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2.
Stem Cell Res ; 52: 102257, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33626493

RESUMO

Here, we describe the generation of an induced pluripotent stem cell (iPSC) line, from a female patient diagnosed with Parkinson's disease (PD). The patient carries a heterozygous intermediate-length GGC repeat expansions mutation in the NOTCH2NLC gene. Skin fibroblasts were reprogrammed using the non-integrating Sendai virus technology to deliver Klf4, OCT3/4, SOX2 and c-MYC factors. The generated iPSC line (ZZUi020-A) presented with expression of common pluripotency markers, showed potential of differentiating into derivatives of the three germ layers, and displayed a normal karyotype. The clone ZZUi020-A is presented thereafter, it can be used to study the mechanisms underlying NOTCH2NLC-PD pathogenesis.


Assuntos
Células-Tronco Pluripotentes Induzidas , Doença de Parkinson , Diferenciação Celular , Células Cultivadas , Feminino , Camadas Germinativas , Heterozigoto , Humanos , Mutação , Doença de Parkinson/genética
3.
Ann Neurol ; 89(1): 182-187, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33016348

RESUMO

NOTCH2NLC GGC repeat expansions were recently identified in neuronal intranuclear inclusion disease (NIID); however, it remains unclear whether they occur in other neurodegenerative disorders. This study aimed to investigate the role of intermediate-length NOTCH2NLC GGC repeat expansions in Parkinson disease (PD). We screened for GGC repeat expansions in a cohort of 1,011 PD patients and identified 11 patients with intermediate-length repeat expansions ranging from 41 to 52 repeats, with no repeat expansions in 1,134 controls. Skin biopsy revealed phospho-alpha-synuclein deposition, confirming the PD diagnosis in 2 patients harboring intermediate-length repeat expansions instead of NIID or essential tremor. Fibroblasts from PD patients harboring intermediate-length repeat expansions revealed NOTCH2NLC upregulation and autophagic dysfunction. Our results suggest that intermediate-length repeat expansions in NOTCH2NLC are potentially associated with PD. ANN NEUROL 2021;89:182-187.


Assuntos
Doenças Neurodegenerativas/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Adulto , Idoso , Biópsia , Encéfalo/patologia , Estudos de Coortes , Feminino , Humanos , Corpos de Inclusão Intranuclear/metabolismo , Corpos de Inclusão Intranuclear/patologia , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/metabolismo , Linhagem , Receptor Notch2/metabolismo
4.
Cell Death Dis ; 11(9): 727, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908122

RESUMO

Carboxy-terminus of Hsc70-interacting protein (CHIP) functions both as a molecular co-chaperone and ubiquitin E3 ligase playing a critical role in modulating the degradation of numerous chaperone-bound proteins. To date, it has been implicated in the regulation of numerous biological functions, including misfolded-protein refolding, autophagy, immunity, and necroptosis. Moreover, the ubiquitous expression of CHIP in the central nervous system suggests that it may be implicated in a wide range of functions in neurological diseases. Several recent studies of our laboratory and other groups have highlighted the beneficial role of CHIP in the pathogenesis of several neurological diseases. The objective of this review is to discuss the possible molecular mechanisms that contribute to the pathogenesis of neurological diseases in which CHIP has a pivotal role, such as stroke, intracerebral hemorrhage, Alzheimer's disease, Parkinson's disease, and polyglutamine diseases; furthermore, CHIP mutations could also cause neurodegenerative diseases. Based on the available literature, CHIP overexpression could serve as a promising therapeutic target for several neurological diseases.


Assuntos
Doenças do Sistema Nervoso/terapia , Doenças Neurodegenerativas/terapia , Ubiquitina-Proteína Ligases/uso terapêutico , Animais , Humanos , Ubiquitina-Proteína Ligases/farmacologia
6.
Parkinsonism Relat Disord ; 73: 1-2, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32151945

RESUMO

We screened the RFC1 intronic AAGGG repeat expansions in late-onset ataxia cases, MSA patients and controls. The data suggested that no biallelic repeat expansion carrier was found in our cohort and the heterozygous intronic AAGGG repeat expansions may not lead to an increased risk of late-onset ataxia or MSA.


Assuntos
Ataxia Cerebelar/genética , Expansão das Repetições de DNA , Atrofia de Múltiplos Sistemas/genética , Proteína de Replicação C/genética , Adulto , Idade de Início , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
7.
Transl Stroke Res ; 11(2): 296-309, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31325153

RESUMO

Cell death is a hallmark of secondary brain injury following intracerebral hemorrhage (ICH). The E3 ligase CHIP has been reported to play a key role in mediating necroptosis-an important mechanism of cell death after ICH. However, there is currently no evidence supporting a function of CHIP in ICH. In the present study, we aimed to determine whether CHIP plays an essential role in brain injury after ICH. Our findings indicated that CHIP expression was increased in the peri-hematomal area in rat models of ICH. The AAV/BBB viral platform enables non-invasive, widespread, and long-lasting global neural expression of target genes. Treatment with AAV/BBB-CHIP ameliorated brain injury and inhibited neuronal necroptosis and inflammation in wild type (WT) rats following ICH. Furthermore, rats with CHIP deficiency experienced severe brain injury and increased levels of neuronal necroptosis and inflammation relative to their WT counterparts. However, treatment with AAV/BBB-CHIP attenuated the effects of CHIP deficiency after ICH. Collectively, our results demonstrate that CHIP inhibits necroptosis and pathological inflammation following ICH, and that overexpression of CHIP may represent a therapeutic intervention for ICH. Moreover, the AAV/BBB viral platform may provide a novel avenue for the treatment of brain injury.


Assuntos
Lesões Encefálicas/metabolismo , Hemorragia Cerebral/metabolismo , Técnicas de Transferência de Genes , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Lesões Encefálicas/etiologia , Lesões Encefálicas/patologia , Hemorragia Cerebral/complicações , Hemorragia Cerebral/patologia , Vetores Genéticos , Ratos , Transcriptoma
8.
Front Neurol ; 10: 1094, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31749756

RESUMO

Background: Spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease (MJD) is the most common type of autosomal dominant ataxia. Like other neurodegenerative diseases, is characterized by the dysfunction of the protein quality control (PQC) system. The carboxyl terminus of the Hsp70-interacting protein (CHIP), an important component of PQC, participates in the clearance of misfolded proteins to maintain cellular homeostasis. While no cure for SCA3 exists, the disease progresses slowly. Thus, the identification of biomarkers that indicate the severity and prognosis of this disease would be valuable. Methods: In this exploratory case-control study, we quantitatively evaluated the concentrations of CHIP in the sera of 80 patients with SCA3 and 80 age and sex-matched controls, using the enzyme-linked immunosorbent assay (ELISA). CHIP levels in the cerebrospinal fluid (CSF) donated by six patients and six healthy volunteers, who were matched for sex and age were also measured. All the baseline data were collected, and the patients underwent clinical evaluation. The correlations between CHIP levels and several clinical measurements were analyzed. Results: The serum CHIP level in the SCA3 group was (80.93 ± 28.68) ng/mL, which was significantly higher than those in the control group [(40.37 ± 18.55) ng/mL]. Similar results were observed for the CSF [(164.59 ± 42.99) ng/mL and (37.47 ± 7.85) ng/mL, respectively]. CSF CHIP levels were significantly higher than the serum CHIP levels in the SCA3 group but not in the control group. The Dunn-Bonferroni post-hoc for Kruskal-Wallis test revealed no significant difference between the serum and CSF of the patients and the control group. Multivariate linear regression showed that serum CHIP levels correlated positively with disease severity, as measured by the Scale for the Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS). Moreover, we found that serum CHIP levels were moderately correlated with age in healthy controls. Conclusion: The present study determined that CHIP levels increased significantly in the serum and CSF of patients with SCA3 and that serum CHIP levels were corelated with disease severity. Thus, CHIP is a promising biomarker for SCA3.

9.
Front Mol Neurosci ; 12: 159, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31316347

RESUMO

Spinocerebellar ataxia 3, also known as Machado-Joseph disease (SCA3/MJD), is a rare autosomal-dominant neurodegenerative disease caused by an abnormal expansion of CAG repeats in the ATXN3 gene. In the present study, we performed a global metabolomic analysis to identify pathogenic biochemical pathways and novel biomarkers implicated in SCA3 patients. Metabolic profiling of serum samples from 13 preclinical SCA3 patients, 13 symptomatic SCA3 patients, and 15 healthy controls were mapped using ultra-high-performance liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry techniques. The symptomatic SCA3 patients showed a metabolic profile significantly distinct from those of the preclinical SCA3 patients and healthy controls. The principal differential metabolites were involved in the amino acid (AA) metabolism and fatty acid metabolism pathways. In addition, four candidate serum biomarkers, FFA 16:1 (palmitoleic acid), FFA 18:3 (linolenic acid), L-Proline and L-Tryptophan, were selected to discriminate between symptomatic SCA3 patients and healthy controls by receiver operator curve analysis with an area under the curve of 0.979. Our study demonstrates that symptomatic SCA3 patients present distinct metabolic profiles with perturbed AA metabolism and fatty acid metabolism, and FFA 16:1, FFA 18:3, L-Proline and L-Tryptophan are identified as potential disease biomarkers.

10.
Neuromuscul Disord ; 29(7): 549-553, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31255525

RESUMO

Limb-girdle myasthenia with tubular aggregates, a subtype of congenital myasthenic syndrome, is an extremely rare autosomal recessive genetic disease characterized by prominent limb-girdle weakness and good response to acetylcholinesterase inhibitor therapy. Herein, we reported two novel mutations of GFPT1 gene in a Chinese pedigree. Two siblings presented with fatigue, weakness of limb-girdle and decrement of the muscle action potential with repetitive nerve stimulation. Thus, myasthenia gravis was initially suspected, but anti-AChR antibodies were negative. Two novel missense mutations (p.Lys154Asn and p.Asn363Ser) in GFPT1 were identified through genetic testing conducted on 167 well-established genes associated with muscular diseases by targeted high throughput sequencing. Both mutations have not been recorded in the dsSNP database, Exome Aggregation Consortium database and 1000 Genomes Project database. The mutation sites were co-segregated with the phenotype and conserved between the different species. The mutations were not found in the 200 unrelated normal controls. Muscle biopsies revealed tubular aggregates, in accordance with previous reports with GFPT1 mutations. Subsequently, dramatic improvement in strength occurred following anti-cholinesterase therapy. Our study will be helpful for the diagnosis and treatment for Limb-girdle myasthenia with tubular aggregates.


Assuntos
Glutamina-Frutose-6-Fosfato Transaminase (Isomerizante)/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Mutação de Sentido Incorreto/genética , Miopatias Congênitas Estruturais/genética , Potenciais de Ação , Animais , Inibidores da Colinesterase/uso terapêutico , Bases de Dados Genéticas , Estimulação Elétrica , Feminino , Testes Genéticos , Humanos , Masculino , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/tratamento farmacológico , Distrofia Muscular do Cíngulo dos Membros/patologia , Miopatias Congênitas Estruturais/tratamento farmacológico , Miopatias Congênitas Estruturais/patologia , Linhagem , Polimorfismo de Nucleotídeo Único , Brometo de Piridostigmina/uso terapêutico , Adulto Jovem
11.
J Neurol ; 266(7): 1796-1800, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31041581

RESUMO

BACKGROUND: Recently, rs2421947 in DNM3 (dynamin 3) was reported as a genetic modifier of age at onset (AAO) of LRRK2 G2019S-related Parkinson's disease (PD) in a genome-wide association study in Arab-Berber population. Rs356219 in SNCA (α-synuclein) was also reported to regulate the AAO of LRRK2-related PD in European populations, and GAK (Cyclin G-associated kinase) rs1524282 was reported to be associated with an increased PD risk with an interaction with SNCA rs356219. G2019S variant is rare in Asian populations, whereas two other Asian-specific LRRK2 variants, G2385R and R1628P, are more frequent with a twofold increased risk of PD. METHODS: In this study, we investigated whether rs2421947, rs356219 and rs1524282 modified AAO in LRRK2-related PD patients in Han Chinese population. We screened LRRK2 G2385R and R1628P variants in 732 PD patients and 1992 healthy controls, and genotyped DNM3 rs2421947, SNCA rs356219 and GAK rs1524282 among the LRRK2 carriers. RESULTS: The SNCA rs356219-G allele was found to increase the risk of PD in LRRK2 carriers (OR 1.50, 95%CI 1.08-2.01, P = 0.016), and the AAO of AG + GG genotypes was 4 years earlier than AA genotype (P = 0.006). Nonetheless, no similar association was found in DNM3 rs2421947 and GAK rs1524282. CONCLUSIONS: Our results show that SNCA but not DNM3 or GAK is associated with AAO of LRRK2-PD patients in Chinese population.


Assuntos
Dinamina III/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Doença de Parkinson/epidemiologia , Doença de Parkinson/genética , alfa-Sinucleína/genética , Idade de Início , Idoso , China/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico , Vigilância da População
12.
PLoS Genet ; 14(9): e1007664, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30222779

RESUMO

CHIP (carboxyl terminus of heat shock 70-interacting protein) has long been recognized as an active member of the cellular protein quality control system given the ability of CHIP to function as both a co-chaperone and ubiquitin ligase. We discovered a genetic disease, now known as spinocerebellar autosomal recessive 16 (SCAR16), resulting from a coding mutation that caused a loss of CHIP ubiquitin ligase function. The initial mutation describing SCAR16 was a missense mutation in the ubiquitin ligase domain of CHIP (p.T246M). Using multiple biophysical and cellular approaches, we demonstrated that T246M mutation results in structural disorganization and misfolding of the CHIP U-box domain, promoting oligomerization, and increased proteasome-dependent turnover. CHIP-T246M has no ligase activity, but maintains interactions with chaperones and chaperone-related functions. To establish preclinical models of SCAR16, we engineered T246M at the endogenous locus in both mice and rats. Animals homozygous for T246M had both cognitive and motor cerebellar dysfunction distinct from those observed in the CHIP null animal model, as well as deficits in learning and memory, reflective of the cognitive deficits reported in SCAR16 patients. We conclude that the T246M mutation is not equivalent to the total loss of CHIP, supporting the concept that disease-causing CHIP mutations have different biophysical and functional repercussions on CHIP function that may directly correlate to the spectrum of clinical phenotypes observed in SCAR16 patients. Our findings both further expand our basic understanding of CHIP biology and provide meaningful mechanistic insight underlying the molecular drivers of SCAR16 disease pathology, which may be used to inform the development of novel therapeutics for this devastating disease.


Assuntos
Cognição , Atividade Motora/genética , Domínios Proteicos/genética , Ataxias Espinocerebelares/genética , Ubiquitina-Proteína Ligases/genética , Animais , Comportamento Animal , Sistemas CRISPR-Cas/genética , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Mutagênese Sítio-Dirigida , Fenótipo , Mutação Puntual , Multimerização Proteica/genética , Ratos , Ratos Sprague-Dawley , Ataxias Espinocerebelares/congênito , Ubiquitina-Proteína Ligases/metabolismo
13.
Sci Rep ; 8(1): 6379, 2018 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-29686306

RESUMO

Necroptosis is an essential pathophysiological process in cerebral ischemia-related diseases. Therefore, targeting necroptosis may prevent cell death and provide a much-needed therapy. Ansiomycin is an inhibitor of protein synthesis which can also activate c-Jun N-terminal kinases. The present study demonstrated that anisomycin attenuated necroptosis by upregulating CHIP (carboxyl terminus of Hsc70-interacting protein) leading to the reduced levels of receptor-interacting protein kinase 1 (RIPK1) and receptor-interacting protein kinase 3 (RIPK3) proteins in two in vitro models of cerebral ischemia. Further exploration in this research revealed that losing neither the co-chaperone nor the ubiquitin E3 ligase function of CHIP could abolish its ability to reduce necroptosis. Collectively, this study identifies a novel means of preventing necroptosis in two in vitro models of cerebral ischemia injury through activating the expression of CHIP, and it may provide a potential target for the further study of the disease.


Assuntos
Anisomicina/farmacologia , Apoptose , Glucose/deficiência , Necrose , Neuroblastoma/prevenção & controle , Ubiquitina-Proteína Ligases/metabolismo , Animais , Antibacterianos/farmacologia , Hipóxia Celular , Feminino , Regulação Enzimológica da Expressão Gênica , Camundongos , Neuroblastoma/etiologia , Neuroblastoma/patologia , Oxigênio/metabolismo , Ratos , Ratos Sprague-Dawley , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/genética
14.
Neurosci Lett ; 666: 165-168, 2018 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-29275184

RESUMO

Recently, a genome-wide association study of a Caucasian population identified variant rs3794087 in intron 4 of the SLC1A2 gene, which may increase the risk of essential tremor (ET). Considering the overlap in the pathological features and clinical manifestations of ET and Parkinson's disease (PD), several studies on the association between rs3794087 and PD were later performed in other populations. However, results about the role of SLC1A2 rs3794087 in PD were inconsistent. We thus performed a case-control study in a Chinese Han population to investigate the role of SLC1A2 rs3794087 in Chinese patients with PD. Overall, 1096 subjects comprising 546 patients with PD and 550 control subjects were genotyped. A meta-analysis of the data obtained from the current sample-set and those available from prior studies was performed. Taking all patients and controls into consideration, rs3794087 was found to have no significant effect on PD susceptibility in analyses using allelic (p = .486), genotype (p = .736), additive (p = .764), dominant (p = .438), and recessive (p = .878) genetic models. The results of the meta-analysis were in agreement with our findings (the pooled OR was 0.97 and 95% CI = 0.85, 1.10). Our study suggested that rs3794087 does not lead to an increased risk of PD in the Chinese Han population. The role of single nucleotide polymorphism rs3794087 in the development of PD remains to be further studied.


Assuntos
Tremor Essencial/genética , Predisposição Genética para Doença , Proteínas de Transporte de Glutamato da Membrana Plasmática/genética , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único/genética , /genética , Estudos de Casos e Controles , Transportador 2 de Aminoácido Excitatório , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade
15.
Sci Rep ; 7(1): 1190, 2017 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-28446760

RESUMO

TMEM230 mutations have been recently reported to cause autosomal dominant Parkinson's disease (PD). However, there are limited studies from different ethnic populations to support the role of TMEM230 in sporadic PD. In this study, we performed a comprehensive TMEM230 mutation screening in 550 sporadic PD patients and 560 controls to elaborate the genetic contribution of TMEM230 to sporadic PD. Overall, we did not find any pathogenic mutations in the coding sequence, while we identified four variants (c.68 + 182G > A, c.78A > G, c.552 + 11A > G and c.174 + 11C > T) both in the patients and controls, and c.68 + 182G > A appeared to be associated with an increased risk of PD (odds ratio 1.782, 95% confidence interval 1.035-3.067, p < 0.05). After Bonferroni correction, however, c. 68 + 182G > A had no significant association with sporadic PD (p c = 0.136, p c > 0.05). Thus our results suggest that TMEM230 gene mutations may be rare in Chinese populations, and the variability of TMEM230 gene may not be a main factor for sporadic PD patients in Chinese Han populations. More evidence is still needed to clarify this question.


Assuntos
Predisposição Genética para Doença , Proteínas de Membrana/genética , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único , Frequência do Gene , Humanos , Mutação Puntual
16.
Parkinsonism Relat Disord ; 34: 59-61, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27814975

RESUMO

INTRODUCTION: A founder mutation, p.L302P, in sphingomyelin phosphodiesterase 1, acid lysosomal (SMPD1), causing Niemann-Pick disease, a recessive lysosomal storage disorder, was reported to be associated with increased risk of Parkinson's disease (PD) in Ashkenazi Jewish population. Several other studies about the association between SMPD1 variants and PD were performed afterward in other populations. However, the results on the role of SMPD1 mutations for PD have been conflicting. This study aimed to investigate the role of mutations in SMPD1 in Chinese PD patients. METHODS: We sequenced all the exons of this gene in 512 Chinese Han cases with sporadic Parkinson's disease and 495 matched healthy control subjects. RESULTS: We identified Leu-Ala (Val) repeat variants and six known single nucleotide variants (p.A36V, p.D212D, p.P332R, p.G508R, p.P533L, p.T544T) in SMPD1 in both patients and normal controls. Case-control analysis showed the association between Leu-Ala (Val) repeat variants in SMPD1and Chinese Han patients with PD (χ2 = 8.771, p = 0.012), and the allele with less than seven LeuAla (Val) repeats may increase the risk of PD (p = 0.010). CONCLUSION: We identified association between Leu-Ala (Val) repeat variants in SMPD1 and Chinese Han patients with sporadic Parkinson's disease. Our results provide further support for the role of lysosomal pathways in PD development.


Assuntos
Estudos de Associação Genética , Variação Genética/genética , Doença de Parkinson/genética , Esfingomielina Fosfodiesterase/genética , Idoso , /genética , Estudos de Casos e Controles , Dipeptídeos/genética , Éxons/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
17.
Mov Disord ; 31(12): 1905-1909, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27943471

RESUMO

OBJECTIVES: Mutations in RAB39B have been reported as a potential cause of X-linked Parkinson's disease (PD), a rare form of familial PD. We conducted a genetic analysis on RAB39B to evaluate whether RAB39B mutations are related to PD in the Chinese population. METHODS: In this study, 2 patients from an X-linked juvenile parkinsonism pedigree were clinically characterized and underwent whole-exome sequencing. A comprehensive screening for RAB39B mutations in 505 sporadic patients with PD and 510 healthy controls in a Chinese population was also performed. RESULTS: A novel mutation, c. 536dupA (p.E179fsX48), in RAB39B was identified in the juvenile parkinsonism pedigree. Brain MRI and CT scans in the 2 patients revealed calcification within the bilateral globus pallidus. No other potentially disease-causing RAB39B mutations were found in sporadic PD patients and controls. CONCLUSIONS: X-linked juvenile parkinsonism could be caused by a RAB39B mutation, and basal ganglia calcification may be a novel clinical feature of RAB39B-related parkinsonism. © 2016 International Parkinson and Movement Disorder Society.


Assuntos
Doenças dos Gânglios da Base/genética , Calcinose/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doença de Parkinson/genética , Transtornos Parkinsonianos/genética , Proteínas rab de Ligação ao GTP/genética , Adulto , Doenças dos Gânglios da Base/diagnóstico por imagem , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico por imagem , Transtornos Parkinsonianos/diagnóstico por imagem , Linhagem
19.
Neurobiol Aging ; 42: 217.e5-6, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27084066

RESUMO

Recently, a variant p.R160W in the MC1R gene was identified that increased the risk of Parkinson's disease (PD) in Spanish population. To explore whether the MC1R gene variants are associated with sporadic PD in Chinese population, we performed a case-control comparison study for comprehensive MC1R variant screening in 510 Chinese Han patients and 495 healthy controls as ethnically matched controls. We identify 5 nonsynonymous variants, including rs34090186 (p.R67Q), rs2228479 (p.V92M), rs33932559 (p.I120T), rs885479 (p.R163Q), and rs372152373 (p.R223W). However, variants mentioned previously did not show association with PD. Our results suggest that variants in MC1R do not play a major role in PD in the Chinese population.


Assuntos
Estudos de Associação Genética , Variação Genética/genética , Doença de Parkinson/genética , Receptor Tipo 1 de Melanocortina/genética , /genética , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Risco
20.
Neurobiol Aging ; 38: 217.e9-217.e13, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26705026

RESUMO

Mutations in CHCHD2 gene have been reported in autosomal dominant Parkinson's disease (ADPD). However, there is still lack of evidence supported CHCHD2 mutations lead to ADPD in other populations. We performed whole exome sequencing, positron emission tomography (PET), and haplotype analyses in an ADPD pedigree and then comprehensively screened for CHCHD2 gene mutations in additional 18 familial parkinsonism pedigrees, 364 sporadic PD patients, and 384 healthy controls to assess the frequencies of known and novel rare nonsynonymous CHCHD2 mutations. We identified a heterozygous variant (c.182C>T; p.Thr61Ile) in the CHCHD2 gene in the ADPD pedigree. PET revealed a significant reduction in dopamine transporter binding in the putamen and caudate nucleus of the proband, similar to idiopathic PD. The single nucleotide variant 5C>T (Pro2Leu) in CHCHD2 was confirmed to have a significantly higher frequency among sporadic PD patients than controls. Our results confirm that ADPD can be caused by CHCHD2 mutations and show that the Pro2Leu variant in CHCHD2 may be a risk factor for sporadic PD in Chinese populations.


Assuntos
Estudos de Associação Genética , Proteínas Mitocondriais/genética , Mutação/genética , Doença de Parkinson/genética , Fatores de Transcrição/genética , Núcleo Caudado/metabolismo , Proteínas de Ligação a DNA , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Exoma/genética , Genes Dominantes/genética , Haplótipos , Doença de Parkinson/metabolismo , Linhagem , Polimorfismo de Nucleotídeo Único , Tomografia por Emissão de Pósitrons , Putamen/metabolismo , Fatores de Risco , Análise de Sequência de DNA
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