RESUMO
BACKGROUND AND PURPOSE: We recently reported a novel -62 G/A polymorphism within ataxin 8 (ATXN8) gene promoter region, with -62 G displaying significantly higher luciferase activity compared with -62 A. Phenotypic variability in spinocerebellar ataxia type 8 (SCA8) has been suggested, and large SCA8 repeats were found in patients with Parkinson's disease (PD). We aimed to investigate the association of ATXN8 -62 G/A polymorphism with the risk of Taiwanese PD, and identify the trans-acting factor modulating the ATXN8 promoter activity. METHODS: A case-control study in a cohort of 569 PD cases and 547 ethnically matched controls was conducted by polymerase chain reaction (PCR) and restriction enzyme analysis. The trans-acting factor binding to the ATXN8 promoter was examined by chromatin immunoprecipitation (ChIP)-PCR assay, cDNA co-transfection and luciferase reporter assay. RESULTS: When genotype distribution was calculated by comparing the rare AA genotype with the GG + GA genotypes (recessive model), a significant difference was found (P = 0.035, 1 df). Individuals carrying AA genotype exhibited a decreased risk of developing PD (odds ratio: 0.73; 95% CI: 0.55-0.98, P = 0.035). After stratification by age, individuals over 60 years of age carrying AA genotype demonstrated a further decrease in the risk of developing PD (odds ratio: 0.64; 95% CI: 0.43-0.96, P = 0.030). ChIP-PCR and cDNA over-expression revealed that CCAAT/enhancer-binding protein alpha binds to the ATXN8 proximal promoter to upregulate ATXN8 expression in neuroblastoma SK-N-SH cells. CONCLUSIONS: Our data suggest that ATXN8 -62 G/A polymorphism plays a role in Taiwanese PD susceptibility.
Assuntos
Predisposição Genética para Doença/genética , Proteínas do Tecido Nervoso/genética , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Western Blotting , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase , Fatores de Risco , Taiwan , Adulto JovemRESUMO
The inverse association of the functional ubiquitin carboxy-terminal hydrolase L1 (UCHL1) S18Y variant with Parkinson's disease (PD) among Caucasian populations has been debated. We conducted a large-scale analysis to investigate the age-of-onset effect of the UCHL1 variant in PD among ethnic Chinese. Individual data sets from 5 centers comprising a total of 4088 study subjects were analyzed. In the univariate analysis, only data from 1 center showed a trend towards a protective effect among young subjects. However, in the combined analysis, no significant association between the UCHL1 variant and PD was detected (A allele frequency 0.531 vs. 0.528, p=0.87, OR 1.01, 95% CI 0.92-1.1). Among subjects less than 60 years old, the OR is 0.99 (95% CI 0.84-1.16, p=0.88). A multivariate logistic regression analysis showed that family history, UCHL1 variant and the interaction of UCHL1 variant and age at onset (p=0.816) were not significantly associated with PD.
Assuntos
Variação Genética/genética , Doença de Parkinson/enzimologia , Doença de Parkinson/genética , Ubiquitina Tiolesterase/genética , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/etnologia , Povo Asiático/genética , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/epidemiologia , Singapura/epidemiologia , Singapura/etnologia , Taiwan/epidemiologia , Taiwan/etnologia , Ubiquitinação/genética , Adulto JovemRESUMO
BACKGROUND: Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, among patients with Parkinson's disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson's disease. METHODS: Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson's disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers. RESULTS: All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations. CONCLUSIONS: Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson's disease.
Assuntos
Glucosilceramidase/genética , Mutação , Doença de Parkinson/genética , Idoso , Estudos de Casos e Controles , Genótipo , Humanos , Judeus/genética , Modelos Logísticos , Pessoa de Meia-Idade , Análise Multivariada , Razão de ChancesRESUMO
Endoplasmic reticulum (ER) chaperone heat shock 70 kDa protein 5 (HSPA5/GRP78) is known to be involved in the metabolism of amyloid precursor protein and neuronal death in Alzheimer's disease (AD) could arise from dysfunction of the ER. Through a case-control study and an expression assay, we investigated the association of HSPA5 -415 G/A (rs391957), -370 C/T (rs17840761) and -180 del/G (rs3216733) polymorphisms with Taiwanese AD. The overall genotype and allele frequency distribution at the completely linked -415 G/A and -180 del/G sites showed significant difference between AD cases and controls (P = 0.020 and 0.009, respectively). A decrease in risk of developing AD was demonstrated for -415 AA/-180 GG genotype [OR = 0.38, 95% confidence interval (CI) = 0.18-0.75, P = 0.007] and -415 A/-180 G allele (OR = 0.69, 95% CI = 0.51-0.91, P = 0.009). The HSPA5 transcriptional activity of the -415 A/-180 G allele was significantly lower than that of the -415 G/-180 del alleles, whereas induction of HSPA5 expression after ER stress was markedly increased in the cells with the -415 A/-180 G allele. Therefore, our preliminary results may suggest a protective role of the HSPA5 -415 A/-180 G allele in Taiwanese AD susceptibility.
Assuntos
Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Proteínas de Choque Térmico/biossíntese , Proteínas de Choque Térmico/genética , Chaperonas Moleculares/biossíntese , Chaperonas Moleculares/genética , Idoso , Alelos , DNA/genética , Chaperona BiP do Retículo Endoplasmático , Feminino , Expressão Gênica/fisiologia , Frequência do Gene , Genótipo , Humanos , Masculino , Razão de Chances , Polimorfismo Genético/genética , Regiões Promotoras Genéticas/genética , Fatores de Risco , Taiwan/epidemiologia , Células Tumorais CultivadasRESUMO
BACKGROUND AND PURPOSE: This study examines whether angiotensin-converting enzyme (ACE) gene polymorphisms are associated with the risk of spontaneous deep intracerebral hemorrhage (SDICH) in Taiwan using a case-control study. METHODS: Totally, 217 SDICH patients and 283 controls were recruited. Associations of ACE A-240T and ACE I/D polymorphisms with SDICH were examined under the additive model and adjusted for gender, age, body mass index, total cholesterol level, smoking history, alcohol use, hypertension, and use of ACE inhibitors. RESULTS: Hypertension, diabetes mellitus, family history of spontaneous intracerebral hemorrhage (SICH), and low cholesterol level increase risk of female SDICH, whereas hypertension, alcohol use, smoking history, family history of SICH, and low cholesterol level are an important risk factor for male SDICH. After adjusting for covariates, only haplotype ACE T-D (OR = 2.7, 95% CI, 1.1-6.5, P = 0.02) was associated with female SDICH. CONCLUSIONS: This study demonstrates that environmental risk factors play a major role and ACE polymorphisms play a minor role in contributing risk of SDICH in Taiwan.
Assuntos
Hemorragia Cerebral/genética , Predisposição Genética para Doença/genética , Peptidil Dipeptidase A/genética , Polimorfismo Genético/genética , Idoso , Estudos de Casos e Controles , Hemorragia Cerebral/fisiopatologia , Colesterol/sangue , Análise Mutacional de DNA , Meio Ambiente , Feminino , Frequência do Gene , Marcadores Genéticos/genética , Testes Genéticos , Genótipo , Haplótipos , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fatores de Risco , Caracteres Sexuais , TaiwanRESUMO
Diagnosis of heterozygous Fabry patients is difficult because of its variable clinical manifestations and overlapping serum alpha-galactosidase A (AGA) activity between carriers and non-carriers. We tried to facilitate diagnosis of heterozygous Fabry patients by detailed clinical examination. We analyzed clinical presentations, biochemical, electrophysiological and genetic characteristics of 16 patients with Fabry disease in a large Chinese family. Male patients demonstrated significantly higher pain scores, poorer renal function, and higher frequency of hypohidrosis and corpora angiokeratomas than female patients. Interestingly, all the males and females had corneal verticilata by slit lamp examination. However, there was no association of serum AGA activity with renal function or pain symptom scores. The results indicated that detailed ocular and neurological examination might provide an alternative way of detecting heterozygous patients. We also report a novel large deletion spanning across the joint of Alu repetitive elements in introns 1 and 2 with resultant exon 2 deletion in a Chinese family with Fabry disease.
Assuntos
Doença de Fabry/enzimologia , Doença de Fabry/genética , Deleção de Genes , Mutação/genética , alfa-Galactosidase/genética , Povo Asiático/genética , Doenças da Córnea/enzimologia , Doenças da Córnea/genética , Doenças da Córnea/fisiopatologia , Análise Mutacional de DNA/métodos , Doença de Fabry/diagnóstico , Feminino , Triagem de Portadores Genéticos/métodos , Marcadores Genéticos/genética , Testes Genéticos/métodos , Genótipo , Heterozigoto , Humanos , Masculino , Medição da Dor , Linhagem , Valor Preditivo dos Testes , Qualidade de Vida , Insuficiência Renal/enzimologia , Insuficiência Renal/genética , Insuficiência Renal/fisiopatologia , Caracteres Sexuais , Acidente Vascular Cerebral/enzimologia , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/fisiopatologia , Taiwan/etnologiaRESUMO
Inflammatory events may contribute to the pathogenesis of Parkinson's disease (PD) and interleukin 1 (IL-1) may exert both neurotoxic and neuroprotective effects. We conducted a case-control study in a cohort of 493 PD cases and 388 ethnically matched controls to investigate the association of IL-1alpha C-889T and IL-1beta C-511T polymorphisms with the risk of PD. No significant difference in the genotype distribution of the analyzed polymorphisms was found between PD and controls. However, after stratification by age, individuals over 70 years of age carrying IL-1alpha-889 C/T genotype demonstrated a significant decrease in risk of developing PD (OR = 0.44; 95% CI = 0.22-0.88, p = 0.021) and the decrease is strengthened by IL-1beta-511 T-carrying genotype (OR = 0.28; 95% CI = 0.11-0.71, p = 0.008). Our data suggest that IL-1alpha, acting synergistically with IL-1beta, plays role in PD susceptibility among Taiwanese people older than 70 years of age.
Assuntos
Interleucina-1alfa/genética , Doença de Parkinson/epidemiologia , Doença de Parkinson/genética , Polimorfismo Genético/genética , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Predisposição Genética para Doença/epidemiologia , Humanos , Interleucina-1beta/genética , Masculino , Pessoa de Meia-Idade , Taiwan/epidemiologiaRESUMO
A critical role of mitochondrial dysfunction has been implicated in the pathogenesis of Parkinson's disease (PD). The association of mitochondrial DNA (mtDNA) polymorphisms 9055G/A, 10398G/A and 13708G/A with PD has been controversial. In this study we analyzed whether these three genetic polymorphisms are associated with PD in a cohort of 416 PD cases and 372 ethnically matched controls. The allele frequency distribution of any of these three analyzed polymorphisms was not significantly different between the cases and the controls. None of the six haplotypes derived influences risk of PD. Notably, after stratification by age, individuals over 70 years of age carrying the haplotype 9055G-10398A-13708G demonstrated a significant decrease in risk of developing PD (OR = 0.44, 95% CI = 0.24-0.80, p = 0.008). These results suggest that the mtDNA haplotype 9055G-10398A-13708G plays a role in PD susceptibility among Taiwanese people older than 70 years of age.
Assuntos
DNA Mitocondrial/genética , Predisposição Genética para Doença/genética , Doença de Parkinson/genética , Polimorfismo Genético/genética , Adulto , Distribuição por Idade , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Química Encefálica/genética , Análise Mutacional de DNA , Feminino , Frequência do Gene/genética , Testes Genéticos , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/epidemiologia , Fatores de Risco , Taiwan/epidemiologiaRESUMO
Increased alpha-synuclein expression may be involved in the pathogenesis of Parkinson's disease (PD). We investigated the association of Rep1 microsatellite and RsaI T-to-C substitution in the alpha-synuclein promoter region with the risk of PD by a case-control study. The RsaI C/C genotype and C allele were found less frequently in PD patients than in controls. A reduced risk of the Rep1-RsaI 0-C haplotype (OR = 0.57, 95% CI = 0.36-0.90) with PD was evident. The quantitative real-time PCR study showed that the alpha-synuclein mRNA expression was increased (although not significantly) in PD patients with RsaI T/T genotype or Rep1-RsaI 0-T haplotype as compared to T/C genotype or 0-C haplotype. Reporter constructs containing the RsaI C allele drove significantly lower transcriptional activity compared with the RsaI T allele in both IMR32 and 293 cells. The findings suggest that the RsaI T-to-C substitution may have a functional relevance to the susceptibility to PD.
Assuntos
Predisposição Genética para Doença , Doença de Parkinson/genética , Polimorfismo Genético , Regiões Promotoras Genéticas/genética , alfa-Sinucleína/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Feminino , Genótipo , Haplótipos , Humanos , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de RiscoRESUMO
Lipoproteins and vascular factors may play roles in the development of Alzheimer's disease (AD) and/or vascular dementia (VaD). In this study, odd ratios (ORs) and 95% confidence intervals (CIs) for apolipoprotein E (APOE), angiotensin-converting enzyme (ACE), and kallikrein (KLK1) polymorphisms were computed to test their association with the disease by a case-control study. The risk of AD was significantly increased for individuals with APOE varepsilon4 allele (OR = 3.73, 95% CI = 2.38-5.98). The risk of AD was also significant for people with ACE DD genotype, D allele, or T-D haplotype [OR (95% CI) = 4.29 (1.96-10.23), 1.90 (1.35-2.70), or 2.91 (1.71-5.10), respectively]. The above association between ACE-VaD was also strong (p = 0.0012, 0.0050, 0.0007, respectively). Reporter constructs containing the -240 A or T allele displayed similar transcriptional activity in both HEK-293 and IMR-32 cells. Thus, another putative pathogenic marker that is linked with the Alu D allele might affect the risk of AD and VaD in Taiwan.
Assuntos
Doença de Alzheimer/genética , Apolipoproteínas E/genética , Demência Vascular/genética , Predisposição Genética para Doença , Calicreínas/genética , Peptidil Dipeptidase A/genética , Estudos de Casos e Controles , Genótipo , Humanos , Reação em Cadeia da Polimerase , Polimorfismo Genético , Regiões Promotoras Genéticas , Fatores de RiscoRESUMO
This study was to determine whether polymorphisms of heat shock protein 70-1 (HSP70-1) and tumor necrosis factor alpha (TNF-alpha) are associated with the risk of Alzheimer's disease (AD) and vascular dementia (VaD). Using the criteria of the NINCDS-ADRDA and NINDS-AIREN, 125 AD patients, 57 VaD patients and 109 ethnically matched nondemented controls were enrolled. The HSP70-1 -110 A/C and TNF-alpha -1031 T/C, -863 C/A and -857 C/T polymorphisms were analyzed by means of genotype or haplotype association methods. None of the four genotypes examined showed a statistically significant difference in genotype distribution between the AD cases and controls. However, the HSP70-1 -110 CC genotype occurred more frequently among AD cases (p=0.0821; odds ratio: 2.08; 95% confidence interval, CI: 0.92-4.98). The overall genotype distribution among the VaD cases tended to be different at the HSP70-1 -110 and TNF-alpha -1031 sites (p=0.0604 and 0.0316, respectively). The HSP70-1 -110 CC genotype was more frequent (p=0.0459), and the association of the -110 CC genotype with VaD was evident (p=0.0207; odds ratio: 3.22; 95% CI: 1.20-8.87). The more frequent TNF-alpha -1031 TC genotype (p=0.0614) was also evidently associated with VaD (p=0.0209; odds ratio: 2.32; 95% CI: 1.14-4.78). Multivariate analysis demonstrated the synergistic effect of the HSP70-1 -110 CC and TNF-alpha -1031 TC/CC genotypes on VaD (p=0.0091; odds ratio: 10.09; 95% CI: 2.01-75.97). Haplotype analysis among TNF-alpha -1031, -863, -857 sites revealed that -1031C-857C may act as a risk haplotype among VaD cases (p=0.0132, odds ratio: 2.26; 95% CI: 1.19-4.33). Our results suggest a potential protective role for HSP70 in both VaD and AD, whereas TNF-alpha may act as a risk factor only for VaD, and not for AD.
Assuntos
Demência/etnologia , Demência/genética , Proteínas de Choque Térmico HSP70/genética , Polimorfismo Genético/genética , Fator de Necrose Tumoral alfa/genética , Idoso , Alelos , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Primers do DNA/genética , Demência/diagnóstico , Progressão da Doença , Feminino , Genótipo , Haplótipos/genética , Humanos , Imageamento por Ressonância Magnética , Masculino , Taiwan , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene mutations have been found in patients with distal myopathy with rimmed vacuoles (DMRV). It is not clear how the same GNE gene mutations can result in different phenotypes in the same family with DMRV. METHODS: The clinical, neurophysiological, histopathological, and genetic characteristics of two patients with DMRV from a Chinese family from Taiwan were investigated. RESULTS: Two novel compound heterozygous mutations in different domains of the protein, Ile241Ser in the epimerase and Trp513stop in the kinase domain, were detected in both patients. However, the two patients demonstrated different patterns of disease progression: one had slow disease progression with a typical feature of DMRV (that is, weakness beginning in the distal leg muscles, typically anterior tibialis, with the quadriceps remaining relatively unaffected), and the other had rapid disease progression with an atypical presentation of DMRV. CONCLUSIONS: The results of the present study indicate that GNE gene mutations and probably modifier gene(s) or additional factors may result in different phenotypes of DMRV.
Assuntos
Variação Genética/genética , Distrofias Musculares , Fenótipo , Vacúolos/patologia , Adulto , China , Análise Mutacional de DNA , Éxons/genética , Feminino , Haplótipos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Complexos Multienzimáticos/genética , Fibras Musculares Esqueléticas/patologia , Distrofias Musculares/etnologia , Distrofias Musculares/genética , Distrofias Musculares/patologia , Linhagem , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Mutação Puntual/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Trinucleotide repeat (TNR) expansion in the gene for TATA binding protein (TBP) has recently been described as causal for spinocerebellar ataxia type 17. The normal number of repeats has been considered to be 42 or less. An intermediate range with reduced penetrance has been assumed to be 43-47 CAA/CAG repeats. We examined this gene in 30 patients with autosomal-dominant cerebellar ataxia (ADCA), 35 patients with sporadic ataxia, 11 patients with Huntington's disease (HD), 351 patients with idiopathic Parkinson's disease (PD), 105 patients with Alzheimer's disease (AD), and 291 controls with no history of neurodegenerative disease. Three patients (one with sporadic PD and two with AD) carrying more than 42 TNRs in the TBP gene were identified. This reveals that the phenotype associated with CAG/CAA expansion in the TBP gene may be heterogeneous.
Assuntos
Encéfalo/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Peptídeos/genética , Proteína de Ligação a TATA-Box/genética , Expansão das Repetições de Trinucleotídeos/genética , Idoso , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Ataxia Cerebelar/genética , Ataxia Cerebelar/metabolismo , Ataxia Cerebelar/fisiopatologia , Análise Mutacional de DNA , Feminino , Frequência do Gene/genética , Testes Genéticos , Genótipo , Humanos , Doença de Huntington/genética , Doença de Huntington/metabolismo , Doença de Huntington/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Doenças Neurodegenerativas/fisiopatologia , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , FenótipoRESUMO
We studied the expanded CAG repeat and adjacent CCG repeat in 53 Huntington's disease (HD) patients and 172 unrelated normal subjects matched to the patients for ethnic origin. The range of the CAG repeat varied from 38 to 109 in the HD patients and from 10 to 29 in the control group. A significant negative correlation was found between the age at onset and the CAG expansion, with no significant influence of the adjacent CCG repeat on the age at onset by multiple regression analysis. Allelic association using CCG repeat and 2 flanking dinucleotide repeat markers within 150 kb of the HD gene revealed linkage disequilibrium for 2 of 3 markers. Haplotype analysis of 24 HD families using these markers identified 3 major haplotypes underlying 87.5% of HD chromosomes. The data suggested frequent haplotypes in the Taiwanese population on which one or more mutational events leading to the disease occurred.
Assuntos
Haplótipos/genética , Doença de Huntington/genética , Repetições de Trinucleotídeos/genética , Alelos , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Cromossomos/genética , Saúde da Família , Humanos , Doença de Huntington/epidemiologia , Doença de Huntington/etnologia , Desequilíbrio de Ligação , Mutação/genética , Reação em Cadeia da Polimerase , Taiwan/epidemiologiaRESUMO
DNA tests in normal subjects and patients with ataxia and Parkinson's disease (PD) were carried out to assess the frequency of spinocerebellar ataxia (SCA) and to document the distribution of SCA mutations underlying ethnic Chinese in Taiwan. MJD/SCA3 (46%) was the most common autosomal dominant SCA in the Taiwanese cohort, followed by SCA6 (18%) and SCA1 (3%). No expansions of SCA types 2, 10, 12, or dentatorubropallidoluysian atrophy (DRPLA) were detected. The clinical phenotypes of these affected SCA patients were very heterogeneous. All of them showed clinical symptoms of cerebellar ataxia, with or without other associated features. The frequencies of large normal alleles are closely associated with the prevalence of SCA1, SCA2, MJD/SCA3, SCA6, and DRPLA among Taiwanese, Japanese, and Caucasians. Interestingly, abnormal expansions of SCA8 and SCA17 genes were detected in patients with PD. The clinical presentation for these patients is typical of idiopathic PD with the following characteristics: late onset of disease, resting tremor in the limbs, rigidity, bradykinesia, and a good response to levodopa. This study appears to be the first report describing the PD phenotype in association with an expanded allele in the TATA-binding protein gene and suggests that SCA8 may also be a cause of typical PD.
Assuntos
Proteínas do Tecido Nervoso/genética , Doença de Parkinson/genética , Ataxias Espinocerebelares/genética , Expansão das Repetições de Trinucleotídeos , Idade de Início , Idoso , Estudos de Casos e Controles , Feminino , Frequência do Gene , Testes Genéticos/métodos , Humanos , Pessoa de Meia-Idade , Epilepsias Mioclônicas Progressivas/genética , Fenótipo , RNA Longo não Codificante , RNA não Traduzido , Ataxias Espinocerebelares/etiologia , Proteína de Ligação a TATA-Box/genética , Taiwan/epidemiologiaRESUMO
Sanfilippo syndrome type A (mucopolysaccharidosis type IIIA; MPS IIIA) is caused by a deficiency of the lysosomal enzyme haparan N-sulphatase (NS). The genomic DNA segments of the NS gene from two Chinese patients with MPS IIIA were amplified by polymerase chain reaction, followed by DNA sequencing to study the molecular lesions. Four mutations (i.e. N42K, D235N, P293S and R377C) and five polymorphisms (i.e. IVS2-72A --> G, IVS2-26T --> C, IVS5+17C --> T, IVS5-37GC --> CTGT and R456H) were identified. Transfection of COS-7 cells with cDNA mutagenized to the corresponding mutations did not yield active enzyme, demonstrating the deleterious nature of the mutations. Western blot analysis revealed a 62-kDa precursor and 56-kDa mature forms for cells transfected with wild-type and polymorphic R456H enzymes. For cells transfected with mutant enzymes, the reduction in precursor and mature forms suggests an increased degradation of the mutant enzymes. The polymorphic DNA haplotype of the NS gene was analysed in 52 unrelated subjects. All five polymorphisms were in Hardy-Weinberg equilibrium. The strong non-random association among the five polymorphisms suggests little or no recombination in the NS gene.
Assuntos
Mucopolissacaridose III/genética , Mutação , Polimorfismo Genético , Adolescente , Animais , Células COS/metabolismo , Criança , Frequência do Gene , Heterogeneidade Genética , Marcadores Genéticos , Genótipo , Haplótipos , Heterozigoto , Humanos , Desequilíbrio de Ligação , Mucopolissacaridose III/enzimologia , Sulfatases/genética , TransfecçãoRESUMO
Long QT syndrome (LQT) is a cardiovascular disorder causing syncope and sudden death from arrhythmias. Mutations in KCNQ1, KCNH2, KCNE1, KCNE2, and SCN5A genes encoding cardiac potassium and sodium ion channels cause LQT. Two Taiwanese LQT families were screened for mutations in these ion channel genes. In family H87, the diagnosis was made in the 25-year-old female proband and six family members based on recurrent syncope and/or a prolonged QT interval. Genotyping revealed a novel nonsense mutation, R744X (C to T transition in codon 744), in the KCNH2 potassium channel gene, resulting in truncation of the putative cyclic nucleotide-binding domain and C-terminal region of the HERG K(+)-channel in all affected family members. The mutation was confirmed by DdeI endonuclease digestion of the DNA from each family member. The 26-year-old female proband in family L89 developed repeated syncope with QTc of 0.61 seconds. After linkage and mutation analysis, the syndrome in this family was associated with a novel KCNQ1 missense mutation, T309I, causing the substitution of a threonine residue at position 309, in the pore region of the KvLQT1 K(+)-channel, with an isoleucine. By Tsp45I restriction analysis, the mutation was noted in the proband and the proband's asymptomatic brother, but was not detected in 100 unrelated normal individuals. Identification of a mutation has clinical implications for presymptomatic diagnosis and therapy.
Assuntos
Ligação Genética , Síndrome do QT Longo/genética , Mutação , Canais de Potássio/genética , Canais de Sódio/genética , Adulto , Códon sem Sentido , Feminino , Humanos , Masculino , Mutação de Sentido Incorreto , Linhagem , Polimorfismo Conformacional de Fita SimplesRESUMO
Familial defective apolipoprotein (apo) B-100 (FDB) is caused by R3500Q mutation of the apo B gene resulting in decreased binding of LDL to the LDL receptor. Two other apo B mutations, R3500W and R3531C, affecting binding are known to date. We screened the apo B gene segment around codon 3500 by heteroduplex analysis and single strand conformation polymorphism (SSCP) analysis in a total of 373 hyperlipidemic individuals. Two single-base mutations were detected and confirmed by DNA sequencing. One mutation, ACA(3528)-->ACG change, resulted in degenerate codon with no amino acid substitution. The other mutation, CGG(3500)-->CAG mutation, resulted in an Arg(3500)-->Gln substitution (R3500Q). The prevalence of heterozygote in this selected population was 0.3% (95% confidence interval, 0.01-1.5%) for the R3500Q mutation, and 2.4% (95% confidence interval, 1.1-4.5%) for the previously described R3500W mutation. The results suggest that the R3500Q mutation is not a significant factor contributing to moderate hypercholesterolemia in Chinese (P=0.027). Family studies of the R3500Q carrier revealed a further two individuals heterozygous for the mutation, both of whom were hypercholesterolemic. Analysis of the R3500Q allele using six diallelic markers and the 3'HVR marker revealed a haplotype which was the same as that reported in a Chinese American but differed from that reported in a Chinese Canadian. Our data support limited multiple recurrent origins for R3500Q in Chinese population.
Assuntos
Apolipoproteínas B/genética , Haplótipos , Hiperlipidemias/genética , Mutação Puntual , Adulto , Idoso , Substituição de Aminoácidos , Apolipoproteína B-100 , Criança , Pré-Escolar , China , Feminino , Frequência do Gene , Heterozigoto , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita SimplesRESUMO
DNA screening for mutations in the alpha-L-iduronidase (IDUA) gene was performed in a Chinese mucopolysaccharidosis type IH/S patient. The patient had two different mutations: the maternal allele has L346R (t-g transversion in codon 346) and the paternal allele has 388-3c-g (c-g transversion at position -3 of the 3' splice site of intron 2). In transfected COS-7 cells, L346R showed no appreciable IDUA activity (0.4% of normal activity), although it did not cause an apparent reduction in IDUA mRNA or protein level. The 388-3c-g mutation profoundly affects normal splicing leading to a very unstable mRNA. Expression of the IDUA cDNA containing the mutated acceptor splice site showed trace amounts of enzyme activity (1.6% of normal activity). The results provide further support for the importance of cytosine at the -3 position in RNA processing.