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1.
Parkinsonism Relat Disord ; 84: 29-34, 2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33548880

RESUMO

INTRODUCTION: A recent study reported that rare variants in NUS1 were associated with Parkinson's disease (PD). We aimed to assess the relative contribution of rare and common coding/non-coding variants of NUS1 to late-onset PD patients (LOPD). METHODS: Whole genome sequencing data were analyzed for target NUS1 regions, derived from a cohort of 1962 cases and 1279 controls. The genetic association analyses were performed using logistic regression analysis and Sequence Kernel association test. Expression quantitative trait loci (eQTL) analysis was conducted to further explore the association of variants with NUS1 expression based on the data from GTEx database. RESULTS: We identified 18 rare coding variants. p.Y131C was first identified in LOPD. However, no significant burden of rare NUS1 coding variants in LOPD was found. The rare variant sets of two regulatory elements (GH06J117605 and GH06J117674) were significantly enriched in LOPD even after Bonferroni correction (adjusted P = 0.013; adjusted P = 0.010). Considering the joint effect of rare and common variants, all variant sets within GH06J117605 and GH06J117674 showed association with LOPD but were no longer significant after Bonferroni correction. None of the common variants within coding/non-coding regions were significant after Bonferroni correction. The eQTL results suggested these variants in GH06J117605 and GH06J117674 could potentially have eQTL effects on the brain tissues. CONCLUSIONS: These findings provide novel insight into the role of NUS1 regulatory regions in the development of LOPD and indicate that the variants in regulatory elements of NUS1 may be associated with LOPD by influencing the gene expression level.

2.
Neurosci Lett ; 740: 135441, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33184037

RESUMO

BACKGROUND: A recent study on early onset Parkinson's disease (PD) revealed that NUS1 is a risk gene for PD. Clinically, essential tremor (ET) is closely related to PD. In this study, we aimed to detect NUS1 variants and assess the effect of those variants on patients with ET. METHODS: The 5 coding regions and the exon-intron boundaries of NUS1 were directly sequenced in 395 patients with ET and an equal number of healthy controls, matched for age and sex. The function of variants was assessed by pathogenic predictive software programs. Genetic analysis of variants was used to evaluate susceptibility to ET. RESULTS: A total of 6 exonic variants were identified, including 3 synonymous and 3 missense variants. The non-synonymous variants were predicted to be tolerable. No variants had significant association with ET (none of the p-values were less than 0.05, using Fisher's exact test). CONCLUSION: Our study suggested that NUS1 variants may not contribute to the risk of ET.

5.
Transl Neurodegener ; 9(1): 31, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32746945

RESUMO

BACKGROUND: Common and rare variants of guanosine triphosphate cyclohydrolase 1 (GCH1) gene may play important roles in Parkinson's disease (PD). However, there is a lack of comprehensive analysis of GCH1 genotypes, especially in non-coding regions. The aim of this study was to explore the genetic characteristics of GCH1, including rare and common variants in coding and non-coding regions, in a large population of PD patients in Chinese mainland, as well as the phenotypic characteristics of GCH1 variant carriers. METHODS: In the first cohort of this case-control study, we performed whole-exome sequencing in 1555 patients with early-onset or familial PD and 2234 healthy controls; then in the second cohort, whole-genome sequencing was performed in sporadic late-onset PD samples (1962 patients), as well as 1279 controls. Variants at target GCH1 regions were extracted, and then genetic and detailed phenotypic data were analyzed using regression models and the sequence kernel association test. We also performed a meta-analysis to correlate deleterious GCH1 variants with age at onset (AAO) in PD patients. RESULTS: For coding variants, we identified a significant burden of GCH1 deleterious variants in early-onset or familial PD cases compared to controls (1.2% vs 0.1%, P < 0.0001). In the analysis of possible regulatory variants in GCH1 non-coding regions, rs12323905 (P = 0.001, odds ratio = 1.19, 95%CI 1.07-1.32) was significantly associated with PD, and variant sets in untranslated regions and intron regions, GCH1 brain-specific expression quantitative trait loci, and two possible promoter/enhancer (GH14J054857 and GH14J054880) were suggestively associated with PD. Genotype-phenotype correlation analysis revealed that the carriers of GCH1 deleterious variants manifested younger AAO (P < 0.0001), and had milder motor symptoms, milder fatigue symptoms and more autonomic nervous dysfunctions. Meta-analysis of six studies demonstrated 6.4-year earlier onset in GCH1 deleterious variant carriers (P = 0.0009). CONCLUSIONS: The results highlight the importance of deleterious variants and non-coding variants of GCH1 in PD in Chinese mainland and suggest that GCH1 mutation can influence the PD phenotype, which may help design experimental studies to elucidate the mechanisms of GCH1 in the pathogenesis of PD.

6.
Brain ; 143(1): 222-233, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31819945

RESUMO

Essential tremor is one of the most common movement disorders. Despite its high prevalence and heritability, the genetic aetiology of essential tremor remains elusive. Up to now, only a few genes/loci have been identified, but these genes have not been replicated in other essential tremor families or cohorts. Here we report a genetic study in a cohort of 197 Chinese pedigrees clinically diagnosed with essential tremor. Using a comprehensive strategy combining linkage analysis, whole-exome sequencing, long-read whole-genome sequencing, repeat-primed polymerase chain reaction and GC-rich polymerase chain reaction, we identified an abnormal GGC repeat expansion in the 5' region of the NOTCH2NLC gene that co-segregated with disease in 11 essential tremor families (5.58%) from our cohort. Clinically, probands that had an abnormal GGC repeat expansion were found to have more severe tremor phenotypes, lower activities of daily living ability. Obvious genetic anticipation was also detected in these 11 essential tremor-positive families. These results indicate that abnormal GGC repeat expansion in the 5' region of NOTCH2NLC gene is associated with essential tremor, and provide strong evidence that essential tremor is a family of diseases with high clinical and genetic heterogeneities.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Tremor Essencial/genética , Expansão das Repetições de Trinucleotídeos/genética , Adulto , Idoso , Feminino , Sequência Rica em GC , Ligação Genética , Humanos , Corpos de Inclusão Intranuclear/genética , Corpos de Inclusão Intranuclear/ultraestrutura , Masculino , Microscopia Eletrônica , Pessoa de Meia-Idade , Doenças Neurodegenerativas/genética , Linhagem , Reação em Cadeia da Polimerase , Pele/ultraestrutura , Sequenciamento Completo do Exoma , Sequenciamento Completo do Genoma
7.
Am J Hum Genet ; 105(1): 166-176, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31178126

RESUMO

Neuronal intranuclear inclusion disease (NIID) is a slowly progressing neurodegenerative disease characterized by eosinophilic intranuclear inclusions in the nervous system and multiple visceral organs. The clinical manifestation of NIID varies widely, and both familial and sporadic cases have been reported. Here we have performed genetic linkage analysis and mapped the disease locus to 1p13.3-q23.1; however, whole-exome sequencing revealed no potential disease-causing mutations. We then performed long-read genome sequencing and identified a large GGC repeat expansion within human-specific NOTCH2NLC. Expanded GGC repeats as the cause of NIID was further confirmed in an additional three NIID-affected families as well as five sporadic NIID-affected case subjects. Moreover, given the clinical heterogeneity of NIID, we examined the size of the GGC repeat among 456 families with a variety of neurological conditions with the known pathogenic genes excluded. Surprisingly, GGC repeat expansion was observed in two Alzheimer disease (AD)-affected families and three parkinsonism-affected families, implicating that the GGC repeat expansions in NOTCH2NLC could also contribute to the pathogenesis of both AD and PD. Therefore, we suggest defining a term NIID-related disorders (NIIDRD), which will include NIID and other related neurodegenerative diseases caused by the expanded GGC repeat within human-specific NOTCH2NLC.


Assuntos
Corpos de Inclusão Intranuclear/patologia , Doenças Neurodegenerativas/patologia , Receptores Notch/genética , Expansão das Repetições de Trinucleotídeos/genética , Adulto , Idoso , Feminino , Humanos , Corpos de Inclusão Intranuclear/genética , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/genética , Linhagem , Sequenciamento Completo do Exoma
8.
Front Neurol ; 10: 121, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30837940

RESUMO

Objective: To explore the clinical features and correlates of excessive daytime sleepiness (EDS) in a Chinese population of Parkinson's disease (PD) patients. Methods: Patients with clinically established or clinically probable PD were recruited. Clinical and demographic data were collected, and participants were evaluated using standardized assessment protocols. Patients were divided into PD with EDS and PD without EDS groups based on the Epworth sleepiness scale (ESS) scores, with a cutoff score of 10. Clinical manifestations were compared between patients with and without EDS, and correlates of EDS were also studied. In addition, the relationship between EDS and poor nighttime sleep quality was analyzed. Results: A total of 1,221 PD patients were recruited in our study. The mean ESS (min, max) score was 7.6 ± 6.1 (0, 24), and 34.1% of the patients had ESS scores ≥10. No difference was seen in lifestyle (except for alcohol consumption), environmental factors, BMI, levodopa equivalent dose (LED), initial presentation of motor symptoms, motor subtype, and wearing off between patients with and without EDS. The PD with EDS group had a higher proportion of male patients and a higher average patient age. Moreover, the PD with EDS group showed older age at PD onset, lower educational level, and longer disease duration. Patients with EDS had higher scores on the Hoehn-Yahr scale and the Unified Parkinson's Disease Rating Scale (UPDRS) parts I, II, and III score, more severe non-motor symptoms, and poorer quality of sleep and life. Logistic regression analyses demonstrated that EDS was associated with male sex, age, cognitive impairment, PD-related sleep problems, rapid eye movement sleep behavior disorder (RBD), and worse quality of life (QoL). Conclusion: EDS is a general clinical manifestation in PD, and there were significant differences in clinical features between patients with and without EDS. Moreover, our study proved that many factors were associated with EDS, including male sex, age, cognitive impairment, PD-related sleep problems, RBD, and worse QoL. Understanding the clinical characteristics of EDS in PD patients may help identify EDS early, improve QoL, and reduce the occurrence of accidents.

9.
Brain Res ; 1712: 25-33, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30707893

RESUMO

PLA2G6-associated neurodegeneration (PLAN, NBIA2) is the second most common type of neurodegeneration with brain iron accumulation (NBIA), caused by recessive mutations of PLA2G6 gene, which encodes Ca2+-independent phospholipase A2ß (iPLA2ß). In most PLAN cases, decreased iPLA2ß activity and iron deposition was observed meanwhile, and researchers also identified a PLA2G6 mutation family without iron deposition shown by MRI images. This brought us the question of whether decreased iPLA2ß activity was the cause of iron deposition in PLAN. In this study, we used S-BEL as the antagonist of iPLA2ß to block its activity and used SH-SY5Y cells as the expression system. We incubated SH-SY5Y cells with different concentrations of S-BEL. The results showed that decreased iPLA2ß activity led no obvious iron accumulation, while changes of cells state and activation of apoptosis were observed. To further investigate the cause of unchanged iron level, we examined the cellular iron regulatory proteins involved in iron uptake, storage and export. The results were as follows: TfR1 (iron uptake protein) expression was decreased, the expression of ferritin heavy chain and light chain (iron storage protein) was increased. There was no alteration of the expression of DMT1 (iron uptake protein) and FPN1 (iron export protein). Under the condition of decreased iPLA2ß activity, there was no obvious iron accumulation but iron uptake activity decreased and iron storage activity increased. Therefore, we speculate that the decreased iPLA2ß activity may not be the main reason for iron deposition in PLAN.


Assuntos
Fosfolipases A2 do Grupo VI/metabolismo , Ferro/metabolismo , Distrofias Neuroaxonais/metabolismo , Antígenos CD/metabolismo , Apoferritinas/metabolismo , Fenômenos Bioquímicos , Transporte Biológico , Encéfalo/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Linhagem Celular Tumoral , Fosfolipases A2 do Grupo VI/genética , Humanos , Imagem por Ressonância Magnética , Naftalenos/farmacologia , Distrofias Neuroaxonais/genética , Pironas/farmacologia , Receptores da Transferrina/metabolismo , Fatores de Transcrição/metabolismo
10.
Proc Natl Acad Sci U S A ; 115(45): 11567-11572, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30348779

RESUMO

Whole-exome sequencing has been successful in identifying genetic factors contributing to familial or sporadic Parkinson's disease (PD). However, this approach has not been applied to explore the impact of de novo mutations on PD pathogenesis. Here, we sequenced the exomes of 39 early onset patients, their parents, and 20 unaffected siblings to investigate the effects of de novo mutations on PD. We identified 12 genes with de novo mutations (MAD1L1, NUP98, PPP2CB, PKMYT1, TRIM24, CEP131, CTTNBP2, NUS1, SMPD3, MGRN1, IFI35, and RUSC2), which could be functionally relevant to PD pathogenesis. Further analyses of two independent case-control cohorts (1,852 patients and 1,565 controls in one cohort and 3,237 patients and 2,858 controls in the other) revealed that NUS1 harbors significantly more rare nonsynonymous variants (P = 1.01E-5, odds ratio = 11.3) in PD patients than in controls. Functional studies in Drosophila demonstrated that the loss of NUS1 could reduce the climbing ability, dopamine level, and number of dopaminergic neurons in 30-day-old flies and could induce apoptosis in fly brain. Together, our data suggest that de novo mutations could contribute to early onset PD pathogenesis and identify NUS1 as a candidate gene for PD.


Assuntos
Encéfalo/metabolismo , Neurônios Dopaminérgicos/metabolismo , Mutação , Proteínas do Tecido Nervoso/genética , Doença de Parkinson/genética , Receptores de Superfície Celular/genética , Adulto , Idade de Início , Animais , Apoptose/genética , Translocador Nuclear Receptor Aril Hidrocarboneto/antagonistas & inibidores , Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Translocador Nuclear Receptor Aril Hidrocarboneto/metabolismo , Sequência de Bases , Encéfalo/patologia , Estudos de Casos e Controles , Estudos de Coortes , Modelos Animais de Doenças , Dopamina/metabolismo , Neurônios Dopaminérgicos/patologia , Proteínas de Drosophila/antagonistas & inibidores , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Diagnóstico Precoce , Feminino , Expressão Gênica , Redes Reguladoras de Genes , Humanos , Masculino , Proteínas do Tecido Nervoso/metabolismo , Pais , Doença de Parkinson/diagnóstico , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores de Superfície Celular/metabolismo , Irmãos
11.
Transl Neurodegener ; 6: 34, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29255601

RESUMO

Background: PINK1 (PTEN-induced putative kinase 1) gene is the causal gene for recessive familial type 6 of Parkinson's disease (PARK6), which is an early-onset autosomal recessive inherited neurodegenerative disease. PINK1 has been reported to exert both autophosphorylation and phosphorylation activity, affecting cell damage under stress and other physiological responses. However, there has been no report on the identification of PINK1 autophosphorylation sites and their physiological functions. Methods: (1) We adopted mass spectrometry assay to identify the autophosphorylation site of PINK1, and autoradiography assay was further conducted to confirm this result. (2) Kinase activity assay was used to compare the kinase activity of both Ser465 mutant PINK1 and disease-causing mutant PINK1. (3) We use Pulse-chase analysis to measure whether Ser465 may affect PINK1 degradation. (4) Immunocytochemistry staining was used to study the PINK1 subcellular localization and Parkin transition in subcellular level. Result: In our study, we identified the 465th serine residue (Ser465) as one of the autophosphorylation sites in PINK1 protein. The inactivation of Ser465 can decrease the kinase activity of PINK1. Either dissipated or excessive Ser465 site phosphorylation of PINK1 can slow down its degradation. PINK1 autophosphorylation contributes to the transit of Parkin to mitochondria, and has no effect on its subcellular localization. PARK6 causal mutations, T313 M and R492X, display the same characteristics as Ser465A mutation PINK1 protein, such as decreasing PINK1 kinase activity and affecting its interaction with Parkin. Conclusion: Ser465 was identified as one of the autophosphorylation sites of PINK1, which affected PINK1 kinase activity. In addition, Ser465 is involved in the degradation of PINK1 and the transit of Parkin to mitochondria. T313 M and R492X, two novel PARK6 mutations on Thr313 and Arg492, were similar to Ser465 mutation, including decreasing PINK1 phosphorylation activity and Parkin subcellular localization.

12.
Sci Rep ; 6: 34502, 2016 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-27694831

RESUMO

Recently, RAB39B mutations were reported to be a causative factor in patients with Parkinson's disease (PD). To validate the role of RAB39B in familial PD, a total of 195 subjects consisting of 108 PD families with autosomal-dominant (AD) inheritance and 87 PD families with autosomal-recessive (AR) inheritance in the Chinese Han population from mainland China were included in this study. We did not identify any variants in the coding region or the exon-intron boundaries of the gene by Sanger sequencing method in the DNA samples of 180 patients (100 with AD and 80 with AR). Furthermore, we did not find any variants in the RAB39B gene when Whole-exome sequencing (WES) was applied to DNA samples from 15 patients (8 with AD and 7 with AR) for further genetic analysis. Additionally, when quantitative real-time PCR was used to exclude large rearrangement variants in these patients, we found no dosage mutations in RAB39B gene. Our results suggest that RAB39B mutation is very rare in familial PD and may not be a major cause of familial PD in the Chinese Han Population.


Assuntos
Exoma , Mutação , Transtornos Parkinsonianos/genética , Proteínas rab de Ligação ao GTP/genética , Adulto , Idoso , China/etnologia , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Parkinsonianos/etnologia
13.
Neurosci Lett ; 621: 133-136, 2016 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-27085534

RESUMO

Parkinson's disease (PD) is known as the most common neurodegenerative disease after Alzheimer's disease (AD). The precise pathogenic mechanism of PD remains unclear, but genetic and environmental factors are widely recognized to be associated with it. Although many associated genes have been discovered, they account for only a few PD patients. Recently, there are growing evidences indicating that patients with PD and AD share similarities in clinical features, pathology and genetic risks. However, no study has been conducted on the relations between AD associated genes and age at onset (AAO) of PD. In this study, we have detected 14 single nucleotide polymorphisms (SNPs) in 9 AD genome wide association studies top hit genes and 4 SNPs in 4 PD-cognitive impairment related genes among 297 Chinese PD patients. Through the linear regression analysis, we identified the significant associations of the GBA L444P mutation and DYRK1A rs8126696 T allele with the earlier AAO in PD patients, and the A allele at MS4A6A rs610932 with the delayed AAO of PD. This is the first report of significant associations of DYRK1A and MS4A6A SNPs and the AAO of PD. On account of their effects both in AD and PD, it is indicated that AD and PD possibly share some common pathways.


Assuntos
Glucosilceramidase/genética , Proteínas de Membrana/genética , Doença de Parkinson/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/etnologia , Polimorfismo de Nucleotídeo Único
14.
Neurobiol Aging ; 39: 217.e9-11, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26724962

RESUMO

Alzheimer's disease (AD), Parkinson's disease (PD), and cognitive impairment in PD have overlapping clinical and pathological features. To examine whether there is a genetic link for these diseases, we performed a case-control study in Chinese population to evaluate the association of AD genome-wide association studies top hits with both PD and cognitive function in PD, investigating 13 single-nucleotide polymorphisms in 9 genes (BIN1, CLU, ABCA7, CR1, PICALM, MS4A6A, CD33, MS4A4E, and CD2AP). A total of 454 controls and 442 PD patients were genotyped, including 75 mild cognitive impairment and 99 dementia. As a result, no significant association of the AD-susceptibility loci was identified in PD cases, PD-dementia, or PD-mild cognitive impairment. Our findings imply that the 13 single-nucleotide polymorphisms from AD genome-wide association studies may not play major role in the genetic predisposition with PD and cognitive function in PD in a Chinese population.


Assuntos
Doença de Alzheimer/genética , Cognição , Disfunção Cognitiva/genética , Demência/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Doença de Parkinson/genética , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Disfunção Cognitiva/etiologia , Demência/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Doença de Parkinson/psicologia , Polimorfismo de Nucleotídeo Único , Risco
15.
Parkinsons Dis ; 2015: 916971, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26421210

RESUMO

GBA has been identified as a genetic risk factor for PD. Whether the clinical manifestations of PD patients with or without GBA mutations are different has still not reached a consensus. We firstly detected the GBA mutation L444P in 1147 Chinese PD patients and simultaneously evaluated their corresponding clinical data. Then we compared the phenotypes between 646 PD patients with GBA mutations and 10344 PD patients without GBA mutations worldwide through meta-analysis. Through the method of meta-analysis, there was significant difference in age at onset (MD = -3.10 [95% CI: -4.88, -1.32]), bradykinesia as an initial symptom (OR = 1.49 [95% CI: 1.15, 1.94]), having family history (OR = 1.50 [95% CI: 1.18, 1.91]), and dementia (OR = 3.21 [95% CI: 1.97, 5.24]) during the comparison between PD patients with and without GBA mutations. While, in the aspect of tremor as an initial symptom (OR = 0.81 [95% CI: 0.64, 1.03]), the severity of motor symptoms such as H-Y (MD = 0.06 [95% CI: -0.06, 0.17]) and UPDRS-III (MD = 1.61 [95% CI: -0.65, 3.87]) and having dyskinesia (OR = 1.60 [95% CI: 0.90, 2.84]) during the comparison between the two groups revealed no statistical differences. Our results suggested that the phenotypes of PD patients with GBA mutations are different from GBA noncarriers.

16.
Neurol Sci ; 36(11): 2073-9, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26152800

RESUMO

The contribution of the gene of GIGYF2, Grb10-Interacting GYF Protein 2, to Parkinson's disease (PD) is still ambiguous. To explore the contribution of GIGYF2 to PD at the genetic level, we analyzed the relationship between all reported GIGYF2 variants (including mutations and polymorphisms) and PD through a meta-analysis. Databases including Medline, Embase, etc., were searched to find relevant studies. All eligible publications have to meet the strict inclusion and exclusion criteria listed. Two authors independently selected trials, assessed the article's quality and extracted data. Odds ratios (ORs) and relative risks with 95 % confidence intervals (CIs) were used to evaluate the strength of associations. All analyses were carried out by using the Review Manager software package v.5.2. More than 100 variants of GIGYF2 were reported either or both in patients and controls in 10 included publications. The 10 publications totally included 5466 patients and 6517 controls. We conducted meta-analyses for the following variants: N56S, N457T, Del LPQQQQQQ 1209-1216, Del Q 1210 (rs10555297), rs12328151, rs2289912, rs2305138, rs3816334, A572A and H1171R. The ORs for N56S were 2.86 (95 % CI 1.10, 7.41) for PD and 4.75 (95 % CI 1.35, 16.68) for FPD. And the OR for N457T in FPD was 4.53 (95 % CI 1.04, 19.66). On the other hand, other variants involved in meta-analyses were not related to PD. This research results suggest that the N56S and N457T of GIGYF2 are risk factors for PD in Caucasians, but not in Asians.


Assuntos
Proteínas de Transporte/genética , Predisposição Genética para Doença , Mutação , Doença de Parkinson/genética , Polimorfismo Genético , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Humanos , Doença de Parkinson/etnologia , Fatores de Risco
17.
Neurobiol Aging ; 36(3): 1600.e9-11, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25559334

RESUMO

A recent meta-analysis of genome-wide association studies in Parkinson's disease (PD) has identified the rs12456492 variant in RIT2 as a new susceptibility loci. Because the characteristics of this locus in a Han Chinese population from mainland China was still unknown, we performed a case-control replication study in this population and investigated RIT2 rs12456492 variant in a large cohort of Chinese Han individuals. In total, 933 subjects comprising 460 PD patients and 473 control subjects were genotyped. We found a significant difference in the distributions of genotype and allele between PD and control groups (genotype p = 0.008, allele p = 0.007, odds ratio = 1.296, 95% confidence interval = 1.075-1.563). This study replicates the association between rs12456492 variant and risk of developing PD in a Han Chinese population.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Proteínas Monoméricas de Ligação ao GTP/genética , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único/genética , Idoso , Alelos , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Risco
18.
Neurosci Lett ; 587: 68-71, 2015 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-25528405

RESUMO

Large-scale meta-analyses of genome-wide association studies in Parkinson's disease (PD) have identified a number of susceptibility loci in sporadic PD. Since the characteristics of those loci in a Han Chinese population from mainland China were unknown, we performed a case-control replication study in this population and evaluated several single nucleotide polymorphisms (SNPs) identified in a recent GWAS-meta-analysis. In total, 933 subjects comprised of 460 PD patients and 473 controls were genotyped. We found strong evidence of an association for rs708723 in RAB7L1 in the total sample (genotype p=0.01, allele p=0.01, OR=0.78, 95% CI=0.65-0.94). With rs156429 in GPNMB, there was a significant difference in genotype and allele distribution between male PD patients and the control subgroup (genotype p=0.01, allele p=0.01, OR=0.67, 95% CI=0.49-0.92). However, we did not observe any significant difference in genotype or allele distribution between PD and control for rs34016896 in NMD3 and rs6812193 in STBD1.


Assuntos
Loci Gênicos , Doença de Parkinson/genética , Estudos de Casos e Controles , China , Feminino , Fatores de Crescimento de Fibroblastos/genética , Estudos de Associação Genética , Humanos , Masculino , Glicoproteínas de Membrana/genética , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Proteínas Musculares/genética , Polimorfismo de Nucleotídeo Único , Proteínas de Ligação a RNA/genética , Proteínas rab de Ligação ao GTP , Proteínas rab1 de Ligação ao GTP/genética
19.
Hum Vaccin Immunother ; 10(8): 2220-6, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25424925

RESUMO

Human enterovirus 71 (EV71) plays an important role in hand, foot, and mouth disease (HFMD), which recently caused the death of hundreds of children in the Asia-Pacific region. However, there are no specific treatments available for EV71 infections; thus, a safe and effective vaccine is needed urgently. In this study, we developed an effective and economical method for producing EV71 polyprotein (P1 protein) in Pichia pastoris. Furthermore, we evaluated the potential of P1 protein as a candidate vaccine against EV71 virus. The data revealed that P1 protein induced persistent high cross-neutralization antibodies for different EV71 subtypes, and elicited significant splenocyte proliferation. The high levels of interleukin-10(IL-10) and interferon-gamma (IFN-γ) showed that P1 protein induced Th1 and Th2 immune responses. Interestingly, vaccinating female mice with the P1 protein conferred cross-protection against different EV71 subtypes to their neonatal offspring.Compared with heat-inactivated EV71, the P1 protein elicited improved humoral and cellular immune responses and showed good cross-protection with different EV71 subtypes. Therefore, the EV71-P1 protein produced by P. pastoris is a promising candidate vaccine against EV71.


Assuntos
Enterovirus Humano A/imunologia , Doença de Mão, Pé e Boca/prevenção & controle , Poliproteínas/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Proliferação de Células , Reações Cruzadas , Enterovirus Humano A/genética , Feminino , Expressão Gênica , Interferon gama/metabolismo , Leucócitos Mononucleares/imunologia , Camundongos Endogâmicos BALB C , Pichia/genética , Pichia/crescimento & desenvolvimento , Poliproteínas/administração & dosagem , Poliproteínas/genética , Poliproteínas/isolamento & purificação , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/isolamento & purificação , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Vacinas Sintéticas/isolamento & purificação , Vacinas Virais/administração & dosagem , Vacinas Virais/genética , Vacinas Virais/isolamento & purificação
20.
PLoS One ; 9(9): e106388, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25181484

RESUMO

Dopa-responsive dystonia, a rare disorder typically presenting in early childhood with lower limb dystonia and gait abnormality, responds well to levodopa. However, it is often misdiagnosed with the wide spectrum of phenotypes. By exome sequencing, we make a rapid genetic diagnosis for two atypical dopa-responsive dystonia pedigrees. One pedigree, presented with prominent parkinsonism, was misdiagnosed as Parkinson's disease until a known mutation in GCH1 (GTP cyclohydrolase 1) gene (NM_000161.2: c.631_632delAT, p.Met211ValfsX38) was found. The other pedigree was detected with a new compound heterozygous mutation in TH (tyrosine hydroxylase) gene [(NM_000360.3: c.911C>T, p.Ala304Val) and (NM_000360.3: c.1358G>A, p.Arg453His)], whose proband, a pregnant woman, required a rapid and less-biased genetic diagnosis. In conclusion, we demonstrated that exome sequencing could provide a precise and rapid genetic testing in the diagnosis of Mendelian diseases, especially for diseases with wide phenotypes.


Assuntos
Distúrbios Distônicos/diagnóstico , Distúrbios Distônicos/genética , Exoma/genética , Testes Genéticos , Análise de Sequência de DNA/métodos , Adolescente , Sequência de Aminoácidos , Sequência de Bases , Extratos Celulares , Pré-Escolar , Feminino , GTP Cicloidrolase/química , GTP Cicloidrolase/genética , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Proteínas Mutantes/metabolismo , Mutação/genética , Transfecção , Tirosina 3-Mono-Oxigenase/metabolismo , Adulto Jovem
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