RESUMEN
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.
Asunto(s)
Epistasis Genética/genética , Glucógeno Sintasa Quinasa 3/genética , Enfermedad de Parkinson/genética , alfa-Sinucleína/genética , Proteínas tau/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Variación Genética/genética , Glucógeno Sintasa Quinasa 3 beta , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/etnología , Polimorfismo de Nucleótido Simple/genética , Estudios Prospectivos , Medición de Riesgo/métodos , Adulto JovenRESUMEN
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.
Asunto(s)
Enfermedad de Parkinson/genética , Proteínas tau/genética , Anciano , Estudios de Casos y Controles , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Humanos , Irlanda , Masculino , Noruega , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Análisis de Secuencia de ADN , Parálisis Supranuclear Progresiva/genética , Estados Unidos , Población Blanca/genéticaRESUMEN
OBJECTIVE: Recently, mutations in DCTN1 were found to cause Perry syndrome, a parkinsonian disorder with TDP-43-positive pathology. Previously, mutations in DCTN1 were identified in a family with lower motor neuron disease, in amyotrophic lateral sclerosis (ALS), and in a family with ALS/frontotemporal dementia (FTD), suggesting a central role for DCTN1 in neurodegeneration. METHODS: In this study we sequenced all DCTN1 exons and exon-intron boundaries in 286 samples diagnosed with Parkinson disease (PD), frontotemporal lobar degeneration (FTLD), or ALS. RESULTS: This analysis revealed 36 novel variants (9 missense, 5 silent, and 22 noncoding). Segregation analysis in families and association studies in PD, FTLD, and ALS case-control series did not identify any variants segregating with disease or associated with increased disease risk. CONCLUSIONS: This study suggests that pathogenic mutations in DCTN1 are rare and do not play a common role in the development of Parkinson disease, frontotemporal lobar degeneration, or amyotrophic lateral sclerosis.
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Esclerosis Amiotrófica Lateral/genética , Demencia/genética , Predisposición Genética a la Enfermedad/genética , Proteínas Asociadas a Microtúbulos/genética , Enfermedad de Parkinson/genética , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Análisis Mutacional de ADN , Proteínas de Unión al ADN/genética , Complejo Dinactina , Exones/genética , Femenino , Frecuencia de los Genes/genética , Marcadores Genéticos/genética , Pruebas Genéticas , Variación Genética/genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mutación/genéticaRESUMEN
OBJECTIVE: To report the study of a multigenerational Swiss family with dopa-responsive dystonia (DRD). METHODS: Clinical investigation was made of available family members, including historical and chart reviews. Subject examinations were video recorded. Genetic analysis included a genome-wide linkage study with microsatellite markers (STR), GTP cyclohydrolase I (GCH1) gene sequencing, and dosage analysis. RESULTS: We evaluated 32 individuals, of whom 6 were clinically diagnosed with DRD, with childhood-onset progressive foot dystonia, later generalizing, followed by parkinsonism in the two older patients. The response to levodopa was very good. Two additional patients had late onset dopa-responsive parkinsonism. Three other subjects had DRD symptoms on historical grounds. We found suggestive linkage to the previously reported DYT14 locus, which excluded GCH1. However, further study with more stringent criteria for disease status attribution showed linkage to a larger region, which included GCH1. No mutation was found in GCH1 by gene sequencing but dosage methods identified a novel heterozygous deletion of exons 3 to 6 of GCH1. The mutation was found in seven subjects. One of the patients with dystonia represented a phenocopy. CONCLUSIONS: This study rules out the previously reported DYT14 locus as a cause of disease, as a novel multiexonic deletion was identified in GCH1. This work highlights the necessity of an accurate clinical diagnosis in linkage studies as well as the need for appropriate allele frequencies, penetrance, and phenocopy estimates. Comprehensive sequencing and dosage analysis of known genes is recommended prior to genome-wide linkage analysis.
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Distonía/genética , GTP Ciclohidrolasa/genética , Levodopa/uso terapéutico , Linaje , Eliminación de Secuencia/genética , Adulto , Anciano , Secuencia de Aminoácidos , Distonía/tratamiento farmacológico , Femenino , Ligamiento Genético/genética , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Sitios de Carácter Cuantitativo/genética , SuizaRESUMEN
Lrrk2 G2019S is predominantly associated with alpha-synuclein-immunopositive Lewy body pathology. We have identified Family SK where Lrrk2 G2019S segregates with slowly progressive parkinsonism and the affected proband has tau-immunopositive neurofibrillary tangle pathology. Thus alpha-synucleinopathy and tauopathy, the predominant pathologies associated with parkinsonism, may be alternate outcomes of the same underlying genetic cause. Intriguingly, we observe no evidence of a direct interaction between either the tau or alpha-synuclein protein with Lrrk2.
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Mutación , Ovillos Neurofibrilares/metabolismo , Trastornos Parkinsonianos/genética , Trastornos Parkinsonianos/patología , Proteínas Serina-Treonina Quinasas/genética , Proteínas tau/metabolismo , Anciano , Encéfalo/metabolismo , Encéfalo/patología , Línea Celular , Evaluación de la Discapacidad , Progresión de la Enfermedad , Femenino , Glicina , Humanos , Inmunohistoquímica , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Masculino , Persona de Mediana Edad , Ovillos Neurofibrilares/patología , Trastornos Parkinsonianos/fisiopatología , Linaje , Serina , alfa-Sinucleína/metabolismoRESUMEN
Mutation of the LRRK2 gene has been associated with autosomal dominant parkinsonism. An R1441C pathogenic substitution was identified in Family D, a large Western Nebraskan kindred, with four members demonstrating pleomorphic pathology at autopsy. One member of this family displayed tau pathology suggestive of progressive supranuclear palsy (PSP). To evaluate the influence of mutation at the R1441 residue in this disorder we screened a series of 242 pathologically confirmed PSP cases. No evidence was found for the presence of a mutation at this codon in our series. These data would suggest that this Lrrk2 variant does not contribute in susceptibility to PSP.
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Encéfalo/patología , Predisposición Genética a la Enfermedad , Proteínas Serina-Treonina Quinasas/genética , Parálisis Supranuclear Progresiva/genética , Anciano , Anciano de 80 o más Años , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Persona de Mediana Edad , MutaciónRESUMEN
We describe a reliable, straightforward procedure for measuring the cholesterol content of serum lipoproteins separated by electrophoresis on cellulose acetate. The lipoprotein fractions are made visible by use of an enzymic reagent and then quantitated by densitometry. Standard electrophoresis equipment is used and the procedure requires just over 1 h for completion. All major fractions except chylomicrons are detected readily. Accuracy and precision agree favorably with results reported for generally accepted methods. Concentration and color development are linearly related to cholesterol concentrations up to 1.5 g/liter in a given lipoprotein fraction. We recommend this method for use in assessing high-density lipoprotein cholesterol and as an aid in lipoprotein phenotyping.