenital hypothyroidism.@*METHODS@#DNA of the patient and his parents was extracted and sequenced by high-throughput sequencing. The results were validated with Sanger sequencing and analyzed with Bioinformatics software.@*RESULTS@#Sequencing result showed that the patient has carried compound variants of c.2654G>T(p.Arg885Leu) and c.943G>T(p.Gly315X) of the DUOX2 gene, which were inherited respectively from his mother and father.@*CONCLUSION@#The missense mutation c.2654G>T and nonsense mutation c.943G>T probably underlie the disease in this child.


Assuntos
Criança , Hipotireoidismo Congênito , Diagnóstico , Genética , Oxidases Duais , Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Mutação de Sentido Incorreto
18.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wprim-775809

RESUMO

OBJECTIVE@#To explore serological and molecular characteristics of a family trio with weak B phenotype.@*METHODS@#ABO blood type of the family was determined with a serological method. Genotypes of the ABO gene were determined with PCR-sequence specific primer (PCR-SSP). Sequences of exons 6 and 7 of the ABO gene were analyzed by PCR sequence-based testing.@*RESULTS@#Serologically, the proband and her father were determined as B subtype (Bw), while her mother was of O group. The genotypes of the proband and her father were Bw12/O, while her mother was O01/O01. Sequencing of exons 6 and 7 of the ABO gene confirmed that the proband and her father were Bw12/O01. Compared with B101/O01, the Bw12 subtype carried a missense mutation (278C>T) in exon 6 of the ABO gene.@*CONCLUSION@#The 278C>T mutation probably underlies the Bw phenotype and can be transmitted stably.


Assuntos
Sistema ABO de Grupos Sanguíneos , Genética , Alelos , Sequência de Bases , Éxons , Feminino , Genótipo , Humanos , Masculino , Mutação de Sentido Incorreto , Fenótipo , Análise de Sequência de DNA
19.
Artigo em Inglês | WPRIM (Pacífico Ocidental) | ID: wprim-719104

RESUMO

X-linked Charcot-Marie-Tooth disease type 1 (CMTX1) is caused by the mutation in GJB1 gene, characterized by the transient central nervous system involvement and long standing peripheral polyneuropathy which does not fulfill the criteria of demyelination or axonopathy. We describe a 37-year-old man with progressive bilateral leg weakness since his early teen. He suffered transient right hemiparesis, followed by quadriparesis at 14 years of age. When we examined him at 37 years of age, he presented a distal muscle weakness on lower extremities with a sensory symptom. The nerve conduction study demonstrated a motor conduction velocity between 26 and 49 m/s. The whole exome sequencing revealed a novel variant c.136 G>A in GJB1. This report will raise awareness in this rare disease, which is frequently misdiagnosed early in its course.


Assuntos
Adolescente , Adulto , Sistema Nervoso Central , Doença de Charcot-Marie-Tooth , Conexinas , Doenças Desmielinizantes , Exoma , Humanos , Perna (Membro) , Extremidade Inferior , Debilidade Muscular , Mutação de Sentido Incorreto , Condução Nervosa , Paresia , Polineuropatias , Quadriplegia , Doenças Raras
20.
Experimental Neurobiology ; : 550-563, 2018.
Artigo em Inglês | WPRIM (Pacífico Ocidental) | ID: wprim-719049

RESUMO

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is frequently linked to microtubule abnormalities and mitochondrial trafficking defects. Whole exome sequencing (WES) of patient-parent trios has proven to be an efficient strategy for identifying rare de novo genetic variants responsible for sporadic ALS (sALS). Using a trio-WES approach, we identified a de novo RAPGEF2 variant (c.4069G>A, p.E1357K) in a patient with early-onset sALS. To assess the pathogenic effects of this variant, we have used patient-derived skin fibroblasts and motor neuron-specific overexpression of the RAPGEF2-E1357K mutant protein in Drosophila. Patient fibroblasts display reduced microtubule stability and defective microtubule network morphology. The intracellular distribution, ultrastructure, and function of mitochondria are also impaired in patient cells. Overexpression of the RAPGEF2 mutant in Drosophila motor neurons reduces the stability of axonal microtubules and disrupts the distribution of mitochondria to distal axons and neuromuscular junction (NMJ) synapses. We also show that the recruitment of the pro-apoptotic protein BCL2-associated X (BAX) to mitochondria is significantly increased in patient fibroblasts compared with control cells. Finally, increasing microtubule stability through pharmacological inhibition of histone deacetylase 6 (HDAC6) rescues defects in the intracellular distribution of mitochondria and BAX. Overall, our data suggest that the RAPGEF2 variant identified in this study can drive ALS-related pathogenic effects through microtubule dysregulation.


Assuntos
Esclerose Amiotrófica Lateral , Axônios , Drosophila , Exoma , Fibroblastos , Histona Desacetilases , Humanos , Microtúbulos , Mitocôndrias , Neurônios Motores , Proteínas Mutantes , Mutação de Sentido Incorreto , Doenças Neurodegenerativas , Junção Neuromuscular , Pele , Sinapses
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA