34 results on '"Simons EJ"'
Search Results
2. GIGYF2 mutations are not a frequent cause of familial Parkinson's disease
- Author
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Di Fonzo, A, Fabrizio, E, Thomas, A, Fincati, E, Marconi, R, Tinazzi, M, Breedveld, Gj, Simons, Ej, Chien, Hf, Ferreira, Jj, Horstink, Mw, Abbruzzese, G, Borroni, B, Cossu, G, Dalla Libera, A, Fabbrini, G, Guidi, M, De Mari, M, Lopiano, L, Martignoni, E, Marini, P, Onofrj, M, Padovani, A, Stocchi, F, Toni, V, Sampaio, C, Barbosa, Er, Meco, G, Italian Parkinson Genetics Network, Oostra, Ba, CollaboratorsBonifati V, Bonifati V., Giraudo, S, Tassorelli, C, Pacchetti, C, Nappi, G, Riboldazzi, G, Bono, GIORGIO GIOVANNI, Raudino, F, Manfredi, M, Bonizzato, A, Ferracci, C, Marchese, R, Montagna, P, Massaro, F, Minardi, C, Rasi, F, Vanacore, N, Berardelli, A, Vacca, L, De Pandis, F, Dell'Aquila, C, Iliceto, G, Lamberti, P, Trianni, G, Mauro, A, De Gaetano, A, Rizzo, M, and Cossu, G.
- Published
- 2009
3. ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease
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Di Fonzo, A, Fabrizio, E, Thomas, A, Fincati, E, Marconi, R, Tinazzi, M, Breedveld, Gj, Simons, Ej, Chien, Hf, Ferreira, Jj, Horstink, Mw, Abbruzzese, G, Borroni, B, Cossu, G, Dalla Libera, A, Fabbrini, G, Guidi, M, De Mari, M, Lopiano, L, Martignoni, E, Marini, P, Onofrj, M, Padovani, A, Stocchi, F, Toni, V, Sampaio, C, Barbosa, Er, Meco, G, Antonini, A, Oostra BA, Bonifati V., Di Fonzo A., Chien H.F., Socal M., Giraudo S., Tassorelli C., Illiceto G., Fabbrini G., Marconi R., Fincati E., Abbruzzese G., Marini P., Squitieri F., Horstink M.W., Montagna P., Libera A.D., Stocchi F., Goldwurm S., Ferreira J.J., Meco G., Martignoni E., Lopiano L., Jardim L.B., OOstra B.A., Barbosa E.R., The Italian Parkinson Genetics Network, Bonifati V., Erasmus MC other, and Clinical Genetics
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Adolescent ,Genotype ,assessment ,DNA Mutational Analysis ,Mutation, Missense ,patients ,Central nervous system disease ,Cohort Studies ,Diagnosis, Differential ,Degenerative disease ,Parkinsonian Disorders ,medicine ,Prevalence ,Dementia ,Missense mutation ,Humans ,Genetic Predisposition to Disease ,young onset Parkinson disease ,Genetic Testing ,Age of Onset ,juvenile parkinsonism ,Child ,Genetics ,business.industry ,Parkinsonism ,ATP13A2 gene mutations ,Brain ,Parkinson Disease ,Middle Aged ,medicine.disease ,Young onset Parkinson disease ,Proton-Translocating ATPases ,Phenotype ,Italy ,Kufor Rakeb syndrome ,Female ,Neurology (clinical) ,business ,Brazil - Abstract
To assess the prevalence, nature, and associated phenotypes of ATP13A2 gene mutations among patients with juvenile parkinsonism (onset21 years) or young onset (between 21 and 40 years) Parkinson disease (YOPD).We studied 46 patients, mostly from Italy or Brazil, including 11 with juvenile parkinsonism and 35 with YOPD. Thirty-three cases were sporadic and 13 had positive family history compatible with autosomal recessive inheritance. Forty-two had only parkinsonian signs, while four (all juvenile-onset) had multisystemic involvement. The whole ATP13A2 coding region (29 exons) and exon-intron boundaries were sequenced from genomic DNA.A novel homozygous missense mutation (Gly504Arg) was identified in one sporadic case from Brazil with juvenile parkinsonism. This patient had symptoms onset at age 12, levodopa-responsive severe akinetic-rigid parkinsonism, levodopa-induced motor fluctuations and dyskinesias, severe visual hallucinations, and supranuclear vertical gaze paresis, but no pyramidal deficit nor dementia. Brain CT scan showed moderate diffuse atrophy. Furthermore, two Italian cases with YOPD without atypical features carried a novel missense mutation (Thr12Met, Gly533Arg) in single heterozygous state.We confirm that ATP13A2 homozygous mutations are associated with human parkinsonism, and expand the associated genotypic and clinical spectrum, by describing a homozygous missense mutation in this gene in a patient with a phenotype milder than that initially associated with ATP13A2 mutations (Kufor-Rakeb syndrome). Our data also suggest that ATP13A2 single heterozygous mutations might be etiologically relevant for patients with YOPD and further studies of this gene in Parkinson disease are warranted.
- Published
- 2007
4. Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease
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Di Fonzo, A, Tassorelli, C, De Mari, M, Chien, Hf, Ferreira, J, Rohé, Cf, Riboldazzi, G, Antonini, A, Albani, G, Mauro, A, Marconi, R, Abbruzzese, G, Lopiano, L, Fincati, E, Guidi, M, Marini, P, Stocchi, F, Onofrj, M, Toni, V, Tinazzi, M, Fabbrini, G, Lamberti, P, Vanacore, N, Meco, G, Leitner, P, Uitti, Rj, Wszolek, Zk, Gasser, T, Simons, Ej, Breedveld, Gj, Goldwurm, S, Pezzoli, G, Sampaio, C, Barbosa, E, Martignoni, E, Oostra, Ba, Bonifati, V, Vancore, N, Fabrizio, E, Locuratolo, N, Martini, L, Scoppetta, C, Colosimo, C, Manfredi, Ma, Tavella, A, Bergamasco, B, Pacchetti, C, Nappi, G, Canesi, M, Calandrella, D, Brono, G, Manfredi, Mi, Raudino, F, Corengia, E, Bonizzato, A, Ferracci, C, Dalla Libera, A, Marchese, R, Montagna, P, Ramat, S, Massaro, F, Minardi, C, Rasi, F, Thomas, A, Vacca, L, De Pandis, F, Diroma, C, Iliceto, G, Trianni, G, De Gaetano, A, Rizzo, M, and Cossu, G.
- Published
- 2006
5. Enriching CRISs through new services for OA repositories
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Dekeyser, Raf, Prosser, David, Asserson, AGS, and Simons, EJ
- Abstract
During the past years several proposals have been formulated or developed for adding new functionality to the network of Open Access Repositories ofr scholarly papers. The workshop is intended to discuss how the content of CRISs can be enriched through linkingt with these new services. ispartof: pages:219-222 ispartof: Enabling interaction and quality: beyond the Hanseatic League pages:219-222 ispartof: International Conference on Current Reseach Information Systems location:Bergen, Norway date:11 May - 13 May 2006 status: published
- Published
- 2006
6. The Opportunities and Challenges of Gene Therapy for Treatment of Inherited Forms of Vision and Hearing Loss.
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Simons EJ and Trapani I
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- Animals, Blindness, Genetic Therapy, Hearing Loss genetics, Hearing Loss therapy, Deaf-Blind Disorders, Deafness genetics, Deafness therapy
- Abstract
Inherited forms of blindness and deafness are highly prevalent and severe conditions that significantly impact the lives of millions of people worldwide. The lack of therapeutic options for these conditions poses a major socioeconomic burden. Over the last decades, gene therapy has proven to be a life changing treatment for hereditary and acquired forms of diseases, and extensive preclinical investigation in animal models of both retinal and inner ear disorders has highlighted promising translational opportunities for these disorders too. This led to dozens of clinical trials investigating the efficiency of gene therapy-based approaches, with some of the products for retinal conditions successfully reaching phase III of development or even market authorization. However, challenges remain for the use of gene therapy, which are related to both the features of the delivery vehicles currently available and characteristics of the retinal and inner ear disorders targeted. Therefore, further developments in gene therapy platforms' design, including exploitation of novel technologies such as genome editing, RNA-targeted therapies, and optogenetics, are actively ongoing, driving the field forward. In this study, we review the ongoing applications and achievements of gene therapy for treatment of inherited forms of blindness and deafness as well as the developments that are being pursued in the field to overcome the current limitations.
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- 2023
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7. Uterine lavage identifies cancer mutations and increased TP53 somatic mutation burden in individuals with ovarian cancer.
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Ghezelayagh TS, Kohrn BF, Fredrickson J, Manhardt E, Radke MR, Katz R, Gray HJ, Urban RR, Pennington KP, Liao JB, Doll KM, Simons EJ, Burzawa JK, Goff BA, Speiser P, Swisher EM, Norquist BM, and Risques RA
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- Humans, Female, Mutation genetics, Clonal Evolution, Tumor Suppressor Protein p53 genetics, Therapeutic Irrigation, Ovarian Neoplasms genetics
- Abstract
Current screening methods for ovarian cancer (OC) have failed to demonstrate a significant reduction in mortality. Uterine lavage combined with TP53 ultra-deep sequencing for the detection of disseminated OC cells has emerged as a promising tool, but this approach has not been tested for early-stage disease or non-serous histologies. In addition, lavages carry multiple background mutations, the significance of which is poorly understood. Uterine lavage was collected preoperatively in 34 patients undergoing surgery for suspected ovarian malignancy including 14 patients with benign disease and 20 patients with OC (6 non-serous and 14 high grade serous-like (serous)). Ultra-deep duplex sequencing (~3000x) with a panel of common OC genes identified the tumor mutation in 33% of non-serous (all early stage) and in 79% of serous cancers (including four early stage). In addition, all lavages carried multiple somatic mutations (average of 25 mutations per lavage), more than half of which corresponded to common cancer driver mutations. Driver mutations in KRAS, PIK3CA, PTEN, PPP2R1A and ARID1A presented as larger clones than non-driver mutations and with similar frequency in lavages from patients with and without OC, indicating prevalent somatic evolution in all patients. Driver TP53 mutations, however, presented as significantly larger clones and with higher frequency in lavages from individuals with OC, suggesting that TP53 -specific clonal expansions are linked to ovarian cancer development. Our results demonstrate that lavages capture cancer cells, even from early-stage cancers, as well as other clonal expansions and support further exploration of TP53 mutation burden as a potential OC risk factor.
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- 2022
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8. Genetic Medicine for Hearing Loss: OTOF as Exemplar.
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Hickox AE, Valero MD, McLaughlin JT, Robinson GS, Wellman JA, McKenna MJ, Sewell WF, and Simons EJ
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- Hearing, Humans, Membrane Proteins genetics, Mutation, Deafness, Hearing Loss genetics, Hearing Loss, Sensorineural genetics
- Abstract
Millions of people worldwide have disabling hearing loss because one of their genes generates an incorrect version of some specific protein the ear requires for hearing. In many of these cases, delivering the correct version of the gene to a specific target cell within the inner ear has the potential to restore cochlear function to enable high-acuity physiologic hearing. Purpose: In this review, we outline our strategy for the development of genetic medicines with the potential to treat hearing loss. We will use the example of otoferlin gene ( OTOF )-mediated hearing loss, a sensorineural hearing loss due to autosomal recessive mutations of the OTOF gene., Competing Interests: None declared., (American Academy of Audiology. This article is published by Thieme.)
- Published
- 2021
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9. Epithelioid angiosarcoma arising in a uterine leiomyoma with associated elevated CA-125: A case report.
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Strickland SV, Kilgore MR, Simons EJ, and Rendi MH
- Abstract
We describe the case of a 67 year old female with longstanding uterine leiomyomas who presented with fatigue, weight loss, elevated CA-125 and an enlarging mass arising from the posterior uterine fundus. Histologic sections of the mass contained a leiomyoma with interspersed foci of malignant epithelioid cells forming anastomosing vascular channels. The neoplastic cells were diffusely positive for CD31 and FLI1, supporting the morphologic impression of epithelioid angiosarcoma. Few cases of epithelioid angiosarcoma arising within a leiomyoma have been described. In this report we discuss this association and describe its relation with elevated CA-125.
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- 2017
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10. Strategies for B-cell receptor repertoire analysis in primary immunodeficiencies: from severe combined immunodeficiency to common variable immunodeficiency.
- Author
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IJspeert H, Wentink M, van Zessen D, Driessen GJ, Dalm VA, van Hagen MP, Pico-Knijnenburg I, Simons EJ, van Dongen JJ, Stubbs AP, and van der Burg M
- Abstract
The antigen receptor repertoires of B- and T-cells form the basis of the adaptive immune response. The repertoires should be sufficiently diverse to recognize all possible pathogens. However, careful selection is needed to prevent responses to self or harmless antigens. Limited antigen receptor repertoire diversity leads to immunodeficiency, whereas unselected or misdirected repertoires can result in autoimmunity. The antigen receptor repertoire harbors information about abnormalities in many immunological disorders. Recent developments in next generation sequencing allow the analysis of the antigen receptor repertoire in much greater detail than ever before. Analyzing the antigen receptor repertoire in patients with mutations in genes responsible for the generation of the antigen receptor repertoire will give new insights into repertoire formation and selection. In this perspective, we describe strategies and considerations for analysis of the naive and antigen-selected B-cell repertoires in primary immunodeficiency patients with a focus on severe combined immunodeficiency and common variable immunodeficiency.
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- 2015
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11. Novel GCH1 variant in Dopa-responsive dystonia and Parkinson's disease.
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Lewthwaite AJ, Lambert TD, Rolfe EB, Olgiati S, Quadri M, Simons EJ, Morrison KE, Bonifati V, and Nicholl DJ
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- Adult, Aged, Aged, 80 and over, Dystonic Disorders physiopathology, Female, Humans, Male, Middle Aged, Mutation, Missense, Parkinson Disease physiopathology, Pedigree, Phenotype, Dystonic Disorders genetics, GTP Cyclohydrolase genetics, Parkinson Disease genetics
- Abstract
Background: GTP cyclohydrolase I (GCH1) mutations are the commonest cause of Dopa-responsive dystonia (DRD). Clinical phenotypes can be broad, even within a single family., Methods: We present clinical, genetic and functional imaging data on a British kindred in which affected subjects display phenotypes ranging from DRD to Parkinson's disease (PD). Twelve family members were studied. Clinical examination, dopamine transporter (DAT) imaging, and molecular genetic analysis of GCH1 and the commonest known familial PD-related genes were performed., Results: We have identified a novel missense variant, c.5A > G, p.(Glu2Gly), within the GCH1 gene in affected family members displaying a range of phenotypes. Two affected subjects carrying this variant had abnormal DAT imaging. These two with abnormal DAT imaging had a PD phenotype, while the remaining three subjects with the novel GCH1 variant had normal DAT imaging and a DRD phenotype., Conclusions: We propose that this GCH1 variant is pathogenic in this family and these findings suggest that similar mechanisms involving abnormal GTP cyclohydolase I may underlie both PD and DRD. GCH1 genetic testing should be considered in patients with PD and a family history of DRD., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2015
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12. Formulations for trans-tympanic antibiotic delivery.
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Khoo X, Simons EJ, Chiang HH, Hickey JM, Sabharwal V, Pelton SI, Rosowski JJ, Langer R, and Kohane DS
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- Animals, Chinchilla, Ciprofloxacin chemistry, Drug Compounding methods, Male, Nanocapsules chemistry, Anti-Bacterial Agents administration & dosage, Anti-Bacterial Agents pharmacokinetics, Ciprofloxacin administration & dosage, Ciprofloxacin pharmacokinetics, Nanocapsules administration & dosage, Otitis Media drug therapy, Tympanic Membrane metabolism
- Abstract
We have developed a drug delivery system for prolonged trans-tympanic antibiotic delivery from a single dose administration. Increased permeability to ciprofloxacin of the intact tympanic membrane (TM) was achieved by chemical permeation enhancers (CPEs--bupivacaine, limonene, sodium dodecyl sulfate); this was also seen by CPEs contained within a hydrogel (poloxamer 407) to maintain the formulation at the TM. The CPE-hydrogel formulation had minimal effects on auditory thresholds and tissue response in vivo. CPE-hydrogel formulations have potential for ototopical delivery of ciprofloxacin for the treatment of acute otitis media (AOM) and other middle ear diseases., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
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- 2013
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13. Analysis of LRRK2, SNCA, Parkin, PINK1, and DJ-1 in Zambian patients with Parkinson's disease.
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Yonova-Doing E, Atadzhanov M, Quadri M, Kelly P, Shawa N, Musonda ST, Simons EJ, Breedveld GJ, Oostra BA, and Bonifati V
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- Adult, DNA Mutational Analysis, Family Health, Female, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Male, Middle Aged, Protein Deglycase DJ-1, Zambia epidemiology, Genetic Predisposition to Disease genetics, Intracellular Signaling Peptides and Proteins genetics, Mutation genetics, Oncogene Proteins genetics, Parkinson Disease genetics, Protein Kinases genetics, Protein Serine-Threonine Kinases genetics, Ubiquitin-Protein Ligases genetics, alpha-Synuclein genetics
- Abstract
Recent studies delineate substantial genetic components in Parkinson's disease (PD). However, very few studies were performed in Sub-Saharan African populations. Here, we explore the contribution of known PD-causing genes in patients of indigenous Zambian ancestry. We studied thirty-nine Zambian patients, thirty-eight with PD and one with parkinsonian-pyramidal syndrome (18% familial; average onset age 54.9 ± 12.2 years). In the whole group, all SNCA exons and LRRK2 exons 29 to 48 (encoding for important functional domains) were sequenced. In the familial patients and those with onset <55 years (n = 22) the whole LRRK2 coding region was sequenced (51 exons). In the patients with onset <50 years (n = 12), all parkin, PINK1, and DJ-1 exons were sequenced, and dosage analysis of parkin, PINK1, DJ-1, LRRK2, and SNCA was performed. Dosage analysis was also performed in the majority of the late-onset patients. The LRRK2 p.Gly2019Ser mutation was not detected. A novel LRRK2 missense variant (p.Ala1464Gly) of possible pathogenic role was found in one case. Two heterozygous, likely disease-causing deletions of parkin (exon 2 and exon 4) were detected in an early-onset case. Pathogenic mutations were not detected in SNCA, PINK1, or DJ-1. We also report variability at several single nucleotide polymorphisms in the above-mentioned genes. This is the first molecular genetic study in Zambian PD patients, and the first comprehensive analysis of the LRRK2 and SNCA genes in a Sub-Saharan population. Common disease-causing mutations were not detected, suggesting that further investigations in PD patients from these populations might unravel the role of additional, still unknown genes., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
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- 2012
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14. Broadening the phenotype of TARDBP mutations: the TARDBP Ala382Thr mutation and Parkinson's disease in Sardinia.
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Quadri M, Cossu G, Saddi V, Simons EJ, Murgia D, Melis M, Ticca A, Oostra BA, and Bonifati V
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- Aged, Alanine genetics, Amino Acid Substitution physiology, Case-Control Studies, Cohort Studies, DNA Mutational Analysis, Female, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Italy epidemiology, Male, Middle Aged, Nerve Degeneration genetics, Parkinson Disease epidemiology, Threonine genetics, DNA-Binding Proteins genetics, Mutation, Missense physiology, Parkinson Disease genetics
- Abstract
Mutations in the TARDBP gene are a cause of autosomal dominant amyotrophic lateral sclerosis (ALS) and of frontotemporal lobar degeneration (FTLD), but they have not been found so far in patients with Parkinson's disease (PD). A founder TARDBP mutation (p.Ala382Thr) was recently identified as the cause of ~30% of ALS cases in Sardinia, a Mediterranean genetic isolate. We studied 327 consecutive Sardinian patients with clinically diagnosed PD (88 familial, 239 sporadic) and 578 Sardinian controls. One family with FTLD and parkinsonism was also included. The p.Ala382Thr heterozygous mutation was detected in eight unrelated PD patients (2.5%). The three patients from the FTLD/parkinsonism family also carried this mutation. Within the control group, there were three heterozygous mutation carriers. During follow-up, one of these individuals developed motoneuron disease and another, a rapidly progressive dementia; the third remains healthy at the age of 79 but two close relatives developed motoneuron disease and dementia. The eight PD patients carrying the p.Ala382Thr mutation had all sporadic disease presentation. Their average onset age was 70.0 years (SD 9.4, range 51-79), which is later but not significantly different from that of the patients who did not carry this mutation. In conclusion, we expand the clinical spectrum associated with TARDBP mutations to FTLD with parkinsonism without motoneuron disease and to clinically definite PD. The TDP-43 protein might be directly involved in a broader neurodegenerative spectrum, including not only motoneuron disease and FTLD but also PD.
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- 2011
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15. The LRRK2 R1441C mutation is more frequent than G2019S in Parkinson's disease patients from southern Italy.
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Criscuolo C, De Rosa A, Guacci A, Simons EJ, Breedveld GJ, Peluso S, Volpe G, Filla A, Oostra BA, Bonifati V, and De Michele G
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- Aged, Disability Evaluation, Female, Gene Frequency, Genetic Association Studies, Genotype, Humans, Italy, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Male, Middle Aged, Amino Acids genetics, Genetic Predisposition to Disease genetics, Parkinson Disease genetics, Polymorphism, Single Nucleotide genetics, Protein Serine-Threonine Kinases genetics
- Abstract
Background: Mutations in the leucine-rich repeat kinase 2 gene are the most frequent cause of familial and sporadic Parkinson's disease, and G2019S is the most common leucine-rich repeat kinase 2 mutation across several Mediterranean countries., Methods: One hundred ninety-two patients with Parkinson's disease from Campania, a region in southern Italy, were screened for R1441C/H/G and G2019S by direct sequencing and SfcI digestion., Results: Among 192 patients with Parkinson's disease (mean age±SD, 63.9±11.8 years; disease onset, 54.0±12.5 years; family history for Parkinson's disease or tremor, 45%), 8 carried a heterozygous R1441C mutation, whereas only 1 had the G2019S mutation. All R1441C patients originate from the province of Naples and share the same haplotype, suggesting a founder effect., Conclusions: G2019S is not ubiquitously the most common leucine-rich repeat kinase 2 mutation; in Campania R1441C is more frequent. Region-specific mutation prevalence data should be taken into account for a sensitive and cost-effective molecular diagnosis and counseling of patients with Parkinson's disease., (Copyright © 2011 Movement Disorder Society.)
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- 2011
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16. Autosomal dominant restless legs syndrome maps to chromosome 20p13 (RLS-5) in a Dutch kindred.
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Sas AM, Di Fonzo A, Bakker SL, Simons EJ, Oostra BA, Maat-Kievit AJ, Boon AJ, and Bonifati V
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- Adolescent, Adult, Aged, Aged, 80 and over, Child, Chromosome Mapping, Female, Gene Expression Profiling methods, Genome-Wide Association Study, Humans, Lod Score, Male, Middle Aged, Oligonucleotide Array Sequence Analysis methods, Pedigree, Young Adult, Chromosomes, Human, Pair 20 genetics, Genetic Predisposition to Disease, Restless Legs Syndrome genetics
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Six chromosomal loci have been mapped for restless legs syndrome (RLS) through family-based linkage analysis (RLS-1 to RLS-6), but confirmation has met with limited success, and causative mutations have not yet been identified. We ascertained a large multigenerational Dutch family with RLS of early onset (average 18 years-old). The clinical study included a follow-up of 2 years. To map the underlying genetic defect, we performed a genome-wide scan for linkage using high-density SNP microarrays. A single, strong linkage peak was detected on chromosome 20p13, under an autosomal-dominant model, in the region of the RLS-5 locus (maximum multipoint LOD score 3.02). Haplotype analysis refined the RLS-5 critical region from 5.2 to 4.5 megabases. In conclusion, we provide the first confirmation of the RLS-5 locus, and we reduce its critical region. The identification of the underlying mutation might reveal an important susceptibility gene for this common movement disorder.
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- 2010
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17. Familial frontotemporal dementia with parkinsonism associated with the progranulin c.C1021T (p.Q341X) mutation.
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Di Fabio R, Tessa A, Simons EJ, Santorelli FM, Casali C, Serrao M, Pierelli F, and Bonifati V
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- Aged, DNA Mutational Analysis methods, Female, Humans, Italy, Male, Middle Aged, Progranulins, Family Health, Frontotemporal Dementia genetics, Intercellular Signaling Peptides and Proteins genetics, Mutation genetics
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- 2010
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18. GIGYF2 mutations are not a frequent cause of familial Parkinson's disease.
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Di Fonzo A, Fabrizio E, Thomas A, Fincati E, Marconi R, Tinazzi M, Breedveld GJ, Simons EJ, Chien HF, Ferreira JJ, Horstink MW, Abbruzzese G, Borroni B, Cossu G, Dalla Libera A, Fabbrini G, Guidi M, De Mari M, Lopiano L, Martignoni E, Marini P, Onofrj M, Padovani A, Stocchi F, Toni V, Sampaio C, Barbosa ER, Meco G, Oostra BA, and Bonifati V
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- Adult, Aged, Humans, Middle Aged, Mutation, Pedigree, Carrier Proteins genetics, Parkinson Disease genetics
- Abstract
Mutations in the Grb10-interacting GYF protein 2 (GIGYF2) gene, within the PARK11 locus, have been nominated as a cause of Parkinson's disease in Italian and French populations. By sequencing the whole GIGYF2 coding region in forty-six probands (thirty-seven Italians) with familial Parkinson's disease compatible with an autosomal dominant inheritance, we identified no mutations. Our data add to a growing body of evidence suggesting that GIGYF2 mutations are not a frequent cause of PD.
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- 2009
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19. FBXO7 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome.
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Di Fonzo A, Dekker MC, Montagna P, Baruzzi A, Yonova EH, Correia Guedes L, Szczerbinska A, Zhao T, Dubbel-Hulsman LO, Wouters CH, de Graaff E, Oyen WJ, Simons EJ, Breedveld GJ, Oostra BA, Horstink MW, and Bonifati V
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- Adolescent, Base Sequence, Child, Female, Heterozygote, Homozygote, Humans, Magnetic Resonance Imaging, Male, Parkinsonian Disorders diagnosis, Parkinsonian Disorders genetics, Pedigree, Phenotype, Protein Isoforms, Syndrome, Tomography, Emission-Computed, Single-Photon, F-Box Proteins genetics, Genes, Recessive, Mutation, Missense, Parkinsonian Disorders physiopathology, Pyramidal Tracts physiopathology
- Abstract
Background: The combination of early-onset, progressive parkinsonism with pyramidal tract signs has been known as pallido-pyramidal or parkinsonian-pyramidal syndrome since the first description by Davison in 1954. Very recently, a locus was mapped in a single family with an overlapping phenotype, and an FBXO7 gene mutation was nominated as the likely disease cause., Methods: We performed clinical and genetic studies in two families with early-onset, progressive parkinsonism and pyramidal tract signs., Results: An FBXO7 homozygous truncating mutation (Arg498Stop) was found in an Italian family, while compound heterozygous mutations (a splice-site IVS7 + 1G/T mutation and a missense Thr22Met mutation) were present in a Dutch family. We also found evidence of expression of novel normal splice-variants of FBXO7. The phenotype associated with FBXO7 mutations consisted of early-onset, progressive parkinsonism and pyramidal tract signs, thereby matching clinically the pallido-pyramidal syndrome of Davison. The parkinsonism exhibits varying degrees of levodopa responsiveness in different patients., Conclusions: We conclusively show that recessive FBXO7 mutations cause progressive neurodegeneration with extrapyramidal and pyramidal system involvement, delineating a novel genetically defined entity that we propose to designate as PARK15. Understanding how FBXO7 mutations cause disease will shed further light on the molecular mechanisms of neurodegeneration, with potential implications also for more common forms of parkinsonism, such as Parkinson disease and multiple system atrophy.
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- 2009
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20. Effect of chemical permeation enhancers on nerve blockade.
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Simons EJ, Bellas E, Lawlor MW, and Kohane DS
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- Animals, Bupivacaine pharmacology, Cell Survival drug effects, Male, Mice, Molecular Structure, Rats, Rats, Sprague-Dawley, Tetrodotoxin pharmacology, Nerve Block
- Abstract
Chemical permeation enhancers (CPEs) have the potential to improve access of local anesthetics to the nerve, thereby improving nerve block performance. We assessed the effects of six CPEs on nerve blockade from tetrodotoxin (TTX) and from bupivacaine. Each of the six surfactants, representing three CPE subgroups (anionic, cationic, and nonionic surfactants) was coinjected with TTX or bupivacaine at the sciatic nerve of Sprague-Dawley rats. Myotoxicity of CPEs, alone and with TTX, was assessed in vitro in C2C12 myotubes and in vivo via histological analysis. All enhancers produced marked concentration-dependent improvements in the frequency and duration of block with TTX but not bupivacaine. An in vitro toxicity assay showed a wide range of CPE myotoxicity, but in vivo histological assessment showed no signs of muscle or nerve damage at concentrations of CPEs that produced a half-maximal increase in the duration of block of TTX (except in the case of the cationic surfactant DDAB). This study demonstrates that CPEs can provide marked prolongation of nerve blockade from TTX but not bupivacaine, without apparent local tissue toxicity. These results may enhance the clinical applicability of TTX for prolonged-duration local anesthesia.
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- 2009
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21. The LRRK2 Arg1628Pro variant is a risk factor for Parkinson's disease in the Chinese population.
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Lu CS, Wu-Chou YH, van Doeselaar M, Simons EJ, Chang HC, Breedveld GJ, Di Fonzo A, Chen RS, Weng YH, Lai SC, Oostra BA, and Bonifati V
- Subjects
- Adolescent, Adult, Age of Onset, Aged, Aged, 80 and over, Amino Acid Sequence, Amino Acid Substitution, Asian People genetics, Case-Control Studies, Child, Female, Haplotypes, Heterozygote, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Male, Middle Aged, Molecular Sequence Data, Polymorphism, Single Nucleotide, Risk Factors, Sequence Homology, Amino Acid, Taiwan, Genetic Variation, Parkinson Disease enzymology, Parkinson Disease genetics, Protein Serine-Threonine Kinases genetics
- Abstract
The c.G4883C variant in the leucine-rich repeat kinase 2 (LRRK2) gene (protein effect: Arg1628Pro) has been recently proposed as a second risk factor for sporadic Parkinson's disease in the Han Chinese population (after the Gly2385Arg variant). In this paper, we analyze the Arg1628Pro variant and the associated haplotype in a large sample of 1,337 Han subjects (834 patients and 543 controls) ascertained from a single referral center in Taiwan. In our sample, the Arg1628Pro allele was more frequent among patients (3.8%) than among controls (1.8%; p = 0.004, OR 2.13, 95% CI 1.29-3.52). Sixty heterozygous and two homozygous carriers of the Arg1628Pro variant were identified among the patients, of which only one was also a carrier of the LRRK2 Gly2385Arg variant. We also show that carriers of the Arg1628Pro variant share a common, extended haplotype, suggesting a founder effect. Parkinson's disease onset age was similar in patients who carried the Arg1628Pro variant and in those who did not carry it. Our data support the contention that the Arg1628Pro variant is a second risk factor for Parkinson's disease in the Han Chinese population. Adding the estimated effects of Arg1628Pro (population attributable risk [PAR] approximately 4%) and Gly2385Arg variants (PAR approximately 6%) yields a total PAR of approximately 10%.
- Published
- 2008
- Full Text
- View/download PDF
22. LRRK2 G2019S mutation and Parkinson's disease: a clinical, neuropsychological and neuropsychiatric study in a large Italian sample.
- Author
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Goldwurm S, Zini M, Di Fonzo A, De Gaspari D, Siri C, Simons EJ, van Doeselaar M, Tesei S, Antonini A, Canesi M, Zecchinelli A, Mariani C, Meucci N, Sacilotto G, Cilia R, Isaias IU, Bonetti A, Sironi F, Ricca S, Oostra BA, Bonifati V, and Pezzoli G
- Subjects
- Adult, Age of Onset, Cognition, Female, Genetic Predisposition to Disease epidemiology, Genetic Testing, Heterozygote, Humans, Italy epidemiology, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Male, Middle Aged, Mood Disorders epidemiology, Mood Disorders genetics, Motor Activity, Neuropsychological Tests, Phenotype, Prevalence, Parkinson Disease epidemiology, Parkinson Disease genetics, Point Mutation, Protein Serine-Threonine Kinases genetics
- Abstract
We analysed the Leucine-Rich Repeat Kinase 2 (LRRK2) gene for the G2019S mutation in 1245 consecutive, unrelated patients with primary degenerative parkinsonism, and collected information on medical history, motor, cognitive and neuropsychiatric functions to characterize the clinical phenotype associated to the G2019S mutation. The mutation was detected in heterozygous state in 19 probands (1.7%), and in five additional affected relatives. Clinical features in carriers were those of typical, idiopathic Parkinson's disease. However, behavioural abnormalities were frequent (87%), suggesting a more widespread limbic involvement in G2019S carriers.
- Published
- 2006
- Full Text
- View/download PDF
23. Dopaminergic innervation of the mouse inner ear: evidence for a separate cytochemical group of cochlear efferent fibers.
- Author
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Darrow KN, Simons EJ, Dodds L, and Liberman MC
- Subjects
- Acetylcholine metabolism, Animals, Cochlea cytology, Cochlea metabolism, Dopamine beta-Hydroxylase metabolism, Efferent Pathways cytology, Hair Cells, Auditory, Inner cytology, Hair Cells, Auditory, Inner metabolism, Hearing physiology, Hearing Loss, Sensorineural metabolism, Hearing Loss, Sensorineural physiopathology, Immunohistochemistry, Mice, Mice, Inbred CBA, Neural Inhibition physiology, Pons cytology, Pons metabolism, Presynaptic Terminals ultrastructure, Synaptic Transmission physiology, Tyrosine 3-Monooxygenase metabolism, Vesicular Acetylcholine Transport Proteins metabolism, Cochlea innervation, Dopamine metabolism, Efferent Pathways metabolism, Presynaptic Terminals metabolism
- Abstract
Immunostaining mouse cochleas for tyrosine hydroxylase (TH) and dopamine beta-hydroxylase suggests that there is a rich adrenergic innervation throughout the auditory nerve trunk and a small dopaminergic innervation of the sensory cell areas. Surgical cuts in the brainstem confirm these dopaminergic fibers as part of the olivocochlear efferent bundle. Within the sensory epithelium, TH-positive terminals are seen only in the inner hair cell area, where they intermingle with other olivocochlear terminals expressing cholinergic markers (vesicular acetylcholine transporter; VAT). Double immunostaining suggests little colocalization of TH and VAT; quantification of terminal volumes suggests that TH-positive fibers constitute only 10-20% of the efferent innervation of the inner hair cell area. Immunostaining of mouse brainstem revealed a small population of TH-positive cells in and around the lateral superior olive. Consistent with cochlear projections, double staining for the cholinergic marker acetylcholinesterase suggested that TH-positive somata are not cholinergic and vice versa. All observations are consistent with the view that a small dopaminergic subgroup of lateral olivocochlear neurons 1) projects to the inner hair cell area, 2) is distinct from the larger cholinergic group projecting there, and 3) may correspond to lateral olivocochlear "shell" neurons described by others (Warr et al. [1997] Hear. Res 108:89-111).
- Published
- 2006
- Full Text
- View/download PDF
24. A common missense variant in the LRRK2 gene, Gly2385Arg, associated with Parkinson's disease risk in Taiwan.
- Author
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Di Fonzo A, Wu-Chou YH, Lu CS, van Doeselaar M, Simons EJ, Rohé CF, Chang HC, Chen RS, Weng YH, Vanacore N, Breedveld GJ, Oostra BA, and Bonifati V
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Amino Acid Sequence, Case-Control Studies, Child, DNA Mutational Analysis, Female, Genetic Testing, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Male, Middle Aged, Molecular Sequence Data, Parkinson Disease epidemiology, Taiwan, Gene Frequency, Genetic Predisposition to Disease, Parkinson Disease genetics, Polymorphism, Single Nucleotide, Protein Serine-Threonine Kinases genetics
- Abstract
Mutations in the LRRK2 gene are a cause of autosomal dominant Parkinson's disease (PD). Whether LRRK2 variants influence susceptibility to the commoner, sporadic forms of PD remains largely unknown. Data are particularly limited concerning the Asian population. In search for novel, biologically relevant variants, we sequenced the LRRK2 coding region in Taiwanese patients with PD. Four newly identified variants and another variant recently found in a Taiwanese PD family were tested for association with the disease in a sample of 608 PD cases and 373 ethnically matched controls. Heterozygosity for the Gly2385Arg variant was significantly more frequent among PD patients than controls (nominal p value=0.004, corrected for multiple comparisons=0.012, gender- and age-adjusted odds ratio=2.24, 95% C.I.: 1.29-3.88); this variant was uniformly distributed across genders and age strata. Two novel variants, Met1869Val and Glu1874Stop, were found in one PD case each; their pathogenic role remains, therefore, uncertain. The remaining two novel variants (Ala419Val and Pro755Leu) were present with similar frequency in cases and controls, and were therefore, interpreted as disease-unrelated polymorphisms. Our findings suggest that the LRRK2 Gly2385Arg is the first identified, functionally relevant variant, which acts as common risk factor for sporadic PD in the population of Chinese ethnicity.
- Published
- 2006
- Full Text
- View/download PDF
25. Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease.
- Author
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Di Fonzo A, Tassorelli C, De Mari M, Chien HF, Ferreira J, Rohé CF, Riboldazzi G, Antonini A, Albani G, Mauro A, Marconi R, Abbruzzese G, Lopiano L, Fincati E, Guidi M, Marini P, Stocchi F, Onofrj M, Toni V, Tinazzi M, Fabbrini G, Lamberti P, Vanacore N, Meco G, Leitner P, Uitti RJ, Wszolek ZK, Gasser T, Simons EJ, Breedveld GJ, Goldwurm S, Pezzoli G, Sampaio C, Barbosa E, Martignoni E, Oostra BA, and Bonifati V
- Subjects
- Adult, Aged, Alternative Splicing, Amino Acid Sequence, Animals, Disease Progression, Exons, Family Health, Female, Genes, Dominant, Genetic Testing, Genotype, Heterozygote, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Male, Middle Aged, Models, Genetic, Molecular Sequence Data, Mutation, Open Reading Frames, Pedigree, Phenotype, Polymorphism, Genetic, Protein Serine-Threonine Kinases metabolism, Protein Structure, Tertiary, Parkinson Disease genetics, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases physiology
- Abstract
Mutations in the gene leucine-rich repeat kinase 2 (LRRK2) have been recently identified in families with Parkinson's disease (PD). However, the prevalence and nature of LRRK2 mutations, the polymorphism content of the gene, and the associated phenotypes remain poorly understood. We performed a comprehensive study of this gene in a large sample of families with Parkinson's disease compatible with autosomal dominant inheritance (ADPD). The full-length open reading frame and splice sites of the LRRK2 gene (51 exons) were studied by genomic sequencing in 60 probands with ADPD (83% Italian). Pathogenic mutations were identified in six probands (10%): the heterozygous p.G2019S mutation in four (6.6%), and the heterozygous p.R1441C mutation in two (3.4%) probands. A further proband carried the heterozygous p.I1371 V mutation, for which a pathogenic role could not be established with certainty. In total, 13 novel disease-unrelated variants and three intronic changes of uncertain significance were also characterized. The phenotype associated with LRRK2 pathogenic mutations is the one of typical PD, but with a broad range of onset ages (mean 55.2, range 38-68 years) and, in some cases, slow disease progression. On the basis of the comprehensive study in a large sample, we conclude that pathogenic LRRK2 mutations are frequent in ADPD, and they cluster in the C-terminal half of the encoded protein. These data have implications both for understanding the molecular mechanisms of PD, and for directing the genetic screening in clinical practice.
- Published
- 2006
- Full Text
- View/download PDF
26. The LRRK2 I2012T, G2019S, and I2020T mutations are rare in Taiwanese patients with sporadic Parkinson's disease.
- Author
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Lu CS, Simons EJ, Wu-Chou YH, Fonzo AD, Chang HC, Chen RS, Weng YH, Rohé CF, Breedveld GJ, Hattori N, Gasser T, Oostra BA, and Bonifati V
- Subjects
- Aged, DNA genetics, Female, Gene Frequency, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Male, Middle Aged, Mutation genetics, Parkinson Disease epidemiology, Taiwan epidemiology, Parkinson Disease genetics, Protein Serine-Threonine Kinases genetics
- Published
- 2005
- Full Text
- View/download PDF
27. The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson's disease and originates from a common ancestor.
- Author
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Goldwurm S, Di Fonzo A, Simons EJ, Rohé CF, Zini M, Canesi M, Tesei S, Zecchinelli A, Antonini A, Mariani C, Meucci N, Sacilotto G, Sironi F, Salani G, Ferreira J, Chien HF, Fabrizio E, Vanacore N, Dalla Libera A, Stocchi F, Diroma C, Lamberti P, Sampaio C, Meco G, Barbosa E, Bertoli-Avella AM, Breedveld GJ, Oostra BA, Pezzoli G, and Bonifati V
- Subjects
- Adult, Aged, Alleles, Base Sequence, Female, Founder Effect, Heterozygote, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Male, Middle Aged, Molecular Sequence Data, Mutation, Parkinson Disease genetics, Protein Serine-Threonine Kinases genetics
- Abstract
Background: Mutations in the gene Leucine-Rich Repeat Kinase 2 (LRRK2) were recently identified as the cause of PARK8 linked autosomal dominant Parkinson's disease., Objective: To study recurrent LRRK2 mutations in a large sample of patients from Italy, including early (<50 years) and late onset familial and sporadic Parkinson's disease., Results: Among 629 probands, 13 (2.1%) were heterozygous carriers of the G2019S mutation. The mutation frequency was higher among familial (5.1%, 9/177) than among sporadic probands (0.9%, 4/452) (p<0.002), and highest among probands with one affected parent (8.7%, 6/69) (p<0.001). There was no difference in the frequency of the G2019S mutation in probands with early v late onset disease. Among 600 probands, one heterozygous R1441C but no R1441G or Y1699C mutations were detected. None of the four mutations was found in Italian controls. Haplotype analysis in families from five countries suggested that the G2019S mutation originated from a single ancient founder. The G2019S mutation was associated with the classical Parkinson's disease phenotype and a broad range of onset age (34 to 73 years)., Conclusions: G2019S is the most common genetic determinant of Parkinson's disease identified so far. It is especially frequent among cases with familial Parkinson's disease of both early and late onset, but less common among sporadic cases. These findings have important implications for diagnosis and genetic counselling in Parkinson's disease.
- Published
- 2005
- Full Text
- View/download PDF
28. Multiple regulatory elements contribute to the vascular-specific expression of the rice HD-Zip gene Oshox1 in Arabidopsis.
- Author
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Scarpella E, Simons EJ, and Meijer AH
- Subjects
- Promoter Regions, Genetic, Arabidopsis genetics, Arabidopsis Proteins genetics, Gene Expression Regulation, Plant genetics, Genes, Homeobox, Homeodomain Proteins genetics, Oryza genetics, Plant Proteins genetics, Regulatory Sequences, Nucleic Acid, Transcription Factors genetics
- Abstract
The primary vascular tissues of plants differentiate from a single precursor tissue, the procambium. The role of upstream regulatory sequences in the transcriptional control of early vascular-specific gene expression is largely unknown. The onset of expression of the rice homeodomain-leucine zipper (HD-Zip) gene Oshox1 marks procambial cells that have acquired their distinctive anatomical features but do not yet display any overt signs of terminal vascular differentiation. The expression pattern of Oshox1 in rice appears to be mainly controlled by the activity of the 1.6 kb upstream promoter region. Here, we show that the Oshox1 promoter directs vascular, auxin- and sucrose-responsive reporter gene expression in Arabidopsis plants in a fashion comparable with that in rice. This is the case not only during normal development but also upon experimental manipulation, suggesting that the cis-acting regulatory elements that are instrumental in Oshox1 expression pattern are conserved between rice and Arabidopsis. Finally, through analysis of reporter gene expression profiles conferred by progressive 5' deletions of the Oshox1 promoter in transgenic Arabidopsis, we have identified upstream regulatory regions required for auxin and sucrose inducibility, and for cell type-, tissue- and organ-specific aspects of Oshox1 expression. Our study suggests that Oshox1 embryonic vascular expression is mainly achieved through suppression of expression in non-vascular tissues.
- Published
- 2005
- Full Text
- View/download PDF
29. Modulation of cholinergic neurotransmission in airways by enkephalin.
- Author
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Russell JA and Simons EJ
- Subjects
- Animals, Depression, Chemical, Dogs, Electric Stimulation, Muscle Contraction drug effects, Muscle, Smooth physiology, Naloxone pharmacology, Parasympathetic Nervous System physiology, Propranolol pharmacology, Receptors, Opioid drug effects, Synaptic Transmission drug effects, Trachea drug effects, Trachea innervation, Acetylcholine antagonists & inhibitors, Enkephalin, Leucine pharmacology, Enkephalin, Methionine pharmacology, Muscle, Smooth drug effects, Parasympathetic Nervous System drug effects
- Abstract
We compared the effects of methionine enkephalin and leucine enkephalin on contractions of isolated canine tracheal smooth muscle strips induced by field electrical stimulation (ES) and exogenous acetylcholine (approximately 10(-5) M). Methionine and leucine enkephalin (10(-8) to 10(-5) M), when added at the peak of airway contractions induced by ES at 1 Hz, depressed the contractions in a concentration-dependent manner by a maximum of 95 and 99%, respectively. Acetylcholine-induced contractions of similar magnitude were depressed only 4% by methionine enkephalin and 12% by leucine enkephalin. Frequency-response curves (0.5-20 Hz) were also obtained before and after incubation of tracheal strips with 10(-5) M methionine and leucine enkephalin. Enkephalin depressed contractions induced by stimulation at 0.5 and 1 Hz by an average of 98 and 95%, respectively. The inhibitory effect of enkephalin progressively decreased at successively higher stimulus frequencies until at 20 Hz there was no significant difference between airway contractions obtained in the presence and absence of enkephalin. Naloxone (3 X 10(-5) M) antagonized the inhibitory effects of both enkephalins. We conclude that methionine and leucine enkephalins inhibit the release of acetylcholine from the postganglionic parasympathetic neurons that innervate airway smooth muscle.
- Published
- 1985
- Full Text
- View/download PDF
30. The sociological pathology of medicine.
- Author
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SIMONS EJ
- Subjects
- Humans, Minnesota, Medicine, Patient Care
- Published
- 1946
31. Medical care problems of the aged.
- Author
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SIMONS EJ
- Subjects
- Humans, Minnesota, Geriatrics
- Published
- 1949
32. Factors in rural health in Minnesota.
- Author
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SIMONS EJ
- Subjects
- Humans, Minnesota, Epidemiology, Public Health, Rural Health
- Published
- 1946
33. Facts and inferences of Minnesota Sanatorium admittances.
- Author
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SIMONS EJ
- Subjects
- Humans, Minnesota, Biometry, Hospitalization, Hospitals, Tuberculosis epidemiology, Tuberculosis statistics & numerical data
- Published
- 1946
34. The changing complexion of medicine.
- Author
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SIMONS EJ
- Subjects
- Humans, Medicine
- Published
- 1948
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