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OBJECTIVE: There are marked mitochondrial abnormalities in parkin-knock-out Drosophila and other model systems. The aim of our study was to determine mitochondrial function and morphology in parkin-mutant patients. We also investigated whether pharmacological rescue of impaired mitochondrial function may be possible in parkin-mutant human tissue. METHODS: We used three sets of techniques, namely, biochemical measurements of mitochondrial function, quantitative morphology, and live cell imaging of functional connectivity to assess the mitochondrial respiratory chain, the outer shape and connectivity of the mitochondria, and their functional inner connectivity in fibroblasts from patients with homozygous or compound heterozygous parkin mutations. RESULTS: Parkin-mutant cells had lower mitochondrial complex I activity and complex I-linked adenosine triphosphate production, which correlated with a greater degree of mitochondrial branching, suggesting that the functional and morphological effects of parkin are related. Knockdown of parkin in control fibroblasts confirmed that parkin deficiency is sufficient to explain these mitochondrial effects. In contrast, 50% knockdown of parkin, mimicking haploinsufficiency in human patient tissue, did not result in impaired mitochondrial function or morphology. Fluorescence recovery after photobleaching assays demonstrated a lower level of functional connectivity of the mitochondrial matrix, which further worsened after rotenone exposure. Treatment with experimental neuroprotective compounds resulted in a rescue of the mitochondrial membrane potential. INTERPRETATION: Our study demonstrates marked abnormalities of mitochondrial function and morphology in parkin-mutant patients and provides proof-of-principle data for the potential usefulness of this new model system as a tool to screen for disease-modifying compounds in genetically homogenous parkinsonian disorders.
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Mitocondrias/metabolismo , Enfermedades Mitocondriales/metabolismo , Mutación/genética , Trastornos Parkinsonianos/complicaciones , Trastornos Parkinsonianos/metabolismo , Ubiquitina-Proteína Ligasas/genética , Adenosina Trifosfato/biosíntesis , Adulto , Células Cultivadas , Regulación hacia Abajo/genética , Evaluación Preclínica de Medicamentos/métodos , Proteínas del Complejo de Cadena de Transporte de Electrón/genética , Metabolismo Energético/genética , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Potencial de la Membrana Mitocondrial/genética , Persona de Mediana Edad , Mitocondrias/genética , Mitocondrias/patología , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/patología , Fármacos Neuroprotectores/farmacología , Trastornos Parkinsonianos/genética , Rotenona/farmacología , Desacopladores/farmacologíaRESUMEN
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been shown to cause autosomal dominant Parkinson's disease. Few mutations in this gene have been identified. We investigated the frequency of a common heterozygous mutation, 2877510 g-->A, which produces a glycine to serine aminoacid substitution at codon 2019 (Gly2019 ser), in idiopathic Parkinson's disease. We assessed 482 patients with the disorder, of whom 263 had pathologically confirmed disease, by direct sequencing for mutations in exon 41 of LRRK2. The mutation was present in eight (1.6%) patients. We have shown that a common single Mendelian mutation is implicated in sporadic Parkinson's disease. We suggest that testing for this mutation will be important in the management and genetic counselling of patients with Parkinson's disease.
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Enfermedad de Parkinson/genética , Mutación Puntual , Proteínas Serina-Treonina Quinasas/genética , Adulto , Anciano , Sustitución de Aminoácidos , Encéfalo/patología , Heterocigoto , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Persona de Mediana Edad , Enfermedad de Parkinson/patologíaRESUMEN
We have established that the frequency of LRRK2 mutations in a series of 118 cases of familial Parkinson's disease is 5.1%. In the largest family with autosomal dominant, late-onset Parkinson's disease where affected subjects share a Y1699C missense mutation we provide a detailed clinical, pathological and imaging report. The phenotype in this large British kindred included asymmetrical, levodopa-responsive parkinsonism where unilateral leg tremor at onset and foot dystonia were prominent features. There was no significant abnormality of cognition but there was prominent behavioural disorder. We observed a lower age of onset in successive generations. Histopathology in one patient showed substantia nigra cell loss and Lewy body formation, with small numbers of cortical Lewy bodies. 18F-dopa positron emission tomography (PET) in another patient showed a pattern of nigrostriatal dysfunction typical of idiopathic Parkinson's disease. 18F-dopa-PET scans in unaffected family members prior to identifying the disease locus did not detect subclinical nigrostriatal dysfunction. Olfaction was assessed in affected subjects and Lewy bodies were identified in the olfactory bulb as well as cortex and brainstem of one deceased patient. In order to assess the role of mutations in this gene in other familial cases we undertook a mutation screen of all 51 exons of LRRK2 in 117 other smaller British kindreds with familial Parkinson's disease. The commonest mutation was G2019S and we also identified two novel mutations, R1941H and T2356I, in the coding sequence. These data suggest that parkinsonism caused by mutations in LRRK2 is likely to represent the commonest locus for autosomal dominant Parkinson's disease with a phenotype, pathology and in vivo imaging similar to idiopathic, late-onset Parkinson's disease.
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Mutación Missense , Enfermedad de Parkinson/genética , Proteínas Serina-Treonina Quinasas/genética , Adulto , Edad de Inicio , Anciano , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Análisis Mutacional de ADN , Inglaterra , Femenino , Genes Dominantes , Ligamiento Genético , Pruebas Genéticas , Haplotipos , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Escala de Lod , Masculino , Persona de Mediana Edad , Mutación Missense/genética , Bulbo Olfatorio/patología , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/patología , Linaje , Tomografía de Emisión de Positrones , RadiofármacosRESUMEN
We provide a pragmatic guide for clinicians, and detail the recent developments in the genetics of Parkinson's disease that have shaped our current understanding and management of this disease and other parkinsonian disorders. These developments have been rapid, and in total over 20 genes have been identified, three of which were discovered in the past year. Although there are undoubtedly more genes to be found, the major challenge for the future is to determine how they function and whether they interact. These genes help us to understand the heterogeneity of parkinsonism, and also inform on the molecular and clinical features of individual parkinsonisms. However, their discovery also requires us to raise issues about genetic testing and genetic counselling.
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Proteínas del Tejido Nervioso/genética , Trastornos Parkinsonianos/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Proteínas Quinasas/genética , Humanos , Trastornos Parkinsonianos/patología , SinucleínasRESUMEN
We undertook the genetic analysis of a classic Li-Fraumeni syndrome (LFS) family with clustering of primary tumours including two maxillary sarcomas, a rare LFS site of tumour occurrence. Our aim was to investigate the presence of a specific type of TP53 mutation that could be associated with this unusual predilection of site for cancer occurrence. Mutational screening of the coding region of TP53 revealed an A>T transversion in codon 144 of exon 5 (CAG>CTG, Gln>Leu) in the germline of one of the three affected members, with loss of heterozygosity (LOH) in the tumour tissue. All other affected members were negative for germline or somatic TP53 mutations. TP53 immunohistochemistry was uninformative. The mutation we report is a de novo constitutional TP53 mutation that has not been previously described in the literature. It could explain the more burdened phenotype of the affected patient (died at 21 months). Alternative mechanisms to explain the overall family phenotype are discussed.
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Genes p53 , Mutación de Línea Germinal/genética , Síndrome de Li-Fraumeni/genética , Neoplasias Maxilares/genética , Adolescente , Adulto , Niño , Preescolar , Condrosarcoma/genética , Femenino , Amplificación de Genes , Genotipo , Humanos , Inmunohistoquímica/métodos , Lactante , Masculino , Osteosarcoma/genética , Linaje , Fenotipo , Polimorfismo Conformacional Retorcido-Simple , Proteína p53 Supresora de Tumor/genéticaRESUMEN
In this review, we address how to best use data from the Human Genome Project to discover new drug targets for common disease. We focus on population genetic approaches to identify variants associated with disease and how these can illuminate new targets and pathways for intervention. We discuss new insights into patterns of human genetic variation, evolving strategies for genome-wide case-control design, and developments in bioinformatic technologies. Hypothesis versus non-hypothesis-driven approaches to target identification are considered.:
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OBJECTIVE: Examine age group effects and sex differences by applying a comprehensive computerized battery of identical behavioral measures linked to brain systems in youths that were already genotyped. Such information is needed to incorporate behavioral data as neuropsychological "biomarkers" in large-scale genomic studies. METHOD: We developed and applied a brief computerized neurocognitive battery that provides measures of performance accuracy and response time for executive-control, episodic memory, complex cognition, social cognition, and sensorimotor speed domains. We tested a population-based sample of 3,500 genotyped youths ages 8-21 years. RESULTS: Substantial improvement with age occurred for both accuracy and speed, but the rates varied by domain. The most pronounced improvement was noted in executive control functions, specifically attention, and in motor speed, with some effect sizes exceeding 1.8 standard deviation units. The least pronounced age group effect was in memory, where only face memory showed a large effect size on improved accuracy. Sex differences had much smaller effect sizes but were evident, with females outperforming males on attention, word and face memory, reasoning speed, and all social cognition tests and males outperforming females in spatial processing and sensorimotor and motor speed. These sex differences in most domains were seen already at the youngest age groups, and age group × sex interactions indicated divergence at the oldest groups with females becoming faster but less accurate than males. CONCLUSIONS: The results indicate that cognitive performance improves substantially in this age span, with large effect sizes that differ by domain. The more pronounced improvement for executive and reasoning domains than for memory suggests that memory capacities have reached their apex before age 8. Performance was sexually modulated and most sex differences were apparent by early adolescence.
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Atención , Desarrollo Infantil , Cognición , Función Ejecutiva , Memoria Episódica , Desempeño Psicomotor , Adolescente , Factores de Edad , Niño , Computadores , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Tiempo de Reacción , Factores Sexuales , Adulto JovenRESUMEN
Mutations in the tau gene (MAPT) have been found in families with frontotemporal dementia with parkinsonism linked to chromosome 17. In addition, the MAPT H1-clade specific sub-haplotype, H1c, has been strongly associated with the tauopathies, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) and, to a lesser extent, with Alzheimer's disease (AD). In Parkinson's disease (PD), there have been several reports of association with the MAPT H1-clade. Although weak to inconclusive, this association is supported by meta-analyses of the various studies. To further investigate this baffling role of MAPT in PD, six haplotype-tagging SNPs were genotyped in a large cohort of sporadic PD cases; 324 pathologically confirmed and 248 clinically diagnosed, and 660 controls. In the single-locus association analysis, the H1-clade was associated with an increased risk of PD (p=0.032). In the haplotype-analysis, the sole H2-derived haplotype was under-represented in all of the PD cases compared to controls (p=0.03). There was no significant difference in the distribution of any of the common haplotypes derived from the H1-clade background. Our study supports the hypothesis that genetic variability in the MAPT gene confers susceptibility to PD. However, the effect is not strong, and the H1c haplotype is not involved, suggesting a mechanism that is distinct to that involved in the associated tauopathies and may be explained by the H1/H2 inversion.
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Predisposición Genética a la Enfermedad/genética , Enfermedad de Parkinson/genética , Polimorfismo de Nucleótido Simple/genética , Proteínas tau/genética , Estudios de Casos y Controles , Estudios de Cohortes , Análisis Mutacional de ADN , Frecuencia de los Genes/genética , Marcadores Genéticos/genética , Pruebas Genéticas , Variación Genética/genética , Genotipo , Haplotipos/genética , Humanos , Degeneración Nerviosa/genéticaRESUMEN
Mutations of the ubiquitin ligase parkin account for most autosomal recessive forms of juvenile Parkinson's disease (AR-JP). Several studies have suggested that parkin possesses DNA-binding and transcriptional activity. We report here that parkin is a p53 transcriptional repressor. First, parkin prevented 6-hydroxydopamine-induced caspase-3 activation in a p53-dependent manner. Concomitantly, parkin reduced p53 expression and activity, an effect abrogated by familial parkin mutations known to either abolish or preserve its ligase activity. ChIP experiments indicate that overexpressed and endogenous parkin interact physically with the p53 promoter and that pathogenic mutations abolish DNA binding to and promoter transactivation of p53. Parkin lowered p53 mRNA levels and repressed p53 promoter transactivation through its Ring1 domain. Conversely, parkin depletion enhanced p53 expression and mRNA levels in fibroblasts and mouse brains, and increased cellular p53 activity and promoter transactivation in cells. Finally, familial parkin missense and deletion mutations enhanced p53 expression in human brains affected by AR-JP. This study reveals a ubiquitin ligase-independent function of parkin in the control of transcription and a functional link between parkin and p53 that is altered by AR-JP mutations.
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Genes Recesivos , Genes p53 , Mutación , Enfermedad de Parkinson/genética , Transcripción Genética/fisiología , Ubiquitina-Proteína Ligasas/fisiología , Adolescente , Humanos , Regiones Promotoras GenéticasRESUMEN
Mitochondrial encephalomyopathy and lactic acidosis with strokelike episodes (MELAS) is a severe young onset stroke disorder without effective treatment. We have identified a MELAS patient harboring a 13528A-->G mitochondrial DNA (mtDNA) mutation in the Complex I ND5 gene. This mutation was homoplasmic in mtDNA from patient muscle and nearly homoplasmic (99.9%) in blood. Fibroblasts from the patient exhibited decreased mitochondrial membrane potential (Deltapsim) and increased lactate production, consistent with impaired mitochondrial function. Transfer of patient mtDNA to a new nuclear background using transmitochondrial cybrid fusions confirmed the pathogenicity of the 13528A-->G mutation; Complex I-linked respiration and Deltapsim were both significantly reduced in patient mtDNA cybrids compared with controls. Inhibition of the adenine nucleotide translocase or the F1F0-ATPase with bongkrekic acid or oligomycin caused a loss of potential in patient mtDNA cybrid mitochondria, indicating a requirement for glycolytically generated ATP to maintain Deltapsim. This was confirmed by inhibition of glycolysis with 2-deoxy-D-glucose, which caused depletion of ATP and mitochondrial depolarization in patient mtDNA cybrids. These data suggest that in response to impaired respiration due to the mtDNA mutation, mitochondria consume ATP to maintain Deltapsim, representing a potential pathophysiological mechanism in human mitochondrial disease.
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Adenosina Trifosfato/metabolismo , Complejo I de Transporte de Electrón/metabolismo , Mitocondrias Musculares/metabolismo , Encefalomiopatías Mitocondriales/metabolismo , Proteínas Mitocondriales/metabolismo , Mutación Puntual , Acidosis Láctica/genética , Acidosis Láctica/metabolismo , Adenosina Trifosfato/genética , Adulto , Antibacterianos/farmacología , Antimetabolitos/farmacología , Ácido Bongcréquico/farmacología , Línea Celular Tumoral , ADN Mitocondrial/genética , Desoxiglucosa/farmacología , Complejo I de Transporte de Electrón/genética , Femenino , Fibroblastos/metabolismo , Glucólisis/efectos de los fármacos , Glucólisis/genética , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Potencial de la Membrana Mitocondrial/genética , Mitocondrias Musculares/genética , Encefalomiopatías Mitocondriales/genética , Proteínas Mitocondriales/genética , Oligomicinas/farmacología , Consumo de Oxígeno/efectos de los fármacos , Consumo de Oxígeno/genética , ATPasas de Translocación de Protón/antagonistas & inhibidores , ATPasas de Translocación de Protón/genética , ATPasas de Translocación de Protón/metabolismo , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/metabolismoRESUMEN
The quest to disentangle the aetiopathogenesis of Parkinson's disease has been heavily influenced by the genes associated with the disease. The alpha-synuclein-centric theory of protein aggregation with the adjunct of parkin-driven proteasome deregulation has, in recent years, been complemented by the discovery and increasing knowledge of the functions of DJ1, PINK1 and OMI/HTRA2, which are all associated with the mitochondria and have been implicated in cellular protection against oxidative damage. We critically review how these genes fit into and enhance our understanding of the role of mitochondrial dysfunction in Parkinson's disease, and consider how oxidative stress might be a potential unifying factor in the aetiopathogenesis of the disease.
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Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/metabolismo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Animales , Serina Peptidasa A2 que Requiere Temperaturas Altas , Humanos , Péptidos y Proteínas de Señalización Intracelular , Mitocondrias/metabolismo , Mitocondrias/patología , Enfermedades Mitocondriales/complicaciones , Proteínas Mitocondriales , Modelos Biológicos , Complejos Multienzimáticos/metabolismo , Proteínas Oncogénicas/genética , Proteínas Oncogénicas/metabolismo , Enfermedad de Parkinson/complicaciones , Proteína Desglicasa DJ-1 , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMEN
The phenotype of 16 members of a family affected by a late-onset, dominant, progressive, motor and autonomic disorder is described. The VAPB (Pro56Ser) mutation was detected in Brazilian families with different phenotypes of motor neuron disorders. In this family, proximal and axial muscle weakness and atrophy, associated with abdominal protrusion, defined the motor phenotype. Death occurred in 10-15 years due to respiratory insufficiency. Tone and tendon reflexes were decreased and a distal tremor was common. Sensation was preserved. Autonomic abnormalities were also present, including choking, chronic intestinal constipation, sexual dysfunction, and sudomotor abnormalities, and on nerve morphology there was involvement of unmyelinated fibers. Electromyography disclosed ongoing denervation and reinnervation. Isolated dysfunction of motor and autonomic neurons is unusual among the spinal muscular atrophies. On this basis, this condition seems to represent a new category of disease.
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Enfermedades del Sistema Nervioso Autónomo/diagnóstico , Enfermedades del Sistema Nervioso Autónomo/genética , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genética , Proteínas de Transporte Vesicular/genética , Adulto , Enfermedades del Sistema Nervioso Autónomo/complicaciones , Brasil , Electromiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Atrofia Muscular Espinal/complicaciones , Mutación , Linaje , Fenotipo , Prolina/química , Prolina/genética , Serina/química , Serina/genéticaRESUMEN
The NR4A2 gene, which may cause autosomal dominant Parkinson's disease (PD), has also been reported to be a susceptibility factor for sporadic PD. Here, we use a haplotype-tagging approach in 802 PD patients and 784 controls and demonstrate that common genetic variation, including NR4A2 haplotypes, does not influence the risk of PD in the Caucasian population.
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Proteínas de Unión al ADN/genética , Predisposición Genética a la Enfermedad , Variación Genética , Enfermedad de Parkinson/genética , Factores de Transcripción/genética , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores NuclearesRESUMEN
OBJECTIVE: To investigate the significance of PINK1 mutations in sporadic Parkinson's disease (PD). METHODS: We determined the frequency of PINK1 mutations by direct sequencing in a large series of PD patients with apparently sporadic disease (n = 768). RESULTS: Twelve heterozygous mutations were identified, nine in PD patients and three in control subjects. INTERPRETATION: Given the difficulty in interpreting the pathogenic significance of the heterozygous mutations that have already been reported in parkin and DJ-1, we first determined the frequency of heterozygous PINK1 mutations in the general population by sequencing a large number of control subjects (n = 768), then subsequently assessed their functional significance by examining their effects on stress-induced alterations to the mitochondrial membrane potential (DeltaPsim). We demonstrate an enrichment of heterozygous mutations in sporadic PD patients compared with matched control subjects (1.2% in PD vs 0.4% in control subjects). Furthermore, we show that they adversely affect DeltaPsim in a similar way to the familial G309D mutation. Although it remains difficult to conclusively demonstrate the pathogenicity of heterozygous mutations, the results of this study and the previously reported subclinical nigrostriatal dysfunction in carriers of heterozygous PINK1 mutations suggest the possibility that these heterozygous mutations are a significant risk factor in the development of later onset PD.
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Mutación/fisiología , Enfermedad de Parkinson/genética , Proteínas Quinasas/genética , Adulto , Edad de Inicio , Anciano , Alelos , Células Cultivadas , Cromosomas/genética , Biología Computacional , Análisis Mutacional de ADN , Femenino , Citometría de Flujo , Frecuencia de los Genes , Heterocigoto , Humanos , Masculino , Potenciales de la Membrana/fisiología , Persona de Mediana Edad , Mitocondrias/fisiología , Sistemas de Lectura Abierta/genética , TransfecciónRESUMEN
Following our identification of PTEN-induced putative kinase 1 (PINK1) gene mutations in PARK6-linked Parkinson's disease (PD), we have recently reported that PINK1 protein localizes to Lewy bodies (LBs) in PD brains. We have used a cellular model system of LBs, namely induction of aggresomes, to determine how a mitochondrial protein, such as PINK1, can localize to aggregates. Using specific polyclonal antibodies, we firstly demonstrated that human PINK1 was cleaved and localized to mitochondria. We demonstrated that, on proteasome inhibition with MG-132, PINK1 and other mitochondrial proteins localized to aggresomes. Ultrastructural studies revealed that the mechanism was linked to the recruitment of intact mitochondria to the aggresome. Fractionation studies of lysates showed that PINK1 cleavage was enhanced by proteasomal stress in vitro and correlated with increased expression of the processed PINK1 protein in PD brain. These observations provide valuable insights into the mechanisms of LB formation in PD that should lead to a better understanding of PD pathogenesis.
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Complejo de la Endopetidasa Proteasomal , Proteínas Quinasas/metabolismo , Estrés Fisiológico/metabolismo , Animales , Western Blotting/métodos , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/ultraestructura , Línea Celular , Clonación Molecular/métodos , Cricetinae , Inhibidores de Cisteína Proteinasa/farmacología , Inhibidores Enzimáticos/farmacología , Técnica del Anticuerpo Fluorescente/métodos , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Leupeptinas/farmacología , Microscopía Inmunoelectrónica/métodos , Mitocondrias/metabolismo , Mitocondrias/ultraestructura , Proteínas Mutantes/genética , Proteínas Mutantes/fisiología , Proteínas del Tejido Nervioso/metabolismo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Proteínas Quinasas/genética , Estrés Fisiológico/inducido químicamente , Transfección/métodosRESUMEN
OBJECTIVE: The UCHL-1 gene is widely cited as a susceptibility factor for sporadic Parkinson's disease (PD). The strongest evidence comes from a meta-analysis of small studies that reported the S18Y polymorphism as protective against PD, after pooling studies of white and Asian subjects. Here, we present data that challenge this association. METHODS: In a new large case-control study in white individuals (3,023 subjects), the S18Y variant was not protective against PD under any genetic model of inheritance. Similarly, a more powerful haplotype-tagging approach did not detect other associated variants. RESULTS: Finally, in an updated S18Y-PD meta-analysis (6,594 subjects), no significant association was observed under additive, recessive, or dominant models (odds ratio = 1.00 [95% confidence interval: 0.74-1.33]; odds ratio = 1.01 [95% confidence interval: 0.76-1.35]; and odds ratio = 0.96 [95% confidence interval: 0.86-1.08], respectively), and a cumulative meta-analysis showed a trend toward a null effect. INTERPRETATION: Based on the current evidence, the UCHL-1 gene does not exhibit a protective effect in PD.
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Desequilibrio de Ligamiento , Enfermedad de Parkinson/genética , Polimorfismo Genético , Ubiquitina Tiolesterasa/genética , Estudios de Casos y Controles , Intervalos de Confianza , Femenino , Genotipo , Humanos , Masculino , Metaanálisis como Asunto , Persona de Mediana Edad , Oportunidad Relativa , Serina/genética , Tirosina/genéticaRESUMEN
To date, the etiology of multiple system atrophy (MSA) has proved impenetrable. We investigated the role of genetic variation in the UCHL-1 gene in MSA and looked for the presence of disease susceptibility alleles. We determined the linkage disequilibrium structure of the gene and employed a haplotype tagging strategy with power to represent 95% of the haplotype diversity. This approach was performed using a set of tagging single nucleotide polymorphisms (SNPs) that can infer the allelic state of all the common SNPs in UCHL-1 with a high coefficient of determination. This strategy enabled us to scan across the gene and maintain the power to detect signal(s) from any potential functional variant(s). In 257 Gilman-probable or -definite MSA subjects and 1,536 controls, we did not detect a case-control frequency difference for either the tagged haplotypes or for individual tagging SNPs. This search included the S18Y variant of UCHL-1, which has been reported to be protective in Parkinson's disease.
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Etiquetas de Secuencia Expresada/metabolismo , Biblioteca de Genes , Haplotipos/genética , Atrofia de Múltiples Sistemas/genética , Atrofia de Múltiples Sistemas/metabolismo , Ubiquitina Tiolesterasa/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Genotipo , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
The identification of Mendelian mutations in rare forms of familial Parkinson's disease (PD) have provided significant insights into the molecular pathogenesis of this common complex disorder. DJ-1 is the third of four genes known to be definitively causal in familial PD, the three others being alpha-synuclein, parkin and the recently identified PINK1. Mutations in the DJ-1 gene were identified in two European families, a Dutch kindred harbouring a large homozygous genomic deletion encompassing exons 1-5 of the gene and an Italian kindred with a homozygous L166P missense mutation. The clinical phenotype of the two families was similar to that of parkin cases. Age of onset was in the mid-thirties with good responsiveness to l-dopa and slow disease progression. Focal dystonias and blepharospasm were also evident as were behavioural disturbances early in the course of the disease. To date, there are no studies of pathological material from known DJ-1 patients. It therefore remains to be determined whether these patients form Lewy bodies and/or Lewy neurites, the eosinophilic fibrillary inclusions that contain predominantly alpha-synuclein and that are the pathological hallmark of PD.