RESUMEN
BACKGROUND: Recently, a novel mutation in exon 24 of DNAJC13 gene (p.Asn855Ser, rs387907571) has been reported to cause autosomal dominant Parkinson's disease (PD) in a multi-incident Mennonite family. METHODS: In the present study the mutation containing exon of the DNAJC13 gene has been sequenced in a Caucasian series consisting of 1938 patients with clinical PD and 838 with pathologically diagnosed Lewy body disease (LBD). RESULTS: Our sequence analysis did not identify any coding variants in exon 24 of DNAJC13. Two previously described variants in intron 23 (rs200204728 and rs2369796) were observed. CONCLUSION: Our results indicate that the region surrounding the DNAJC13 p.Asn855Ser substitution is highly conserved and mutations in this exon are not a common cause of PD or LBD among Caucasian populations.
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Enfermedad por Cuerpos de Lewy/genética , Chaperonas Moleculares/genética , Enfermedad de Parkinson/genética , Adulto , Anciano , Anciano de 80 o más Años , Europa (Continente) , Exones , Femenino , Humanos , Masculino , Persona de Mediana Edad , MutaciónRESUMEN
Mutations in the LRRK2 gene represent the most common genetic cause of late onset Parkinson's disease. The physiological and pathological roles of LRRK2 are yet to be fully determined but evidence points towards LRRK2 mutations causing a gain in kinase function, impacting on neuronal maintenance, vesicular dynamics and neurotransmitter release. To explore the role of physiological levels of mutant LRRK2, we created knock-in (KI) mice harboring the most common LRRK2 mutation G2019S in their own genome. We have performed comprehensive dopaminergic, behavioral and neuropathological analyses in this model up to 24months of age. We find elevated kinase activity in the brain of both heterozygous and homozygous mice. Although normal at 6months, by 12months of age, basal and pharmacologically induced extracellular release of dopamine is impaired in both heterozygous and homozygous mice, corroborating previous findings in transgenic models over-expressing mutant LRRK2. Via in vivo microdialysis measurement of basal and drug-evoked extracellular release of dopamine and its metabolites, our findings indicate that exocytotic release from the vesicular pool is impaired. Furthermore, profound mitochondrial abnormalities are evident in the striatum of older homozygous G2019S KI mice, which are consistent with mitochondrial fission arrest. We anticipate that this G2019S mouse line will be a useful pre-clinical model for further evaluation of early mechanistic events in LRRK2 pathogenesis and for second-hit approaches to model disease progression.
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Encéfalo/enzimología , Dopamina/metabolismo , Mitocondrias/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/fisiología , Animales , Autofagia/genética , Encéfalo/metabolismo , Encéfalo/ultraestructura , Neuronas Dopaminérgicas/metabolismo , Femenino , Técnicas de Sustitución del Gen , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mitocondrias/ultraestructura , Actividad Motora/genética , Prueba de Desempeño de Rotación con Aceleración Constante , Proteínas tau/metabolismoRESUMEN
Vacuolar protein sorting 35 (VPS35) is a core component of the retromer complex, crucial to endosomal protein sorting and intracellular trafficking. We recently linked a mutation in VPS35 (p.D620N) to familial parkinsonism. Here, we characterize human VPS35 and retromer function in mature murine neuronal cultures and investigate neuron-specific consequences of the p.D620N mutation. We find VPS35 localizes to dendritic spines and is involved in the trafficking of excitatory AMPA-type glutamate receptors (AMPARs). Fundamental neuronal processes, including excitatory synaptic transmission, AMPAR surface expression and synaptic recycling are altered by VPS35 overexpression. VPS35 p.D620N acts as a loss-of-function mutation with respect to VPS35 activity regulating synaptic transmission and AMPAR recycling in mouse cortical neurons and dopamine neuron-like cells produced from induced pluripotent stem cells of human p.D620N carriers. Such perturbations to synaptic function likely produce chronic pathophysiological stress upon neuronal circuits that may contribute to neurodegeneration in this, and other, forms of parkinsonism.
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Mutación Missense , Neuronas/metabolismo , Enfermedad de Parkinson/genética , Receptores de Glutamato/metabolismo , Proteínas de Transporte Vesicular/genética , Animales , Espinas Dendríticas/metabolismo , Humanos , Ratones , Transporte de Proteínas , Sinapsis/metabolismoRESUMEN
BACKGROUND AND PURPOSE: Exome sequencing analysis has recently identified a nonsense mutation in fused in sarcoma (FUS) segregating with essential tremor (ET) within a large French-Canadian family. Further characterization of FUS resulted in the identification of additional mutations in ET patients; however, their pathogenicity still remains to be confirmed. The role of FUS in an independent cohort of ET patients from Canada was evaluated. METHODS: The entire coding sequence of FUS in 217 patients diagnosed with ET was analyzed and two missense variants in 219 healthy controls were genotyped by Sanger sequencing. RESULTS: Sequencing of FUS identified a previously reported non-pathogenic mutation p.G174_G175del in one ET patient and two healthy controls, and a novel p.R377W in one patient with family history of disease. This mutation is highly conserved and strongly predicted to be damaging by in silico analysis. CONCLUSION: This study has identified a novel FUS p.R377W substitution in ET patients. Additional genotyping studies in a large number of ET patients and controls are necessary to conclusively define its pathogenicity.
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Temblor Esencial/genética , Predisposición Genética a la Enfermedad , Genotipo , Proteína FUS de Unión a ARN/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Asociación Genética , Variación Genética , Humanos , Masculino , Persona de Mediana EdadRESUMEN
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.
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Proteínas Reguladoras de la Apoptosis/genética , Proteínas Quinasas Dependientes de Calcio-Calmodulina/genética , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Enfermedad de Parkinson/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Proteínas Quinasas Asociadas a Muerte Celular , Femenino , Predisposición Genética a la Enfermedad/etnología , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/etnología , Multimerización de Proteína , Adulto JovenRESUMEN
BACKGROUND: Previous epidemiologic and genetic studies have suggested a link between Parkinson disease (PD), essential tremor (ET), and restless legs syndrome (RLS). METHODS: We describe the clinical, PET, and pathologic characteristics of an extensive kindred from Arkansas with hereditary PD, ET, and RLS. The pedigree contains 138 individuals. Sixty-five family members were examined neurologically up to 3 times from 2004 to 2010. Clinical data were collected from medical records and questionnaires. Genetic studies were performed. Five family members underwent multitracer PET. Two individuals with PD were examined postmortem. RESULTS: Eleven family members had PD with generally mild and slowly progressive symptoms. Age at onset was between 39 and 74 years (mean 59.1, SD 13.4). All individuals treated with l-dopa responded positively. Postural or action tremor was present in 6 individuals with PD, and in 19 additional family members. Fifteen persons reported symptoms of RLS. PET showed reduced presynaptic dopamine function typical of sporadic PD in a patient with PD and ET, but not in persons with ET or RLS. The inheritance pattern was autosomal dominant for PD and RLS. No known pathogenic mutation in PD-related genes was found. Fourteen of the family members with PD, ET, or RLS had depression. Neuropathologic examination revealed pallidonigral pigment spheroid degeneration with ubiquitin-positive axonal spheroids, TDP43-positive pathology in the basal ganglia, hippocampus, and brainstem, and only sparse Lewy bodies. CONCLUSION: Familial forms of PD, ET, RLS, and depression occur in this family. The genetic cause remains to be elucidated.
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Depresión/complicaciones , Temblor Esencial/complicaciones , Salud de la Familia , Trastornos Parkinsonianos/complicaciones , Síndrome de las Piernas Inquietas/complicaciones , Adulto , Anciano , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Encéfalo/patología , Proteínas de Unión al ADN/metabolismo , Depresión/diagnóstico por imagen , Depresión/genética , Complejo Dinactina , Temblor Esencial/diagnóstico por imagen , Temblor Esencial/genética , Factor 4G Eucariótico de Iniciación/genética , Femenino , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Estudios Longitudinales , Masculino , Escala del Estado Mental , Proteínas Asociadas a Microtúbulos/genética , Persona de Mediana Edad , Trastornos Parkinsonianos/diagnóstico por imagen , Trastornos Parkinsonianos/genética , Tomografía de Emisión de Positrones/métodos , Proteínas Serina-Treonina Quinasas/genética , Síndrome de las Piernas Inquietas/diagnóstico por imagen , Síndrome de las Piernas Inquietas/genética , alfa-Sinucleína/genéticaAsunto(s)
Temblor Esencial/genética , Predisposición Genética a la Enfermedad/genética , Haplotipos/genética , Atrofia de Múltiples Sistemas/genética , Polimorfismo de Nucleótido Simple/genética , Proteínas tau/genética , Distribución de Chi-Cuadrado , Análisis Mutacional de ADN , Temblor Esencial/etiología , Frecuencia de los Genes , Humanos , Atrofia de Múltiples Sistemas/etiología , Oportunidad Relativa , Factores de RiesgoRESUMEN
The generation and maturation of adult neural stem/progenitor cells are impaired in many neurodegenerative diseases, among them is Parkinson's disease (PD). In mammals, including humans, adult neurogenesis is a lifelong feature of cellular brain plasticity in the hippocampal dentate gyrus (DG) and in the subventricular zone (SVZ)/olfactory bulb system. Hyposmia, depression, and anxiety are early non-motor symptoms in PD. There are parallels between brain regions associated with non-motor symptoms in PD and neurogenic regions. In autosomal dominant PD, mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are frequent. LRRK2 homologs in non-vertebrate systems play an important role in chemotaxis, cell polarity, and neurite arborization. We investigated adult neurogenesis and the neurite development of new neurons in the DG and SVZ/olfactory bulb system in bacterial artificial chromosome (BAC) human Lrrk2 G2019S transgenic mice. We report that mutant human Lrrk2 is highly expressed in the hippocampus in the DG and the SVZ of adult Lrrk2 G2019S mice. Proliferation of newly generated cells is significantly decreased and survival of newly generated neurons in the DG and olfactory bulb is also severely impaired. In addition, after stereotactic injection of a GFP retrovirus, newly generated neurons in the DG of Lrrk2 G2019S mice exhibited reduced dendritic arborization and fewer spines. This loss in mature, developed spines might point towards a decrease in synaptic connectivity. Interestingly, physical activity partially reverses the decrease in neuroblasts observed in Lrrk2 G2010S mice. These data further support a role for Lrrk2 in neuronal morphogenesis and provide new insights into the role of Lrrk2 in adult neurogenesis.
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Hipocampo/metabolismo , Neuritas/fisiología , Neurogénesis/genética , Proteínas Serina-Treonina Quinasas/biosíntesis , Proteínas Serina-Treonina Quinasas/genética , Animales , Supervivencia Celular/genética , Glicina/genética , Hipocampo/citología , Hipocampo/patología , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Ratones , Ratones Transgénicos , Neuritas/patología , Condicionamiento Físico Animal/fisiología , Serina/genéticaRESUMEN
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.
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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
OBJECTIVES: To analyze the frequency of mutations associated with Parkinson's disease (PD) in a general PD population compared to patients with PD selected for deep brain stimulation (DBS) and evaluate the outcome of surgery. MATERIAL AND METHODS: A total of 630 consecutive patients with PD were genetically screened, and 60 had DBS surgery, 37 subthalamic nucleus (STN), 21 ventrointermediate nucleus of thalamus (VIM), and two globus pallidus internus (GPi). RESULTS: Mutations in LRRK2, PRKN, and PINK1 were found: the first two of these being overrepresented in STN-operated patients, but none being found in VIM-operated patients. Clinical outcome of the surgery was similar in patients with mutations compared to those without. CONCLUSIONS: In a consecutive PD population, patients treated with STN-DBS are overrepresented for PD-related mutations and they seem to benefit from DBS as well as patients without mutations.
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Estimulación Encefálica Profunda/métodos , Predisposición Genética a la Enfermedad/genética , Mutación/genética , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/terapia , Anciano , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/epidemiología , Estudios RetrospectivosRESUMEN
Mutations in the Leucine Rich Repeat Kinase 2 (LRRK2) gene, first described in 2004 have now emerged as the most important genetic finding in both autosomal dominant and sporadic Parkinson's disease (PD). While a formidable research effort has ensued since the initial gene discovery, little is known of either the normal or the pathological role of LRRK2. We have created lines of mice that express human wild-type (hWT) or G2019S Lrrk2 via bacterial artificial chromosome (BAC) transgenesis. In vivo analysis of the dopaminergic system revealed abnormal dopamine neurotransmission in both hWT and G2019S transgenic mice evidenced by a decrease in extra-cellular dopamine levels, which was detected without pharmacological manipulation. Immunopathological analysis revealed changes in localization and increased phosphorylation of microtubule binding protein tau in G2019S mice. Quantitative biochemical analysis confirmed the presence of differential phospho-tau species in G2019S mice but surprisingly, upon dephosphorylation the tau isoform banding pattern in G2019S mice remained altered. This suggests that other post-translational modifications of tau occur in G2019S mice. We hypothesize that Lrrk2 may impact on tau processing which subsequently leads to increased phosphorylation. Our models will be useful for further understanding of the mechanistic actions of LRRK2 and future therapeutic screening.
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Encéfalo/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Transmisión Sináptica/fisiología , Proteínas tau/metabolismo , Animales , Autorradiografía , Cromatografía Líquida de Alta Presión , Cromosomas Artificiales Bacterianos , Dopamina/metabolismo , Humanos , Immunoblotting , Hibridación in Situ , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Masculino , Ratones , Ratones Transgénicos , Microdiálisis , Fosforilación , Procesamiento Proteico-Postraduccional , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
The Leucine Rich Repeat Kinase-2 (LRRK2) gene is a common mutation target in Parkinson's disease (PD), but the cellular mechanisms by which such mutations underlie the pathophysiology of PD remain poorly understood. Thus, to better characterize the neuronal target sites of LRRK2 mutations in the primate brain, we studied the cellular and ultrastructural localization of Lrrk2 immunoreactivity in the monkey basal ganglia. As previously described, the monkey striatum was the most enriched basal ganglia structure in Lrrk2 labeling. Both projection neurons and parvalbumin-containing GABAergic interneurons displayed Lrrk2 immunoreactivity. At the electron microscopic level, striatal Lrrk2 labeling was associated predominantly with dendritic shafts and subsets of putative glutamatergic axon terminals. At the pallidal level, moderate cellular Lrrk2 immunostaining was found in the external globus pallidus (GPe), while neurons in the internal globus pallidus (GPi) were devoid of Lrrk2 immunoreactivity. Strong labeling was associated with cholinergic neurons in the nucleus basalis of Meynert. Midbrain dopaminergic neurons in the primate substantia nigra pars compacta (SNc) and ventral tegmental area harbored a significant level of Lrrk2 labeling, while neurons in the subthalamic nucleus were lightly immunostained. Most thalamic nuclei were enriched in Lrrk2 immunoreactivity, except for the centromedian nucleus that was completely devoid of labeling. Thus, Lrrk2 protein is widely distributed in the monkey basal ganglia, suggesting that gene mutations in PD may result in multifarious pathophysiological effects that could impact various target sites in the functional circuitry of the primate basal ganglia.
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Ganglios Basales/enzimología , Proteínas Serina-Treonina Quinasas/metabolismo , Tálamo/enzimología , Animales , Ganglios Basales/ultraestructura , Núcleo Caudado/enzimología , Núcleo Caudado/ultraestructura , Macaca mulatta , Putamen/enzimología , Putamen/ultraestructura , Tálamo/ultraestructuraRESUMEN
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.
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Enfermedad de Parkinson/genética , Polimorfismo de Nucleótido Simple , Proteína G de Unión al Calcio S100/genética , Adulto , Anciano , Anciano de 80 o más Años , Calbindina 1 , Calbindinas , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Irlanda , Masculino , Persona de Mediana Edad , Noruega , Polonia , Factores de Riesgo , Análisis de Secuencia de ADN , Estados Unidos , Población Blanca/genéticaRESUMEN
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.
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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
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.
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Glucosilceramidasa/genética , Mutación , Enfermedad de Parkinson/genética , Anciano , Estudios de Casos y Controles , Genotipo , Humanos , Judíos/genética , Modelos Logísticos , Persona de Mediana Edad , Análisis Multivariante , Oportunidad RelativaAsunto(s)
Predisposición Genética a la Enfermedad/genética , Proteínas de Homeodominio/genética , Mutación/genética , Proteínas de Neoplasias/genética , Síndrome de las Piernas Inquietas/epidemiología , Síndrome de las Piernas Inquietas/genética , Anciano , Secuencia de Bases , Estudios de Casos y Controles , Secuencia Conservada/genética , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Marcadores Genéticos/genética , Pruebas Genéticas , Genotipo , Humanos , Patrón de Herencia/genética , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Proteína 1 del Sitio de Integración Viral Ecotrópica Mieloide , Proteínas del Tejido Nervioso , Linaje , Prevalencia , Estructura Terciaria de Proteína/genética , Síndrome de las Piernas Inquietas/fisiopatología , Factores de Transcripción/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
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.