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Christine Klein, Nobutaka Hattori, Connie Marras
Given the rapidly increasing number of reported movement disorder genes and clinical-genetic desciptions of mutation carriers, the International Parkinson's Disease and Movement Disorder Society Gene Database (MDSGene) initiative has been launched in 2016 and grown to become a large international project ( MDSGene currently contains >1150 variants described in ∼5700 movement disorder patients in almost 1000 publications including monogenic forms of PD clinically resembling idiopathic (PARK-PINK1, PARK-Parkin, PARK-DJ-1, PARK-SNCA, PARK-VPS35, PARK-LRRK2), as well as of atypical PD (PARK-SYNJ1, PARK-DNAJC6, PARK-ATP13A2, PARK-FBXO7)...
2018: Journal of Parkinson's Disease
Jinyoung Youn, Chung Lee, Eungseok Oh, Jinse Park, Ji Sun Kim, Hee-Tae Kim, Jin Whan Cho, Woong-Yang Park, Wooyoung Jang, Chang-Seok Ki
Early-onset Parkinson's disease (EOPD) can be linked to different genetic backgrounds depending on the disease characteristics. In Korean patients with EOPD, however, only 5 PARK genes have been tested. We recruited 70 patients with EOPD from 4 hospitals in Korea, and 12 PARK genes were screened via multigene panel sequencing. Large insertions or deletions were confirmed by multiplex ligation-dependent probe amplification. We found 20 rare variants (2 in SNCA, 2 in PRKN, 6 in LRRK2, 3 in PINK1, 1 in DJ1, 4 in FBX07, 1 in HTRA2, and 1 in EIG4G1) in 20 subjects regardless of heterogeneity...
November 7, 2018: Neurobiology of Aging
Zhi Dong Zhou, Ji Chao Tristan Lee, Eng King Tan
Mutations of F-box only protein 7 (FBXO7) gene are associated with a severe form of autosomal recessive juvenile Parkinson's disease (PD) (PARK15) with clinical features of Parkinsonian-Pyramidal syndrome (PPS). FBXO7 is an adaptor protein in SCFFBXO7 ubiquitin E3 ligase complex that recognizes and mediates degradative or non-degradative ubiquitination of substrates. The FBXO7 protein can regulate cell cycle, proliferation, mitochondrial and proteasome functions via interactions with multiple target proteins...
October 2018: Mutation Research
A Lunati, S Lesage, A Brice
The cause of Parkinson's disease (PD) remains unknown in most patients. Since 1997, with the first genetic mutation known to cause PD described in SNCA gene, many other genes with Mendelian inheritance have been identified. We summarize genetic, clinical and neuropathological findings related to the 27 genes reported in the literature since 1997, associated either with autosomal dominant (AD): LRRK2, SNCA, VPS35, GCH1, ATXN2, DNAJC13, TMEM230, GIGYF2, HTRA2, RIC3, EIF4G1, UCHL1, CHCHD2, and GBA; or autosomal recessive (AR) inheritance: PRKN, PINK1, DJ1, ATP13A2, PLA2G6, FBXO7, DNAJC6, SYNJ1, SPG11, VPS13C, PODXL, and PTRHD1; or an X-linked transmission: RAB39B...
September 20, 2018: Revue Neurologique
Tereza Bartoníková, Kateřina Menšíková, Kristýna Kolaříková, Radek Vodička, Radek Vrtěl, Pavel Otruba, Michaela Kaiserová, Miroslav Vaštík, Lenka Mikulicová, Josef Ovečka, Ludmila Šáchová, František Dvorský, Jiří Krša, Petr Jugas, Marek Godava, Martin Bareš, Vladimír Janout, Petr Hluštík, Martin Procházka, Petr Kaňovský
An increased prevalence of familial neurodegenerative parkinsonism or cognitive deterioration was recently found in a small region of southeastern Moravia.The aim of the study was to assess the genetic background of this familial disease.Variants in the ADH1C, EIF4G1, FBXO7, GBA + GBAP1, GIGYF2, HTRA2, LRRK2, MAPT, PRKN, DJ-1, PINK1, PLA2G6, SNCA, UCHL1, VPS35 genes were examined in 12 clinically positive probands of the pedigree in which familial atypical neurodegenerative parkinsonism was identified in previous epidemiological studies...
September 2018: Medicine (Baltimore)
Ting Shen, Jiali Pu, Hsin-Yi Lai, Lingjia Xu, Xiaoli Si, Yaping Yan, Yasi Jiang, Baorong Zhang
Several genes have already been certified as causative genes in patients with autosomal recessive early-onset Parkinson's syndrome with pyramidal tract signs, including ATP13A2, PLA2G6 and FBXO7. Variants in these three genes may also play roles in early-onset Parkinson's disease (EOPD). In order to investigate the contribution of genetic variants in these three genes to Chinese sporadic EOPD patients, we screened 101 Chinese sporadic EOPD patients and 83 age- and sex-matched healthy controls using direct sequencing...
September 19, 2018: Scientific Reports
Lei Wei, Li Ding, Haiyan Li, Yinyao Lin, Yongqiang Dai, Xiaofeng Xu, Qing Dong, Yanjun Lin, Ling Long
BACKGROUND: Juvenile-onset parkinsonism is often caused by genetic factors. Mutations in several autosomal genes, including the F-box only protein 7 (FBXO7) gene, have been found in patients suffering from juvenile-onset parkinsonism with pyramidal signs. Only five types of FBXO7 mutations have been described. Here, we present a case report about a Chinese patient presenting with juvenile-onset parkinsonism likely caused by FBXO7 mutations. METHODS: The patient was a 32-year-old Chinese male...
February 2018: Parkinsonism & related Disorders
Sabitha Joseph, Jörg Bernhard Schulz, Judith Stegmüller
Parkinson disease (PD) is, without doubt, a burden on modern society as the prevalence increases significantly with age. Owing to this growing number of PD cases, it is more critical than ever to understand the pathogenic mechanisms underlying PD to identify therapeutic targets. The discovery of genetic mutations associated with PD and parkinsonism paves the way toward this goal. Even though, familial forms of the disease represent the minority of PD cases and some forms are so rare that there are only a few affected families, the research on the associated genes is invaluable...
January 2018: Journal of Neurochemistry
Susanne A Schneider, Roy N Alcalay
Clinical-pathological studies remain the gold-standard for the diagnosis of Parkinson's disease (PD). However, mounting data from genetic PD autopsies challenge the diagnosis of PD based on Lewy body pathology. Most of the confirmed genetic risks for PD show heterogenous neuropathology, even within kindreds, which may or may not include Lewy body pathology. We review the literature of genetic PD autopsies from cases with molecularly confirmed PD or parkinsonism and summarize main findings on SNCA (n = 25), Parkin (n = 20, 17 bi-allelic and 3 heterozygotes), PINK1 (n = 5, 1 bi-allelic and 4 heterozygotes), DJ-1 (n = 1), LRRK2 (n = 55), GBA (n = 10 Gaucher disease patients with parkinsonism), DNAJC13, GCH1, ATP13A2, PLA2G6 (n = 8 patients, 2 with PD), MPAN (n = 2), FBXO7, RAB39B, and ATXN2 (SCA2), as well as on 22q deletion syndrome (n = 3)...
November 2017: Movement Disorders: Official Journal of the Movement Disorder Society
Marta Delgado-Camprubi, Noemi Esteras, Marc Pm Soutar, Helene Plun-Favreau, Andrey Y Abramov
This corrects the article DOI: 10.1038/cdd.2016.104.
December 2017: Cell Death and Differentiation
Laura Scott, Valina L Dawson, Ted M Dawson
Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by the progressive loss of dopaminergic (DA) neurons. Most PD cases are sporadic; however, rare familial forms have been identified. Autosomal recessive PD (ARPD) results from mutations in Parkin, PINK1, DJ-1, and ATP13A2, while rare, atypical juvenile ARPD result from mutations in FBXO7, DNAJC6, SYNJ1, and PLA2G6. Studying these genes and their function has revealed mitochondrial quality control, protein degradation processes, and oxidative stress responses as common pathways underlying PD pathogenesis...
December 2017: Experimental Neurology
Lamei Yuan, Zhi Song, Xiong Deng, Zhijian Yang, Yan Yang, Yi Guo, Hongwei Lu, Hao Deng
Parkinson's disease (PD) is the second most common neurodegenerative disorder and has an elusive etiology. It is likely multifactorial, and genetic defects contribute to its pathogenesis. At least 25 genetic loci and 20 monogenic genes have been identified in monogenic PD. Recessive F-box protein 7 gene (FBXO7) mutations reportedly cause hereditary parkinsonism. To explore the roles of four paralogs (FBXO2, FBXO6, FBXO12, and FBXO41) in PD development, their variants (rs9614, rs28924120, rs6442117, and rs61733550, respectively) were analyzed in 502 Han Chinese patients with PD and 556 age, gender, and ethnicity-matched normal participants in mainland China...
October 2017: Neuroscience Bulletin
Eric M Merzetti, Lindsay A Dolomount, Brian E Staveley
Parkinsonian-pyramidal syndrome (PPS) is an early onset form of Parkinson's disease (PD) that shows degeneration of the extrapyramidal region of the brain to result in a severe form of PD. The toxic protein build-up has been implicated in the onset of PPS. Protein removal is mediated by an intracellular proteasome complex: an E3 ubiquitin ligase, the targeting component, is essential for function. FBXO7 encodes the F-box component of the SCF E3 ubiquitin ligase linked to familial forms of PPS. The Drosophila melanogaster homologue nutcracker (ntc) and a binding partner, PI31, have been shown to be active in proteasome function...
January 2017: Genome Génome / Conseil National de Recherches Canada
Shachi P Patel, Suzanne J Randle, Sarah Gibbs, Anne Cooke, Heike Laman
G1 phase cell cycle proteins, such as cyclin-dependent kinase 6 (Cdk6) and its activating partners, the D-type cyclins, are important regulators of T-cell development and function. An F-box protein, called F-box only protein 7 (Fbxo7), acts as a cell cycle regulator by enhancing cyclin D-Cdk6 complex formation and stabilising levels of p27, a cyclin-dependent kinase inhibitor. We generated a murine model of reduced Fbxo7 expression to test its physiological role in multiple tissues and found that these mice displayed a pronounced thymic hypoplasia...
April 2017: Cellular and Molecular Life Sciences: CMLS
Tereza Bartonikova, Katerina Mensikova, Lenka Mikulicova, Radek Vodicka, Radek Vrtel, Marek Godava, Miroslav Vastik, Michaela Kaiserova, Pavel Otruba, Iva Dolinova, Martin Nevrly, Petr Kanovsky
BACKGROUND: A higher prevalence of parkinsonism was recently identified in southeastern Moravia (Czech Republic). Further research confirmed 3 large pedigrees with familial autosomal-dominant parkinsonism spanning 5 generations. METHODS: This case report concerns a patient belonging to one of these 3 pedigrees, in whom motor and oculomotor symptoms were accompanied by frontal-type dementia, who finally developed a clinical phenotype of progressive supranuclear palsy...
November 2016: Medicine (Baltimore)
Chiung-Mei Chen, I-Cheng Chen, Ying-Lin Chen, Te-Hsien Lin, Wan-Ling Chen, Chih-Ying Chao, Yih-Ru Wu, Yeah-Ting Lu, Cheng-Yu Lee, Hong-Chi Chien, Ting-Shou Chen, Guey-Jen Lee-Chen, Chi-Mei Lee
BACKGROUND: The F-box protein 7 (FBXO7) mutations have been identified in families with early-onset parkinsonism and pyramidal tract signs, and designated as PARK15. In addition, FBXO7 mutations were found in typical and young onset Parkinson's disease (PD). Evidence has also shown that FBXO7 plays an important role in the development of dopaminergic neurons and increased stability and overexpression of FBXO7 may be beneficial to PD. PURPOSE: We screened extracts of medicinal herbs to enhance FBXO7 expression for neuroprotection in MPP(+)-treated cells...
November 15, 2016: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Marta Delgado-Camprubi, Noemi Esteras, Marc Pm Soutar, Helene Plun-Favreau, Andrey Y Abramov
The Parkinson's disease (PD)-related protein F-box only protein 7 (Fbxo7) is the substrate-recognition component of the Skp1-Cullin-F-box protein E3 ubiquitin ligase complex. We have recently shown that PD-associated mutations in Fbxo7 disrupt mitochondrial autophagy (mitophagy), suggesting a role for Fbxo7 in modulating mitochondrial homeostasis. Here we report that Fbxo7 deficiency is associated with reduced cellular NAD+ levels, which results in increased mitochondrial NADH redox index and impaired activity of complex I in the electron transport chain...
January 2017: Cell Death and Differentiation
Felipe Roberti Teixeira, Suzanne J Randle, Shachi P Patel, Tycho E T Mevissen, Grasilda Zenkeviciute, Tie Koide, David Komander, Heike Laman
Fbxo7 is a clinically relevant F-box protein, associated with both cancer and Parkinson's disease (PD). Additionally, SNPs within FBXO7 are correlated with alterations in red blood cell parameters. Point mutations within FBXO7 map within specific functional domains, including near its F-box domain and its substrate recruiting domains, suggesting that deficiencies in SCFFbxo7/PARK15 ubiquitin ligase activity are mechanistically linked to early-onset PD. To date, relatively few substrates of the ligase have been identified...
October 15, 2016: Biochemical Journal
Siv Vingill, David Brockelt, Camille Lancelin, Lars Tatenhorst, Guergana Dontcheva, Christian Preisinger, Nicola Schwedhelm-Domeyer, Sabitha Joseph, Miso Mitkovski, Sandra Goebbels, Klaus-Armin Nave, Jörg B Schulz, Till Marquardt, Paul Lingor, Judith Stegmüller
Mutations in the FBXO7 (PARK15) gene have been implicated in a juvenile form of parkinsonism termed parkinsonian pyramidal syndrome (PPS), characterized by Parkinsonian symptoms and pyramidal tract signs. FBXO7 (F-box protein only 7) is a subunit of the SCF (SKP1/cullin-1/F-box protein) E3 ubiquitin ligase complex, but its relevance and function in neurons remain to be elucidated. Here, we report that the E3 ligase FBXO7-SCF binds to and ubiquitinates the proteasomal subunit PSMA2. In addition, we show that FBXO7 is a proteasome-associated protein involved in proteasome assembly...
September 15, 2016: EMBO Journal
Ana Gorostidi, José Félix Martí-Massó, Alberto Bergareche, Mari Cruz Rodríguez-Oroz, Adolfo López de Munain, Javier Ruiz-Martínez
BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting millions of people. Genome-wide association studies (GWAS) have found >25 genetic risk factors and at least 15 loci directly associated with PD. Recent advances in new next-generation DNA sequencing technologies, such as the semiconductor-based Ion Torrent platform, make multigene sequencing cheaper, faster, and more reliable. OBJECTIVES: Our objective was to test the power of this next-generation sequencing technology to analyze large samples by screening the majority of the most relevant PD-related genes known for single and compound mutations...
October 2016: Molecular Diagnosis & Therapy
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