RESUMO
BACKGROUND AND PURPOSE: Mutations of the LRRK2 gene are now recognized as major risk factors for Parkinson's disease. The Lrrk2 protein is a member of the ROCO family, which also includes Lrrk1 and Dapk1. Functional genetic variants of the DAPK1 gene (rs4877365 and rs4878104) have been previously associated with Alzheimer's disease. METHODS: Herein, we assessed the role of DAPK1 variants (rs4877365 and rs4878104) in risk of Parkinson's disease with Sequenom iPLEX genotyping, employing one Taiwanese series (391 patients with Parkinson's disease, 344 controls) and five separate Caucasian series' (combined sample size 1962 Parkinson's disease patients, 1900 controls). RESULTS: We observed no evidence of association for rs4877365 and rs4878104 and risk of Parkinson's disease in any of the individual series or in the combined Caucasian series under either an additive or recessive model. CONCLUSION: These specific DAPK1 intronic variants do not increase the risk of Parkinson's disease. However, further functional studies are required to elucidate the potential therapeutic implications with the dimerization of the Dapk1 and Lrrk2 proteins.
Assuntos
Proteínas Reguladoras de Apoptose/genética , Proteínas Quinases Dependentes de Cálcio-Calmodulina/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Proteínas Quinases Associadas com Morte Celular , Feminino , Predisposição Genética para Doença/etnologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/etnologia , Multimerização Proteica , Adulto JovemRESUMO
BACKGROUND: Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is a neurodegenerative disorder with various clinical phenotypes. We present the first Central-Eastern European family (Gdansk Family) with FTDP-17 because of a P301L mutation in microtubule-associated protein tau (MAPT). METHODS: We have studied a family consisting of 82 family members, 39 of whom were genetically evaluated. The proband and her affected brother underwent detailed clinical and neuropsychological examinations. RESULTS: P301L mutation in MAPT was identified in two affected and five asymptomatic family members. New features included hemispatial neglect and unilateral resting tremor not previously reported for P301L MAPT mutation. Low blood folic acid levels were also detected. CONCLUSIONS: Our report suggests that FTDP-17 affects patients worldwide, but because of its heterogenous clinical presentation remains underrecognized.
Assuntos
Cromossomos Humanos Par 17/genética , Demência Frontotemporal/genética , Proteínas tau/genética , Adulto , Encéfalo/patologia , Feminino , Demência Frontotemporal/patologia , Demência Frontotemporal/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , PolôniaRESUMO
BACKGROUND AND PURPOSE: Recent evidence suggests that variation in the SNCA, MAPT, and GSK3B genes interacts in affecting risk for Parkinson disease (PD). In the current study, we attempt to validate previously published findings, evaluating gene-gene interactions between SNCA, MAPT, and GSK3B in association with PD. METHODS: Three Caucasian PD patient-control series from the United States, Ireland, and Norway (combined n = 1020 patients and 1095 controls) were genotyped for SNCA rs356219, MAPT H1/H2-discriminating SNP rs1052553, and GSK3B rs334558 and rs6438552. RESULTS: Our findings indicate that as previously reported, the SNCA rs356219-G allele and MAPT rs1052553 (H1 haplotype) were both associated with an increased risk of PD, whilst contrary to previous reports, GSK3B variants were not. No pair-wise interaction was observed between SNCA, MAPT, and GSK3B; the risk effects of SNCA rs356219-G and MAPT rs1052553-H1 were seen in a similar manner across genotypes of other variants, with no evidence suggesting synergistic, antagonistic, or deferential effects. CONCLUSIONS: In the Caucasian patient-control series examined, risk for PD was influenced by variation in SNCA and MAPT but not GSK3B. Additionally, those three genes did not interact in determining disease risk.
Assuntos
Epistasia Genética/genética , Quinase 3 da Glicogênio Sintase/genética , Doença de Parkinson/genética , alfa-Sinucleína/genética , Proteínas tau/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Variação Genética/genética , Glicogênio Sintase Quinase 3 beta , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/epidemiologia , Doença de Parkinson/etnologia , Polimorfismo de Nucleotídeo Único/genética , Estudos Prospectivos , Medição de Risco/métodos , Adulto JovemRESUMO
BACKGROUND AND PURPOSE: Whilst an association between the tau gene (MAPT)-containing H1 haplotype and supranuclear gaze palsy (PSP) has long been recognized, the effect of H1 on risk for Parkinson's disease (PD) has remained more contentious. METHODS: Herein, we examined the association of H1 and PD in three Caucasian PD patient-control series from Ireland, Norway, and the US (combined: n = 2619), by genotyping two H1/H2 single nucleotide polymorphisms (SNPs) in MAPT (rs1052553) and in the Saitohin gene (rs62063857) and one H1-specific SNP (rs242557). RESULTS: We identified a significant association between H1/H2 and risk of PD (rs1052553 OR: 1.43, CI: 1.23-1.64; rs62063857 OR: 1.45, CI: 1.27-1.67), but no effect of the H1-specific SNP rs242557 (OR: 0.92, CI: 0.82-1.03). CONCLUSIONS: Our findings show that the H1 haplotype is a significant risk factor for PD. However, one H1-specific SNP (rs242557) previously implicated in PSP did not alter the risk of PD, indicating that distinct H1 sub-haplotypes probably drive the associations with PD and PSP.
Assuntos
Doença de Parkinson/genética , Proteínas tau/genética , Idoso , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Irlanda , Masculino , Noruega , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Análise de Sequência de DNA , Paralisia Supranuclear Progressiva/genética , Estados Unidos , População Branca/genéticaRESUMO
BACKGROUND AND PURPOSE: Calcium levels have been proposed to play an important role in the selective vulnerability of nigrostriatal dopaminergic neurons in Parkinson's disease (PD). Recently, an association was reported between the calcium buffer, calbindin (rs1805874) and risk of PD in a Japanese patient-control series. METHODS: We genotyped rs1805874 in four independent Caucasian patient-control series (1543 PD patients, 1771 controls). RESULTS: There was no evidence of an association between rs1805874 and disease risk in individual populations or in the combined series (odds ratio: 1.04, 95% CI: 0.82-1.31, P = 0.74). DISCUSSION: Our study shows there is no association between rs1805874 and risk for PD in four Caucasian populations. This suggests the effect of calbindin on PD risk displays population specificity.
Assuntos
Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único , Proteína G de Ligação ao Cálcio S100/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Calbindina 1 , Calbindinas , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Irlanda , Masculino , Pessoa de Meia-Idade , Noruega , Polônia , Fatores de Risco , Análise de Sequência de DNA , Estados Unidos , População Branca/genéticaRESUMO
BACKGROUND AND PURPOSE: A single nucleotide polymorphism in the 3'-untranslated region of the progranulin gene (GRN; 3'UTR+78C>T; rs5848) was reported to alter the risk for frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). rs5848 is located within a micro-RNA binding site and affects the expression of GRN. METHODS: As FTLD-U patients often present with parkinsonism, we investigated the association of GRN rs5848 and risk of Parkinson's disease in two Caucasian patient-control series (n = 1413) from the US and Poland. RESULTS: No association was observed between rs5848 and susceptibility to Parkinson's disease (individual series and combined analysis). CONCLUSIONS: This finding shows that GRN rs5848 does not affect the risk of Parkinson's disease in the US and Polish populations.
Assuntos
Predisposição Genética para Doença , Peptídeos e Proteínas de Sinalização Intercelular/genética , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/epidemiologia , Polônia/epidemiologia , Progranulinas , Fatores de Risco , Estados Unidos/epidemiologia , População Branca/genética , Adulto JovemRESUMO
The case report presents a 61-year-old female patient with profound dementia and coexisting hematological disorders suggesting Addison-Biermer's disease. Two possible diagnoses were considered; dementia of Alzheimer type or dementia secondary to pernicious anaemia. This case report reflects diagnostic difficulties concerning dementia syndrome in the presence of other causative factors.
