Publications by authors named "Ruth Chia"

29 Publications

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Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.

Authors:
Ruth Chia Marya S Sabir Sara Bandres-Ciga Sara Saez-Atienzar Regina H Reynolds Emil Gustavsson Ronald L Walton Sarah Ahmed Coralie Viollet Jinhui Ding Mary B Makarious Monica Diez-Fairen Makayla K Portley Zalak Shah Yevgeniya Abramzon Dena G Hernandez Cornelis Blauwendraat David J Stone John Eicher Laura Parkkinen Olaf Ansorge Lorraine Clark Lawrence S Honig Karen Marder Afina Lemstra Peter St George-Hyslop Elisabet Londos Kevin Morgan Tammaryn Lashley Thomas T Warner Zane Jaunmuktane Douglas Galasko Isabel Santana Pentti J Tienari Liisa Myllykangas Minna Oinas Nigel J Cairns John C Morris Glenda M Halliday Vivianna M Van Deerlin John Q Trojanowski Maurizio Grassano Andrea Calvo Gabriele Mora Antonio Canosa Gianluca Floris Ryan C Bohannan Francesca Brett Ziv Gan-Or Joshua T Geiger Anni Moore Patrick May Rejko Krüger David S Goldstein Grisel Lopez Nahid Tayebi Ellen Sidransky Lucy Norcliffe-Kaufmann Jose-Alberto Palma Horacio Kaufmann Vikram G Shakkottai Matthew Perkins Kathy L Newell Thomas Gasser Claudia Schulte Francesco Landi Erika Salvi Daniele Cusi Eliezer Masliah Ronald C Kim Chad A Caraway Edwin S Monuki Maura Brunetti Ted M Dawson Liana S Rosenthal Marilyn S Albert Olga Pletnikova Juan C Troncoso Margaret E Flanagan Qinwen Mao Eileen H Bigio Eloy Rodríguez-Rodríguez Jon Infante Carmen Lage Isabel González-Aramburu Pascual Sanchez-Juan Bernardino Ghetti Julia Keith Sandra E Black Mario Masellis Ekaterina Rogaeva Charles Duyckaerts Alexis Brice Suzanne Lesage Georgia Xiromerisiou Matthew J Barrett Bension S Tilley Steve Gentleman Giancarlo Logroscino Geidy E Serrano Thomas G Beach Ian G McKeith Alan J Thomas Johannes Attems Christopher M Morris Laura Palmer Seth Love Claire Troakes Safa Al-Sarraj Angela K Hodges Dag Aarsland Gregory Klein Scott M Kaiser Randy Woltjer Pau Pastor Lynn M Bekris James B Leverenz Lilah M Besser Amanda Kuzma Alan E Renton Alison Goate David A Bennett Clemens R Scherzer Huw R Morris Raffaele Ferrari Diego Albani Stuart Pickering-Brown Kelley Faber Walter A Kukull Estrella Morenas-Rodriguez Alberto Lleó Juan Fortea Daniel Alcolea Jordi Clarimon Mike A Nalls Luigi Ferrucci Susan M Resnick Toshiko Tanaka Tatiana M Foroud Neill R Graff-Radford Zbigniew K Wszolek Tanis Ferman Bradley F Boeve John A Hardy Eric J Topol Ali Torkamani Andrew B Singleton Mina Ryten Dennis W Dickson Adriano Chiò Owen A Ross J Raphael Gibbs Clifton L Dalgard Bryan J Traynor Sonja W Scholz

Nat Genet 2021 03 15;53(3):294-303. Epub 2021 Feb 15.

Neurodegenerative Diseases Research Unit, Laboratory of Neurogenetics, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
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http://dx.doi.org/10.1038/s41588-021-00785-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946812PMC
March 2021

Genetic analysis of amyotrophic lateral sclerosis identifies contributing pathways and cell types.

Sci Adv 2021 Jan 15;7(3). Epub 2021 Jan 15.

Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.

Despite the considerable progress in unraveling the genetic causes of amyotrophic lateral sclerosis (ALS), we do not fully understand the molecular mechanisms underlying the disease. We analyzed genome-wide data involving 78,500 individuals using a polygenic risk score approach to identify the biological pathways and cell types involved in ALS. This data-driven approach identified multiple aspects of the biology underlying the disease that resolved into broader themes, namely, neuron projection morphogenesis, membrane trafficking, and signal transduction mediated by ribonucleotides. We also found that genomic risk in ALS maps consistently to GABAergic interneurons and oligodendrocytes, as confirmed in human single-nucleus RNA-seq data. Using two-sample Mendelian randomization, we nominated six differentially expressed genes (, , , , , and ) within the significant pathways as relevant to ALS. We conclude that the disparate genetic etiologies of this fatal neurological disease converge on a smaller number of final common pathways and cell types.
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http://dx.doi.org/10.1126/sciadv.abd9036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810371PMC
January 2021

Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

Neuron 2021 02 26;109(3):448-460.e4. Epub 2020 Nov 26.

Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA; Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London WC1N 1PJ, UK; Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD 21287, USA. Electronic address:

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.
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http://dx.doi.org/10.1016/j.neuron.2020.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864894PMC
February 2021

Mutational Analysis of Known ALS Genes in an Italian Population-Based Cohort.

Neurology 2021 01 18;96(4):e600-e609. Epub 2020 Nov 18.

From "Rita Levi Montalcini" Department of Neuroscience (M.G., A. Calvo, C.M., A. Canosa, U.M., R.V., A. Chiò), University of Turin, Italy; Biocomputational Group (J.D., R.J.G.) and Neuromuscular Diseases Research Section (M.G., R.C., B.J.T.), Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD; Laboratory of Genetics, Department of Clinical Pathology (M. Brunetti, M. Barberis, L.S.), Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin; Department of Health Sciences Interdisciplinary Research Center of Autoimmune Diseases (L.C., S.D.), "Amedeo Avogadro" University of Eastern Piedmont; ALS Center (L.M.), Department of Neurology, Azienda Ospedaliera Universitaria Maggiore della Carità, Novara, Italy; Neurodegenerative Diseases Research Unit, Laboratory of Neurogenetics (S.W.S.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; Department of Neurology (S.W.S., B.J.T.), Johns Hopkins University Medical Center; Department of Anatomy, Physiology & Genetics (C.D.), and The American Genome Center, Collaborative Health Initiative Research Program (C.D.), Uniformed Services University of the Health Sciences, Bethesda, MD; and Institute of Cognitive Sciences and Technologies (A. Chiò), National Council of Research, Rome, Italy.

Objective: To assess the burden of rare genetic variants and to estimate the contribution of known amyotrophic lateral sclerosis (ALS) genes in an Italian population-based cohort, we performed whole genome sequencing in 959 patients with ALS and 677 matched healthy controls.

Methods: We performed genome sequencing in a population-based cohort (Piemonte and Valle d'Aosta Registry for ALS [PARALS]). A panel of 40 ALS genes was analyzed to identify potential disease-causing genetic variants and to evaluate the gene-wide burden of rare variants among our population.

Results: A total of 959 patients with ALS were compared with 677 healthy controls from the same geographical area. Gene-wide association tests demonstrated a strong association with , whose rare variants are the second most common cause of disease after expansion. A lower signal was observed for , proving that its effect on our cohort is driven by a few known causal variants. We detected rare variants in other known ALS genes that did not surpass statistical significance in gene-wise tests, thus highlighting that their contribution to disease risk in our cohort is limited.

Conclusions: We identified potential disease-causing variants in 11.9% of our patients. We identified the genes most frequently involved in our cohort and confirmed the contribution of rare variants in disease risk. Our results provide further insight into the pathologic mechanism of the disease and demonstrate the importance of genome-wide sequencing as a diagnostic tool.
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http://dx.doi.org/10.1212/WNL.0000000000011209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905787PMC
January 2021

The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.

Front Neurosci 2020 5;14:42. Epub 2020 Feb 5.

Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD, United States.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two diseases that form a broad neurodegenerative continuum. Considerable effort has been made to unravel the genetics of these disorders, and, based on this work, it is now clear that ALS and FTD have a significant genetic overlap. TARDBP, SQSTM1, VCP, FUS, TBK1, CHCHD10, and most importantly C9orf72, are the critical genetic players in these neurological disorders. Discoveries of these genes have implicated autophagy, RNA regulation, and vesicle and inclusion formation as the central pathways involved in neurodegeneration. Here we provide a summary of the significant genes identified in these two intrinsically linked neurodegenerative diseases and highlight the genetic and pathological overlaps.
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http://dx.doi.org/10.3389/fnins.2020.00042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012787PMC
February 2020

Genetic analysis of neurodegenerative diseases in a pathology cohort.

Neurobiol Aging 2019 04 17;76:214.e1-214.e9. Epub 2018 Nov 17.

Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

Molecular genetic research provides unprecedented opportunities to examine genotype-phenotype correlations underlying complex syndromes. To investigate pathogenic mutations and genotype-phenotype relationships in diverse neurodegenerative conditions, we performed a rare variant analysis of damaging mutations in autopsy-confirmed neurodegenerative cases from the Johns Hopkins Brain Resource Center (n = 1243 patients). We used NeuroChip genotyping and C9orf72 hexanucleotide repeat analysis to rapidly screen our cohort for disease-causing mutations. In total, we identified 42 individuals who carried a pathogenic mutation in LRRK2, GBA, APP, PSEN1, MAPT, GRN, C9orf72, SETX, SPAST, or CSF1R, and we provide a comprehensive description of the diverse clinicopathological features of these well-characterized cases. Our study highlights the utility of high-throughput genetic screening arrays to establish a molecular diagnosis in individuals with complex neurodegenerative syndromes, to broaden disease phenotypes and to provide insights into unexpected disease associations.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391207PMC
April 2019

Improving vaccination uptake in pediatric Cochlear implant recipients.

J Otolaryngol Head Neck Surg 2018 Sep 17;47(1):56. Epub 2018 Sep 17.

Faculty of Medicine, University of British Columbia, 317-2194 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada.

Background: An Infectious Disease vaccine specialist joined our institution's Cochlear Implant Team in 2010 in order to address the high percentage of non-compliance to immunization prior to surgery identified previously from an internal review. The purpose of this study was to (1) review the immunization status of cochlear implant recipients in 2010-2014, (2) assess if introducing a vaccine specialist made a significant change in vaccination compliance and (3) elucidate any barriers to vaccination compliance.

Methods: Retrospective chart review and a telephone survey. Medical records of 116 cochlear implant recipients between 2010 and 2014 were reviewed. A telephone survey was conducted to obtain the current vaccination status in children who required post-operative vaccinations with incomplete records on chart review and, if applicable, the reason for non-compliance.

Results: Between 2010 and 2014, 98% of children were up-to-date at the time of surgery, compared to 67% up-to-date at the time of surgery between 2002 and 2007. 27 children were included in our post-operative immunization analysis. 29.6% (8/27) failed to receive necessary vaccinations post-surgery. Pneumovax-23, a vaccine for high-risk patients (such as cochlear implant candidates) was missed in all cases.

Conclusion: Pre-operative vaccination for cochlear implant recipients improved dramatically with the addition of a vaccine specialist. However, a significant proportion of patients requiring vaccinations post-surgery did not receive them. The main reason for non-compliance was due to parents being unaware that their children required this vaccine postoperatively by being "high-risk". Although improvement was demonstrated, a communication gap continued to impede the adequacy of vaccination uptake in pediatric cochlear implant recipients following surgery at age 2 when the high-risk vaccine was due.
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http://dx.doi.org/10.1186/s40463-018-0308-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142635PMC
September 2018

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene.

Authors:
Aude Nicolas Kevin P Kenna Alan E Renton Nicola Ticozzi Faraz Faghri Ruth Chia Janice A Dominov Brendan J Kenna Mike A Nalls Pamela Keagle Alberto M Rivera Wouter van Rheenen Natalie A Murphy Joke J F A van Vugt Joshua T Geiger Rick A Van der Spek Hannah A Pliner Shankaracharya Bradley N Smith Giuseppe Marangi Simon D Topp Yevgeniya Abramzon Athina Soragia Gkazi John D Eicher Aoife Kenna Gabriele Mora Andrea Calvo Letizia Mazzini Nilo Riva Jessica Mandrioli Claudia Caponnetto Stefania Battistini Paolo Volanti Vincenzo La Bella Francesca L Conforti Giuseppe Borghero Sonia Messina Isabella L Simone Francesca Trojsi Fabrizio Salvi Francesco O Logullo Sandra D'Alfonso Lucia Corrado Margherita Capasso Luigi Ferrucci Cristiane de Araujo Martins Moreno Sitharthan Kamalakaran David B Goldstein Aaron D Gitler Tim Harris Richard M Myers Hemali Phatnani Rajeeva Lochan Musunuri Uday Shankar Evani Avinash Abhyankar Michael C Zody Julia Kaye Steven Finkbeiner Stacia K Wyman Alex LeNail Leandro Lima Ernest Fraenkel Clive N Svendsen Leslie M Thompson Jennifer E Van Eyk James D Berry Timothy M Miller Stephen J Kolb Merit Cudkowicz Emily Baxi Michael Benatar J Paul Taylor Evadnie Rampersaud Gang Wu Joanne Wuu Giuseppe Lauria Federico Verde Isabella Fogh Cinzia Tiloca Giacomo P Comi Gianni Sorarù Cristina Cereda Philippe Corcia Hannu Laaksovirta Liisa Myllykangas Lilja Jansson Miko Valori John Ealing Hisham Hamdalla Sara Rollinson Stuart Pickering-Brown Richard W Orrell Katie C Sidle Andrea Malaspina John Hardy Andrew B Singleton Janel O Johnson Sampath Arepalli Peter C Sapp Diane McKenna-Yasek Meraida Polak Seneshaw Asress Safa Al-Sarraj Andrew King Claire Troakes Caroline Vance Jacqueline de Belleroche Frank Baas Anneloor L M A Ten Asbroek José Luis Muñoz-Blanco Dena G Hernandez Jinhui Ding J Raphael Gibbs Sonja W Scholz Mary Kay Floeter Roy H Campbell Francesco Landi Robert Bowser Stefan M Pulst John M Ravits Daniel J L MacGowan Janine Kirby Erik P Pioro Roger Pamphlett James Broach Glenn Gerhard Travis L Dunckley Christopher B Brady Neil W Kowall Juan C Troncoso Isabelle Le Ber Kevin Mouzat Serge Lumbroso Terry D Heiman-Patterson Freya Kamel Ludo Van Den Bosch Robert H Baloh Tim M Strom Thomas Meitinger Aleksey Shatunov Kristel R Van Eijk Mamede de Carvalho Maarten Kooyman Bas Middelkoop Matthieu Moisse Russell L McLaughlin Michael A Van Es Markus Weber Kevin B Boylan Marka Van Blitterswijk Rosa Rademakers Karen E Morrison A Nazli Basak Jesús S Mora Vivian E Drory Pamela J Shaw Martin R Turner Kevin Talbot Orla Hardiman Kelly L Williams Jennifer A Fifita Garth A Nicholson Ian P Blair Guy A Rouleau Jesús Esteban-Pérez Alberto García-Redondo Ammar Al-Chalabi Ekaterina Rogaeva Lorne Zinman Lyle W Ostrow Nicholas J Maragakis Jeffrey D Rothstein Zachary Simmons Johnathan Cooper-Knock Alexis Brice Stephen A Goutman Eva L Feldman Summer B Gibson Franco Taroni Antonia Ratti Cinzia Gellera Philip Van Damme Wim Robberecht Pietro Fratta Mario Sabatelli Christian Lunetta Albert C Ludolph Peter M Andersen Jochen H Weishaupt William Camu John Q Trojanowski Vivianna M Van Deerlin Robert H Brown Leonard H van den Berg Jan H Veldink Matthew B Harms Jonathan D Glass David J Stone Pentti Tienari Vincenzo Silani Adriano Chiò Christopher E Shaw Bryan J Traynor John E Landers

Neuron 2018 03;97(6):1268-1283.e6

Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address:

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
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http://dx.doi.org/10.1016/j.neuron.2018.02.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867896PMC
March 2018

Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications.

Lancet Neurol 2018 01 16;17(1):94-102. Epub 2017 Nov 16.

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Department of Neurology, Brain Sciences Institute, Johns Hopkins Hospital, Baltimore, MD, USA.

Background: The disease course of amyotrophic lateral sclerosis (ALS) is rapid and, because its pathophysiology is unclear, few effective treatments are available. Genetic research aims to understand the underlying mechanisms of ALS and identify potential therapeutic targets. The first gene associated with ALS was SOD1, identified in 1993 and, by early 2014, more than 20 genes had been identified as causative of, or highly associated with, ALS. These genetic discoveries have identified key disease pathways that are therapeutically testable and could potentially lead to the development of better treatments for people with ALS.

Recent Developments: Since 2014, seven additional genes have been associated with ALS (MATR3, CHCHD10, TBK1, TUBA4A, NEK1, C21orf2, and CCNF), all of which were identified by genome-wide association studies, whole genome studies, or exome sequencing technologies. Each of the seven novel genes code for proteins associated with one or more molecular pathways known to be involved in ALS. These pathways include dysfunction in global protein homoeostasis resulting from abnormal protein aggregation or a defect in the protein clearance pathway, mitochondrial dysfunction, altered RNA metabolism, impaired cytoskeletal integrity, altered axonal transport dynamics, and DNA damage accumulation due to defective DNA repair. Because these novel genes share common disease pathways with other genes implicated in ALS, therapeutics targeting these pathways could be useful for a broad group of patients stratified by genotype. However, the effects of these novel genes have not yet been investigated in animal models, which will be a key step to translating these findings into clinical practice. WHERE NEXT?: The identification of these seven novel genes has been important in unravelling the molecular mechanisms underlying ALS. However, our understanding of what causes ALS is not complete, and further genetic research will provide additional detail about its causes. Increased genetic knowledge will also identify potential therapeutic targets and could lead to the development of individualised medicine for patients with ALS. These developments will have a direct effect on clinical practice when genome sequencing becomes a routine and integral part of disease diagnosis and management.
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http://dx.doi.org/10.1016/S1474-4422(17)30401-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5901717PMC
January 2018

NeuroChip, an updated version of the NeuroX genotyping platform to rapidly screen for variants associated with neurological diseases.

Neurobiol Aging 2017 09 17;57:247.e9-247.e13. Epub 2017 May 17.

Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA. Electronic address:

Genetics has proven to be a powerful approach in neurodegenerative diseases research, resulting in the identification of numerous causal and risk variants. Previously, we introduced the NeuroX Illumina genotyping array, a fast and efficient genotyping platform designed for the investigation of genetic variation in neurodegenerative diseases. Here, we present its updated version, named NeuroChip. The NeuroChip is a low-cost, custom-designed array containing a tagging variant backbone of about 306,670 variants complemented with a manually curated custom content comprised of 179,467 variants implicated in diverse neurological diseases, including Alzheimer's disease, Parkinson's disease, Lewy body dementia, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy. The tagging backbone was chosen because of the low cost and good genome-wide resolution; the custom content can be combined with other backbones, like population or drug development arrays. Using the NeuroChip, we can accurately identify rare variants and impute over 5.3 million common SNPs from the latest release of the Haplotype Reference Consortium. In summary, we describe the design and usage of the NeuroChip array and show its capability for detecting rare pathogenic variants in numerous neurodegenerative diseases. The NeuroChip has a more comprehensive and improved content, which makes it a reliable, high-throughput, cost-effective screening tool for genetic research and molecular diagnostics in neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.neurobiolaging.2017.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5534378PMC
September 2017

The G2385R risk factor for Parkinson's disease enhances CHIP-dependent intracellular degradation of LRRK2.

Biochem J 2017 04 24;474(9):1547-1558. Epub 2017 Apr 24.

Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, 35 Convent Drive, Room 1A-116, Bethesda, MD 20892-3707, U.S.A.

Autosomal dominant mutations in () are associated with Parkinson's disease (PD). Most pathogenic mutations result in amino acid substitutions in the central ROC (Ras of complex proteins)-C-terminus of ROC-kinase triple domain and affect enzymatic functions of the protein. However, there are several variants in , including the risk factor G2385R, that affect PD pathogenesis by unknown mechanisms. Previously, we have shown that G2385R LRRK2 has decreased kinase activity and altered affinity to LRRK2 interactors. Specifically, we found an increased binding to the chaperone Hsp90 (heat shock protein 90 kDa) that is known to stabilize LRRK2, suggesting that G2385R may have structural effects on LRRK2. In the present study, we further explored the effects of G2385R on LRRK2 in cells. We found that G2385R LRRK2 has lower steady-state intracellular protein levels compared with wild-type LRRK2 due to increased protein turnover of the mutant protein. Mechanistically, this is a consequence of a higher affinity of G2385R compared with the wild-type protein for two proteins involved in proteasomal degradation, Hsc70 and carboxyl-terminus of Hsc70-interacting protein (CHIP). Overexpression of CHIP decreased intracellular protein levels of both G2385R mutant and wild-type LRRK2, while short interfering RNA CHIP knockdown had the opposite effect. We suggest that the G2385R substitution tilts the equilibrium between refolding and proteasomal degradation toward intracellular degradation. The observation of lower steady-state protein levels may explain why G2385R is a risk factor rather than a penetrant variant for inherited PD.
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http://dx.doi.org/10.1042/BCJ20160909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6178381PMC
April 2017

Health-Related Quality of Life Among Young Children With Cochlear Implants and Developmental Disabilities.

Ear Hear 2017 Jul/Aug;38(4):399-408

1Department of School Counseling and Special Education, Tel Aviv University, Tel Aviv, Israel; 2Human Early Learning Partnership, University of British Columbia, Vancouver, BC, Canada; 3Department of Educational and Counselling Psychology, and Special Education, University of British Columbia, Vancouver, BC, Canada; 4British Columbia Children's Hospital, Vancouver, BC, Canada; and 5Department of Surgery, University of British Columbia, Vancouver, BC, Canada.

Objective: The present study examined differences in health-related quality of life (HRQoL) between deaf children with cochlear implants (CI) with and without developmental disabilities (DD) and differences across HRQoL domains within both groups of children.

Methods: Ninety-two parents of children with CI aged 3-7 years participated in this cross-sectional study. Of these children, 43 had DD (i.e., CI-DD group) and 49 had no DD or chronic illness, demonstrating overall typical development (i.e., CI-TD group). Parents of children in both groups completed the KINDL, a generic HRQoL questionnaire. Parents also provided anecdotal comments to open-ended questions, and parent comments were evaluated on a CI benefits scale to assess parent-perceived benefits of CI for the deaf children with and without disabilities.

Results: Children in the CI-DD group had significantly lower HRQoL compared to children in the CI-TD group, including lower scores on the self-esteem, friend, school, and family HRQoL subscales. No significant differences among groups were found on the physical well-being and emotional well-being subscales. For the CI-TD group, age at implantation correlated negatively with self-esteem and school HRQoL subscales. In the CI-DD group, children's current age correlated negatively with family and with the total HRQoL scores. Parent anecdotal comments and scores on the CI-benefits scale indicated strong parent perceptions of benefits of implantation for children in both groups.

Conclusion: Based on parents' proxy report, findings suggest that having DD affects multiple domains of HRQoL among young children with CIs above and beyond that of the CI itself. Parents of deaf children with DD may need greater support through the CI process and follow-up than parents of deaf children without DD.
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http://dx.doi.org/10.1097/AUD.0000000000000410DOI Listing
May 2018

Critical periods after stroke study: translating animal stroke recovery experiments into a clinical trial.

Front Hum Neurosci 2015 29;9:231. Epub 2015 Apr 29.

Department of Rehabilitation Medicine, Center for Brain Plasticity and Recovery, Georgetown University and MedStar National Rehabilitation Hospital Washington, DC, USA ; Department of Neurology, Georgetown University Washington, DC, USA.

Introduction: Seven hundred ninety-five thousand Americans will have a stroke this year, and half will have a chronic hemiparesis. Substantial animal literature suggests that the mammalian brain has much potential to recover from acute injury using mechanisms of neuroplasticity, and that these mechanisms can be accessed using training paradigms and neurotransmitter manipulation. However, most of these findings have not been tested or confirmed in the rehabilitation setting, in large part because of the challenges in translating a conceptually straightforward laboratory experiment into a meaningful and rigorous clinical trial in humans. Through presentation of methods for a Phase II trial, we discuss these issues and describe our approach.

Methods: In rodents there is compelling evidence for timing effects in rehabilitation; motor training delivered at certain times after stroke may be more effective than the same training delivered earlier or later, suggesting that there is a critical or sensitive period for strongest rehabilitation training effects. If analogous critical/sensitive periods can be identified after human stroke, then existing clinical resources can be better utilized to promote recovery. The Critical Periods after Stroke Study (CPASS) is a phase II randomized, controlled trial designed to explore whether such a sensitive period exists. We will randomize 64 persons to receive an additional 20 h of upper extremity therapy either immediately upon rehab admission, 2-3 months after stroke onset, 6 months after onset, or to an observation-only control group. The primary outcome measure will be the Action Research Arm Test (ARAT) at 1 year. Blood will be drawn at up to 3 time points for later biomarker studies.

Conclusion: CPASS is an example of the translation of rodent motor recovery experiments into the clinical setting; data obtained from this single site randomized controlled trial will be used to finalize the design of a Phase III trial.
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http://dx.doi.org/10.3389/fnhum.2015.00231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413691PMC
May 2015

Phosphorylation of LRRK2 by casein kinase 1α regulates trans-Golgi clustering via differential interaction with ARHGEF7.

Nat Commun 2014 Dec 15;5:5827. Epub 2014 Dec 15.

Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Bethesda, Maryland 20892-3707, USA.

LRRK2, a gene relevant to Parkinson's disease, encodes a scaffolding protein with both GTPase and kinase activities. LRRK2 protein is itself phosphorylated and therefore is subject to regulation by cell signalling; however, the kinase(s) responsible for this event have not been definitively identified. Here using an unbiased siRNA kinome screen, we identify and validate casein kinase 1α (CK1α) as being responsible for LRRK2 phosphorylation, including in the adult mouse striatum. We further show that LRRK2 recruitment to TGN46-positive Golgi-derived vesicles is modulated by constitutive LRRK2 phosphorylation by CK1α. These effects are mediated by differential protein interactions of LRRK2 with a guanine nucleotide exchange factor, ARHGEF7. These pathways are therefore likely involved in the physiological maintenance of the Golgi in cells, which may play a role in the pathogenesis of Parkinson's disease.
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http://dx.doi.org/10.1038/ncomms6827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268884PMC
December 2014

Cochlear implantation among deaf children with additional disabilities: parental perceptions of benefits, challenges, and service provision.

J Deaf Stud Deaf Educ 2015 Jan 15;20(1):41-50. Epub 2014 Sep 15.

University of British Columbia, and BC Children's Hospital.

Although increasing numbers of children with additional disabilities are receiving cochlear implants (CIs), little is known about family perspectives of the benefits and the challenges of cochlear implantation in this pediatric population. This study examines perceptions among parents of deaf children with additional disabilities regarding satisfaction with service provision, benefits, and challenges of the CI process. This was a mixed-methods study, which included a survey and interviews. Twenty-three families of deaf children with additional disabilities participated in this study, and 17 of these parents participated in in-depth interviews regarding their child's experience with the CI, including benefits and challenges. Interviews were analyzed through inductive thematic analysis. Parent-perceived benefits of cochlear implantation included children's improved sound awareness, communication skills, and greater well-being compared to preimplantation status. However, the majority of families felt that they and their children were not receiving enough services. Major challenges included managing funding; coping with limited availability of specialized services, particularly in rural areas; and continuing concerns about the child's communication, social skills, and academic performance. Results suggest that children with additional disabilities benefit from CIs, but they and their families also face unique challenges that professionals should consider when working with these families.
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http://dx.doi.org/10.1093/deafed/enu030DOI Listing
January 2015

Arsenite stress down-regulates phosphorylation and 14-3-3 binding of leucine-rich repeat kinase 2 (LRRK2), promoting self-association and cellular redistribution.

J Biol Chem 2014 Aug 18;289(31):21386-400. Epub 2014 Jun 18.

From the Reta Lila Weston Institute of Neurological Studies, University College London Institute of Neurology, London WC1N 1PJ, United Kingdom, the Department of Molecular Neuroscience, University College London Institute of Neurology, London WC1N 3BJ, United Kingdom,

Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are a common genetic cause of Parkinson disease, but the mechanisms whereby LRRK2 is regulated are unknown. Phosphorylation of LRRK2 at Ser(910)/Ser(935) mediates interaction with 14-3-3. Pharmacological inhibition of its kinase activity abolishes Ser(910)/Ser(935) phosphorylation and 14-3-3 binding, and this effect is also mimicked by pathogenic mutations. However, physiological situations where dephosphorylation occurs have not been defined. Here, we show that arsenite or H2O2-induced stresses promote loss of Ser(910)/Ser(935) phosphorylation, which is reversed by phosphatase inhibition. Arsenite-induced dephosphorylation is accompanied by loss of 14-3-3 binding and is observed in wild type, G2019S, and kinase-dead D2017A LRRK2. Arsenite stress stimulates LRRK2 self-association and association with protein phosphatase 1α, decreases kinase activity and GTP binding in vitro, and induces translocation of LRRK2 to centrosomes. Our data indicate that signaling events induced by arsenite and oxidative stress may regulate LRRK2 function.
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http://dx.doi.org/10.1074/jbc.M113.528463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118103PMC
August 2014

Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis.

Nat Neurosci 2014 May 30;17(5):664-666. Epub 2014 Mar 30.

Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, 35 Convent Drive, Bethesda, MD 20892, USA.

MATR3 is an RNA- and DNA-binding protein that interacts with TDP-43, a disease protein linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Using exome sequencing, we identified mutations in MATR3 in ALS kindreds. We also observed MATR3 pathology in ALS-affected spinal cords with and without MATR3 mutations. Our data provide more evidence supporting the role of aberrant RNA processing in motor neuron degeneration.
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http://dx.doi.org/10.1038/nn.3688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4000579PMC
May 2014

Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease.

Proc Natl Acad Sci U S A 2014 Feb 7;111(7):2626-31. Epub 2014 Feb 7.

Cell Biology and Gene Expression Section, Computational Biology Core, Laboratory of Neurogenetics, and Molecular Genetics Section, National Institute on Aging/National Institutes of Health, Bethesda, MD 20892.

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause inherited Parkinson disease (PD), and common variants around LRRK2 are a risk factor for sporadic PD. Using protein-protein interaction arrays, we identified BCL2-associated athanogene 5, Rab7L1 (RAB7, member RAS oncogene family-like 1), and Cyclin-G-associated kinase as binding partners of LRRK2. The latter two genes are candidate genes for risk for sporadic PD identified by genome-wide association studies. These proteins form a complex that promotes clearance of Golgi-derived vesicles through the autophagy-lysosome system both in vitro and in vivo. We propose that three different genes for PD have a common biological function. More generally, data integration from multiple unbiased screens can provide insight into human disease mechanisms.
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http://dx.doi.org/10.1073/pnas.1318306111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3932908PMC
February 2014

A direct interaction between leucine-rich repeat kinase 2 and specific β-tubulin isoforms regulates tubulin acetylation.

J Biol Chem 2014 Jan 25;289(2):895-908. Epub 2013 Nov 25.

From the Department of Pharmacology, UCL School of Pharmacy, University College London 29-39 Brunswick Square, London WC1N 1AX, United Kingdom.

Mutations in LRRK2, encoding the multifunctional protein leucine-rich repeat kinase 2 (LRRK2), are a common cause of Parkinson disease. LRRK2 has been suggested to influence the cytoskeleton as LRRK2 mutants reduce neurite outgrowth and cause an accumulation of hyperphosphorylated Tau. This might cause alterations in the dynamic instability of microtubules suggested to contribute to the pathogenesis of Parkinson disease. Here, we describe a direct interaction between LRRK2 and β-tubulin. This interaction is conferred by the LRRK2 Roc domain and is disrupted by the familial R1441G mutation and artificial Roc domain mutations that mimic autophosphorylation. LRRK2 selectively interacts with three β-tubulin isoforms: TUBB, TUBB4, and TUBB6, one of which (TUBB4) is mutated in the movement disorder dystonia type 4 (DYT4). Binding specificity is determined by lysine 362 and alanine 364 of β-tubulin. Molecular modeling was used to map the interaction surface to the luminal face of microtubule protofibrils in close proximity to the lysine 40 acetylation site in α-tubulin. This location is predicted to be poorly accessible within mature stabilized microtubules, but exposed in dynamic microtubule populations. Consistent with this finding, endogenous LRRK2 displays a preferential localization to dynamic microtubules within growth cones, rather than adjacent axonal microtubule bundles. This interaction is functionally relevant to microtubule dynamics, as mouse embryonic fibroblasts derived from LRRK2 knock-out mice display increased microtubule acetylation. Taken together, our data shed light on the nature of the LRRK2-tubulin interaction, and indicate that alterations in microtubule stability caused by changes in LRRK2 might contribute to the pathogenesis of Parkinson disease.
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http://dx.doi.org/10.1074/jbc.M113.507913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3887213PMC
January 2014

The G2385R variant of leucine-rich repeat kinase 2 associated with Parkinson's disease is a partial loss-of-function mutation.

Biochem J 2012 Aug;446(1):99-111

Cell Biology and Gene Expression Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.

Autosomal-dominant missense mutations in LRRK2 (leucine-rich repeat kinase 2) are a common genetic cause of PD (Parkinson's disease). LRRK2 is a multidomain protein with kinase and GTPase activities. Dominant mutations are found in the domains that have these two enzyme activities, including the common G2019S mutation that increases kinase activity 2-3-fold. However, there is also a genetic variant in some populations, G2385R, that lies in a C-terminal WD40 domain of LRRK2 and acts as a risk factor for PD. In the present study we show that the G2385R mutation causes a partial loss of the kinase function of LRRK2 and deletion of the C-terminus completely abolishes kinase activity. This effect is strong enough to overcome the kinase-activating effects of the G2019S mutation in the kinase domain. Hsp90 (heat-shock protein of 90 kDa) has an increased affinity for the G2385R variant compared with WT (wild-type) LRRK2, and inhibition of the chaperone binding combined with proteasome inhibition leads to association of mutant LRRK2 with high molecular mass native fractions that probably represent proteasome degradation pathways. The loss-of-function of G2385R correlates with several cellular phenotypes that have been proposed to be kinase-dependent. These results suggest that the C-terminus of LRRK2 plays an important role in maintaining enzymatic function of the protein and that G2385R may be associated with PD in a way that is different from kinase-activating mutations. These results may be important in understanding the differing mechanism(s) by which mutations in LRRK2 act and may also have implications for therapeutic strategies for PD.
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http://dx.doi.org/10.1042/BJ20120637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667980PMC
August 2012

Is inhibition of kinase activity the only therapeutic strategy for LRRK2-associated Parkinson's disease?

BMC Med 2012 Feb 23;10:20. Epub 2012 Feb 23.

Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, 35 Convent Drive, Room 1A-116, Bethesda, MD 20892-3707, USA.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a common cause of familial Parkinson's disease (PD). Variation around the LRRK2 locus also contributes to the risk of sporadic PD. The LRRK2 protein contains a central catalytic region, and pathogenic mutations cluster in the Ras of complex protein C terminus of Ras of complex protein (mutations N1437H, R1441G/C and Y1699C) and kinase (G2019S and I2020T) domains. Much attention has been focused on the kinase domain, because kinase-dead versions of mutant LRRK2 are less toxic than kinase-active versions of the same proteins. Furthermore, kinase inhibitors may be able to mimic this effect in mouse models, although the currently tested inhibitors are not completely specific. In this review, we discuss the recent progress in the development of specific LRRK2 kinase inhibitors. We also discuss non-kinase-based therapeutic strategies for LRRK2-associated PD as it is possible that different approaches may be needed for different mutations.
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http://dx.doi.org/10.1186/1741-7015-10-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3308210PMC
February 2012

Superoxide dismutase 1 and tgSOD1 mouse spinal cord seed fibrils, suggesting a propagative cell death mechanism in amyotrophic lateral sclerosis.

PLoS One 2010 May 13;5(5):e10627. Epub 2010 May 13.

Department of Neurodegenerative Disease, University College London Institute of Neurology, London, United Kingdom.

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that specifically affects motor neurons and leads to a progressive and ultimately fatal loss of function, resulting in death typically within 3 to 5 years of diagnosis. The disease starts with a focal centre of weakness, such as one limb, and appears to spread to other parts of the body. Mutations in superoxide dismutase 1 (SOD1) are known to cause disease and it is generally accepted they lead to pathology not by loss of enzymatic activity but by gain of some unknown toxic function(s). Although different mutations lead to varying tendencies of SOD1 to aggregate, we suggest abnormal proteins share a common misfolding pathway that leads to the formation of amyloid fibrils.

Methodology/principal Findings: Here we demonstrate that misfolding of superoxide dismutase 1 leads to the formation of amyloid fibrils associated with seeding activity, which can accelerate the formation of new fibrils in an autocatalytic cascade. The time limiting event is nucleation to form a stable protein "seed" before a rapid linear polymerisation results in amyloid fibrils analogous to other protein misfolding disorders. This phenomenon was not confined to fibrils of recombinant protein as here we show, for the first time, that spinal cord homogenates obtained from a transgenic mouse model that overexpresses mutant human superoxide dismutase 1 (the TgSOD1(G93A) mouse) also contain amyloid seeds that accelerate the formation of new fibrils in both wildtype and mutant SOD1 protein in vitro.

Conclusions/significance: These findings provide new insights into ALS disease mechanism and in particular a mechanism that could account for the spread of pathology throughout the nervous system. This model of disease spread, which has analogies to other protein misfolding disorders such as prion disease, also suggests it may be possible to design assays for therapeutics that can inhibit fibril propagation and hence, possibly, disease progression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0010627PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2869360PMC
May 2010

Modification of superoxide dismutase 1 (SOD1) properties by a GFP tag--implications for research into amyotrophic lateral sclerosis (ALS).

PLoS One 2010 Mar 8;5(3):e9541. Epub 2010 Mar 8.

Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom.

Background: Since the discovery that mutations in the enzyme SOD1 are causative in human amyotrophic lateral sclerosis (ALS), many strategies have been employed to elucidate the toxic properties of this ubiquitously expressed mutant protein, including the generation of GFP-SOD1 chimaeric proteins for studies in protein localization by direct visualization using fluorescence microscopy. However, little is known about the biochemical and physical properties of these chimaeric proteins, and whether they behave similarly to their untagged SOD1 counterparts.

Methodology/principal Findings: Here we compare the physicochemical properties of SOD1 and the effects of GFP-tagging on its intracellular behaviour. Immunostaining demonstrated that SOD1 alone and GFP-SOD1 have an indistinguishable intracellular distribution in PC12 cells. Cultured primary motor neurons expressing GFP or GFP-SOD1 showed identical patterns of cytoplasmic expression and of movement within the axon. However, GFP tagging of SOD1 was found to alter some of the intrinsic properties of SOD1, including stability and specific activity. Evaluation of wildtype and mutant SOD1, tagged at either the N- or C-terminus with GFP, in PC12 cells demonstrated that some chimaeric proteins were degraded to the individual proteins, SOD1 and GFP.

Conclusions/significance: Our findings indicate that most, but not all, properties of SOD1 remain the same with a GFP tag.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0009541PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2833207PMC
March 2010

ENU mutagenesis reveals a novel phenotype of reduced limb strength in mice lacking fibrillin 2.

PLoS One 2010 Feb 9;5(2):e9137. Epub 2010 Feb 9.

Mammalian Genetics of Disease Unit, School of Medicine, University of Sheffield, Sheffield, United Kingdom.

Background: Fibrillins 1 (FBN1) and 2 (FBN2) are components of microfibrils, microfilaments that are present in many connective tissues, either alone or in association with elastin. Marfan's syndrome and congenital contractural arachnodactyly (CCA) result from dominant mutations in the genes FBN1 and FBN2 respectively. Patients with both conditions often present with specific muscle atrophy or weakness, yet this has not been reported in the mouse models. In the case of Fbn1, this is due to perinatal lethality of the homozygous null mice making measurements of strength difficult. In the case of Fbn2, four different mutant alleles have been described in the mouse and in all cases syndactyly was reported as the defining phenotypic feature of homozygotes.

Methodology/principal Findings: As part of a large-scale N-ethyl-N-nitrosourea (ENU) mutagenesis screen, we identified a mouse mutant, Mariusz, which exhibited muscle weakness along with hindlimb syndactyly. We identified an amber nonsense mutation in Fbn2 in this mouse mutant. Examination of a previously characterised Fbn2-null mutant, Fbn2(fp), identified a similar muscle weakness phenotype. The two Fbn2 mutant alleles complement each other confirming that the weakness is the result of a lack of Fbn2 activity. Skeletal muscle from mutants proved to be abnormal with higher than average numbers of fibres with centrally placed nuclei, an indicator that there are some regenerating muscle fibres. Physiological tests indicated that the mutant muscle produces significantly less maximal force, possibly as a result of the muscles being relatively smaller in Mariusz mice.

Conclusions: These findings indicate that Fbn2 is involved in integrity of structures required for strength in limb movement. As human patients with mutations in the fibrillin genes FBN1 and FBN2 often present with muscle weakness and atrophy as a symptom, Fbn2-null mice will be a useful model for examining this aspect of the disease process further.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0009137PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2817753PMC
February 2010

Mutant glycyl-tRNA synthetase (Gars) ameliorates SOD1(G93A) motor neuron degeneration phenotype but has little affect on Loa dynein heavy chain mutant mice.

PLoS One 2009 Jul 13;4(7):e6218. Epub 2009 Jul 13.

Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.

Background: In humans, mutations in the enzyme glycyl-tRNA synthetase (GARS) cause motor and sensory axon loss in the peripheral nervous system, and clinical phenotypes ranging from Charcot-Marie-Tooth neuropathy to a severe infantile form of spinal muscular atrophy. GARS is ubiquitously expressed and may have functions in addition to its canonical role in protein synthesis through catalyzing the addition of glycine to cognate tRNAs.

Methodology/principal Findings: We have recently described a new mouse model with a point mutation in the Gars gene resulting in a cysteine to arginine change at residue 201. Heterozygous Gars(C201R/+) mice have locomotor and sensory deficits. In an investigation of genetic mutations that lead to death of motor and sensory neurons, we have crossed the Gars(C201R/+) mice to two other mutants: the TgSOD1(G93A) model of human amyotrophic lateral sclerosis and the Legs at odd angles mouse (Dync1h1(Loa)) which has a defect in the heavy chain of the dynein complex. We found the Dync1h1(Loa/+);Gars(C201R/+) double heterozygous mice are more impaired than either parent, and this is may be an additive effect of both mutations. Surprisingly, the Gars(C201R) mutation significantly delayed disease onset in the SOD1(G93A);Gars(C201R/+) double heterozygous mutant mice and increased lifespan by 29% on the genetic background investigated.

Conclusions/significance: These findings raise intriguing possibilities for the study of pathogenetic mechanisms in all three mouse mutant strains.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0006218PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2704870PMC
July 2009

An ENU-induced mutation in mouse glycyl-tRNA synthetase (GARS) causes peripheral sensory and motor phenotypes creating a model of Charcot-Marie-Tooth type 2D peripheral neuropathy.

Dis Model Mech 2009 Jul-Aug;2(7-8):359-73. Epub 2009 May 26.

Department of Neurodegenerative Disease, Institute of Neurology, University College London, London WC1N 3BG, UK.

Mutations in the enzyme glycyl-tRNA synthetase (GARS) cause motor and sensory axon loss in the peripheral nervous system in humans, described clinically as Charcot-Marie-Tooth type 2D or distal spinal muscular atrophy type V. Here, we characterise a new mouse mutant, Gars(C201R), with a point mutation that leads to a non-conservative substitution within GARS. Heterozygous mice with a C3H genetic background have loss of grip strength, decreased motor flexibility and disruption of fine motor control; this relatively mild phenotype is more severe on a C57BL/6 background. Homozygous mutants have a highly deleterious set of features, including movement difficulties and death before weaning. Heterozygous animals have a reduction in axon diameter in peripheral nerves, slowing of nerve conduction and an alteration in the recovery cycle of myelinated axons, as well as innervation defects. An assessment of GARS levels showed increased protein in 15-day-old mice compared with controls; however, this increase was not observed in 3-month-old animals, indicating that GARS function may be more crucial in younger animals. We found that enzyme activity was not reduced detectably in heterozygotes at any age, but was diminished greatly in homozygous mice compared with controls; thus, homozygous animals may suffer from a partial loss of function. The Gars(C201R) mutation described here is a contribution to our understanding of the mechanism by which mutations in tRNA synthetases, which are fundamentally important, ubiquitously expressed enzymes, cause axonopathy in specific sets of neurons.
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http://dx.doi.org/10.1242/dmm.002527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2707104PMC
October 2009

A test of static and dynamic balance function in children with cochlear implants: the vestibular olympics.

Arch Otolaryngol Head Neck Surg 2008 Jan;134(1):34-8

Department of Otolaryngology-Head and Neck Surgery, University of Toronto, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.

Objectives: To determine the incidence of static and dynamic balance dysfunction in a group of children with profound sensorineural hearing loss receiving a cochlear implant and to assess the impact of cochlear implant activation on equilibrium.

Design: Observational cross-sectional study of children with single-sided implants, tested under 2 conditions: (1) implant on and (2) implant off in a random order.

Setting: Ambulatory setting within an academic, tertiary care children's hospital.

Participants: Forty-one children (ages 4-17 years) with cochlear implants comprised the study group. Fourteen children with normal hearing served as controls.

Intervention: All participants performed a standardized test of static and dynamic balance function (Bruininks-Oseretsky Test of Motor Proficiency 2 [BOT2], balance subset). Children with implants performed the BOT2 under the 2 randomized conditions.

Main Outcome Measures: Overall performance on the balance subset of the BOT2 and the influence of implant activation on performance.

Results: The mean (SD) age-adjusted scale score for our control group was 17 (5) points (95% confidence interval [CI], 14-20), which was not significantly different (P = .15) from the published age-adjusted mean for the BOT2 balance subset (15 [5] points). The group that had undergone implantation, however, performed significantly more poorly (12 [ 6] points; 95% CI, 10-14) than either the control group or the published test mean (P = .004). Children with implants performed better with their implants on than with their implants off (mean [SD] difference, 1.3 [2.7] points; 95% CI, 0.3-2.3; P = .01).

Conclusions: Large differences exist in the balance ability of children with sensorineural hearing loss requiring cochlear implantation compared with age-matched controls. Implant activation, however, conferred a slight advantage in accomplishing balance-related tasks. These results substantiate the need to further quantify the baseline vestibular dysfunction of our study population of children with cochlear implants, as well as the impact of implant activation on the input and output of the vestibular system.
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http://dx.doi.org/10.1001/archoto.2007.16DOI Listing
January 2008

The origins and uses of mouse outbred stocks.

Nat Genet 2005 Nov;37(11):1181-6

Department of Neurodegenerative Disease, Institute of Neurology, Queen Square, London WC1N 3BG, UK.

Outbred mouse stocks, often used in genetics, toxicology and pharmacology research, have been generated in rather haphazard ways. Understanding the characteristics of these stocks and their advantages and disadvantages is important for experimental design. In many studies these mice are used inappropriately, wasting animals' lives and resources on suboptimal experiments. Recently, however, researchers from the field of complex trait analysis have capitalized on the genetics of outbred stocks to refine the identification of quantitative trait loci. Here we assess the most widely used outbred stocks of mice and present guidelines for their use.
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http://dx.doi.org/10.1038/ng1665DOI Listing
November 2005

The SOD1 transgene in the G93A mouse model of amyotrophic lateral sclerosis lies on distal mouse chromosome 12.

Amyotroph Lateral Scler Other Motor Neuron Disord 2005 Jun;6(2):111-4

Department of Neurodegenerative Disease, Institute of Neurology, Queen Square, London, UK.

The SOD1G93A transgenic mouse strain which carries a human mutant Cu/Zn superoxide dismutase transgene array is a widely studied model of amyotrophic lateral sclerosis. These mice have been used in many breeding experiments to look for interactions with other loci, including transgenic and gene targeted mutations. Therefore, we decided to map the site of the transgene insertion as this may affect the outcome of such breeding experiments. In a fluorescence in situ hybridization experiment we determined that the SOD1G93A transgene insertion site lies on distal mouse chromosome 12. This chromosome also carries the 'Legs at odd angles' locus, which is an entirely unrelated mutation in the dynein heavy chain gene that we have been studying. We have analysed data from a SOD1G93AxLoa cross and determined that the site of the transgene insertion lies proximal of the dynein heavy chain gene on mouse chromosome 12.
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http://dx.doi.org/10.1080/14660820510035351DOI Listing
June 2005