Genetic Testing for Neurologic Disorders MP9497
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Minor snRNA gene delivery improves the loss of proprioceptive synapses on SMA motor neurons Erkan Y. Osman, … , Livio Pellizzoni, Christian L. Lorson JCI Insight. 2020. https://doi.org/10.1172/jci.insight.130574. Research In-Press Preview Neuroscience Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder caused by reduced expression of the survival motor neuron (SMN) protein. SMN has key functions in multiple RNA pathways, including the biogenesis of small nuclear ribonucleoproteins (snRNPs) that are essential components of both major (U2-dependent) and minor (U12-dependent) spliceosomes. Here we investigated the specific contribution of U12 splicing dysfunction to SMA pathology through selective restoration of this RNA pathway in mouse models of varying phenotypic severity. We show that viral-mediated delivery of minor snRNA genes specifically improves select U12 splicing defects induced by SMN deficiency in cultured mammalian cells as well as in the spinal cord and dorsal root ganglia of SMA mice without increasing SMN expression. This approach resulted in a moderate amelioration of several parameters of the disease phenotype in SMA mice including survival, weight gain and motor function. Importantly, minor snRNA gene delivery improved aberrant splicing of the U12 intron-containing gene Stasimon and rescued the severe loss of proprioceptive sensory synapses on SMA motor neurons, which are early signatures of motor circuit dysfunction in mouse models. Taken together, these findings establish the direct contribution of U12 splicing dysfunction to synaptic deafferentation and motor circuit pathology in SMA. Find the latest version: https://jci.me/130574/pdf Minor snRNA gene delivery improves the loss of proprioceptive synapses on SMA motor neurons Erkan Y. -
Genetic Mutations and Mechanisms in Dilated Cardiomyopathy
Genetic mutations and mechanisms in dilated cardiomyopathy Elizabeth M. McNally, … , Jessica R. Golbus, Megan J. Puckelwartz J Clin Invest. 2013;123(1):19-26. https://doi.org/10.1172/JCI62862. Review Series Genetic mutations account for a significant percentage of cardiomyopathies, which are a leading cause of congestive heart failure. In hypertrophic cardiomyopathy (HCM), cardiac output is limited by the thickened myocardium through impaired filling and outflow. Mutations in the genes encoding the thick filament components myosin heavy chain and myosin binding protein C (MYH7 and MYBPC3) together explain 75% of inherited HCMs, leading to the observation that HCM is a disease of the sarcomere. Many mutations are “private” or rare variants, often unique to families. In contrast, dilated cardiomyopathy (DCM) is far more genetically heterogeneous, with mutations in genes encoding cytoskeletal, nucleoskeletal, mitochondrial, and calcium-handling proteins. DCM is characterized by enlarged ventricular dimensions and impaired systolic and diastolic function. Private mutations account for most DCMs, with few hotspots or recurring mutations. More than 50 single genes are linked to inherited DCM, including many genes that also link to HCM. Relatively few clinical clues guide the diagnosis of inherited DCM, but emerging evidence supports the use of genetic testing to identify those patients at risk for faster disease progression, congestive heart failure, and arrhythmia. Find the latest version: https://jci.me/62862/pdf Review series Genetic mutations and mechanisms in dilated cardiomyopathy Elizabeth M. McNally, Jessica R. Golbus, and Megan J. Puckelwartz Department of Human Genetics, University of Chicago, Chicago, Illinois, USA. Genetic mutations account for a significant percentage of cardiomyopathies, which are a leading cause of conges- tive heart failure. -
PTEN Mutations the PTEN Hamartoma Tumor Synd
Updated December 2019 (NCCN v1.2020) Cowden Syndrome/PTEN Hamartoma Tumor Syndrome: PTEN Mutations The PTEN Hamartoma Tumor Syndrome (PHTS) is a spectrum of highly variable conditions with overlapping features. This spectrum includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), and PTEN-related autism spectrum disorder.1-3 The term PHTS describes any individual with a germline pathogenic PTEN mutation, regardless of their clinical presentation.4 PHTS is a multisystem syndrome primarily characterized by noncancerous (benign), tumor-like growths called hamartomas that can develop throughout the body. There is also an increased risk of adult-onset cancers.5 Cancer Risks and General Management Recommendations PTEN Mutation General Surveillance/Management Recommendations9 Carrier Cancer Population Risks2,4-8 Lifetime Cancer Risks Female Breast: 12.4% Surveillance Primary: 33-60% Breast awareness, including periodic, consistent breast self exams, Second Primary: starting at age 18 years 29% within 10 Clinical breast exam every 6-12 months starting at age 25 years, or 5- years10 10 years before the earliest breast cancer diagnosis in the family (whichever comes first) Annual mammogram with consideration of tomosynthesis and breast MRI with contrast at age 30-35 years, or 5-10 years before the earliest breast cancer diagnosis in the family (whichever comes first) Age >75 years: Management should be considered on an individual basis Surgery Discuss option of risk-reducing mastectomy, including degree of protection, reconstruction -
Defining Functional Interactions During Biogenesis of Epithelial Junctions
ARTICLE Received 11 Dec 2015 | Accepted 13 Oct 2016 | Published 6 Dec 2016 | Updated 5 Jan 2017 DOI: 10.1038/ncomms13542 OPEN Defining functional interactions during biogenesis of epithelial junctions J.C. Erasmus1,*, S. Bruche1,*,w, L. Pizarro1,2,*, N. Maimari1,3,*, T. Poggioli1,w, C. Tomlinson4,J.Lees5, I. Zalivina1,w, A. Wheeler1,w, A. Alberts6, A. Russo2 & V.M.M. Braga1 In spite of extensive recent progress, a comprehensive understanding of how actin cytoskeleton remodelling supports stable junctions remains to be established. Here we design a platform that integrates actin functions with optimized phenotypic clustering and identify new cytoskeletal proteins, their functional hierarchy and pathways that modulate E-cadherin adhesion. Depletion of EEF1A, an actin bundling protein, increases E-cadherin levels at junctions without a corresponding reinforcement of cell–cell contacts. This unexpected result reflects a more dynamic and mobile junctional actin in EEF1A-depleted cells. A partner for EEF1A in cadherin contact maintenance is the formin DIAPH2, which interacts with EEF1A. In contrast, depletion of either the endocytic regulator TRIP10 or the Rho GTPase activator VAV2 reduces E-cadherin levels at junctions. TRIP10 binds to and requires VAV2 function for its junctional localization. Overall, we present new conceptual insights on junction stabilization, which integrate known and novel pathways with impact for epithelial morphogenesis, homeostasis and diseases. 1 National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK. 2 Computing Department, Imperial College London, London SW7 2AZ, UK. 3 Bioengineering Department, Faculty of Engineering, Imperial College London, London SW7 2AZ, UK. 4 Department of Surgery & Cancer, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK. -
343747488.Pdf
Washington University School of Medicine Digital Commons@Becker Open Access Publications 6-1-2020 Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2 Simon Hsu Anna A Pimenova Kimberly Hayes Juan A Villa Matthew J Rosene See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Authors Simon Hsu, Anna A Pimenova, Kimberly Hayes, Juan A Villa, Matthew J Rosene, Madhavi Jere, Alison M Goate, and Celeste M Karch Neurobiology of Disease 139 (2020) 104817 Contents lists available at ScienceDirect Neurobiology of Disease journal homepage: www.elsevier.com/locate/ynbdi Systematic validation of variants of unknown significance in APP, PSEN1 T and PSEN2 Simon Hsua, Anna A. Pimenovab, Kimberly Hayesa, Juan A. Villaa, Matthew J. Rosenea, ⁎ Madhavi Jerea, Alison M. Goateb, Celeste M. Karcha, a Department of Psychiatry, Washington University School of Medicine, 425 S Euclid Avenue, St Louis, MO 63110, USA b Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA ARTICLE INFO ABSTRACT Keywords: Alzheimer's disease (AD) is a neurodegenerative disease that is clinically characterized by progressive cognitive APP decline. More than 200 pathogenic mutations have been identified in amyloid-β precursor protein (APP), presenilin PSEN1 1 (PSEN1) and presenilin 2 (PSEN2). Additionally, common and rare variants occur within APP, PSEN1, and PSEN2 PSEN2 that may be risk factors, protective factors, or benign, non-pathogenic polymorphisms. Yet, to date, no Alzheimer's disease single study has carefully examined the effect of all of the variants of unknown significance reported in APP, Cell-based assays PSEN1 and PSEN2 on Aβ isoform levels in vitro. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
Detecting and Tracking Early Neurodegeneration in Familial
University College London Institute of Neurology Detecting and tracking early neurodegeneration in familial Alzheimer’s disease A thesis submitted for the degree of Doctor of Philosophy Philip S.J. Weston 1 For Emma and Evie 2 Declaration of authorship and originality I, Philip S.J. Weston, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Philip S.J. Weston 3 Acknowledgements Above all I would like to thank the FAD family members who so kindly donated their time and energy to participate in research. Without their effort and dedication none of the studies reported in this thesis would have been possible. I am grateful to the Medical Research Council for funding my Clinical Research Training Fellowship, and to the National Institute of Health Research, which provided valuable funds for other aspects of the study. My primary supervisor, Nick Fox, has been a constant source of support, inspiration, and motivation. I am grateful to Nick for entrusting me with such a valuable cohort of special individuals, and for allowing me to oversee the conduct of the studies presented here. I also thank my secondary supervisor Jon Schott for providing additional useful advice and support throughout. Finally I would like to thank my co-workers, collaborators and colleagues. On the two imaging projects: Manja Lehman, Natalie Ryan, Marc Modat, Ivor Simpson, Nico Toussaint, and Seb Ourselin. On the serum neurofilament light project: Henrik Zetterberg, Kaj Blennow, Simon Mead, and Ron Druyeh. On the accelerated long-term forgetting study: Adam Zeman, Chris Butler, Yuying Liang, Seb Crutch, and Susie Henley. -
Genetic Testing for Familial Alzheimer's Disease
Corporate Medical Policy Genetic Testing for Familial Alzheimer’s Disease AHS – M2038 File Name: genetic_testing_for_familial_alzheimers_disease Origination: 1/2019 Last CAP Review: 10/2020 Next CAP Review: 10/2021 Last Review: 10/2020 Description of Procedure or Service Alzheimer disease (AD) is a neurodegenerative disease defined by a gradual decline in memory, cognitive functions, gross atrophy of the brain, and an accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles (Karch, Cruchaga, & Goate, 2014). Familial Alzheimer disease (FAD) is a rare, inherited form of AD. FAD has a much earlier onset than other forms of Alzheimer disease with symptoms developing in individuals in their thirties or forties. Related Policies General Genetic Testing, Germline Disorders AHS – M2145 General Genetic Testing, Somatic Disorders AHS – M2146 ***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician. Policy BCBSNC will provide coverage for genetic testing for familial Alzheimer disease when it is determined the medical criteria or reimbursement guidelines below are met. Benefits Application This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy. -
Mitochondrial Heat Shock Protein 60: Evaluation of Its Role As a Neuroprotectant in Familial ALS and Its Mutation As a Cause of Hereditary Spastic Paraplegia
Mitochondrial Heat Shock Protein 60: Evaluation of its role as a neuroprotectant in familial ALS and its mutation as a cause of hereditary spastic paraplegia By Laura A. Cooper Integrated Program in Neuroscience McGill University, Montreal June 2011 A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of master’s in science © Laura A. Cooper, 2011 TABLE OF CONTENTS ABSTRACT…………………………………………………………………………….vi RÉSUMÉ……………………………………………………………………………….viii ACKNOWLEDGMENTS……………………………………………………………..xi LIST OF FIGURES……………………………………………………………………xiii ABBREVIATIONS………………………………………………………………….....xv INTRODUCTION……………………………………………………………………..xx CHAPTER 1 – Literature Review 1.1 Amyotrophic Lateral Sclerosis 1.1.1 Clinical Overview..................................................................................................1 1.1.2 Sporadic ALS…………………………………………………………………….2 1.1.3 Familial ALS……………………………………………………………………..4 1.1.4 Cu/Zn Superoxide Dismutase Mutation and fALS……………………………….4 1.1.5 Protein Aggregation in SOD1-Related fALS…………………………………….5 1.1.6 Mitochondrial Abnormalities in Mouse Models of SOD1-Related fALS………..7 1.1.7 Relationship Between Mutant SOD1 and Mitochondrial Abnormalities………..8 1.2 Heat Shock Proteins 1.2.1 Normal Function in the Central Nervous System and Relevance to ALS……….9 1.2.2 Heat Shock Proteins as a Therapeutic Target in ALS………………………….10 1.3 Mitochondrial Heat Shock Protein Hsp60 1.3.1 Structure and Function………………………………………………………....12 ii 1.3.2 Mitochondrial Hsp60 in Neuroprotection……………………………………. -
Methodology Report ENU Mutagenesis Screen to Establish Motor Phenotypes in Wild-Type Mice and Modifiers of a Pre-Existing Motor Phenotype in Tau Mutant Mice
Hindawi Publishing Corporation Journal of Biomedicine and Biotechnology Volume 2011, Article ID 130947, 11 pages doi:10.1155/2011/130947 Methodology Report ENU Mutagenesis Screen to Establish Motor Phenotypes in Wild-Type Mice and Modifiers of a Pre-Existing Motor Phenotype in Tau Mutant Mice Xin Liu,1 Michael Dobbie,2 Rob Tunningley,2 Belinda Whittle,2 Yafei Zhang, 2 Lars M. Ittner,1 and Jurgen¨ Gotz¨ 1 1 Alzheimer’s and Parkinson’s Disease Laboratory, Brain & Mind Research Institute, University of Sydney, 100 Mallett Street, Camperdown, NSW 2050, Australia 2 Australian Phenomics Facility, Australian National University, 117 Garran Road, Acton, ACT 0200, Australia Correspondence should be addressed to Jurgen¨ Gotz,¨ [email protected] Received 24 August 2011; Accepted 4 November 2011 Academic Editor: Kurt Burki¨ Copyright © 2011 Xin Liu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Modifier screening is a powerful genetic tool. While not widely used in the vertebrate system, we applied these tools to transgenic mouse strains that recapitulate key aspects of Alzheimer’s disease (AD), such as tau-expressing mice. These are characterized by a robust pathology including both motor and memory impairment. The phenotype can be modulated by ENU mutagenesis, which results in novel mutant mouse strains and allows identifying the underlying gene/mutation. Here we discuss -
Insurance and Advance Pay Test Requisition
Insurance and Advance Pay Test Requisition (2021) For Specimen Collection Service, Please Fax this Test Requisition to 1.610.271.6085 Client Services is available Monday through Friday from 8:30 AM to 9:00 PM EST at 1.800.394.4493, option 2 Patient Information Patient Name Patient ID# (if available) Date of Birth Sex designated at birth: 9 Male 9 Female Street address City, State, Zip Mobile phone #1 Other Phone #2 Patient email Language spoken if other than English Test and Specimen Information Consult test list for test code and name Test Code: Test Name: Test Code: Test Name: 9 Check if more than 2 tests are ordered. Additional tests should be checked off within the test list ICD-10 Codes (required for billing insurance): Clinical diagnosis: Age at Initial Presentation: Ancestral Background (check all that apply): 9 African 9 Asian: East 9 Asian: Southeast 9 Central/South American 9 Hispanic 9 Native American 9 Ashkenazi Jewish 9 Asian: Indian 9 Caribbean 9 European 9 Middle Eastern 9 Pacific Islander Other: Indications for genetic testing (please check one): 9 Diagnostic (symptomatic) 9 Predictive (asymptomatic) 9 Prenatal* 9 Carrier 9 Family testing/single site Relationship to Proband: If performed at Athena, provide relative’s accession # . If performed at another lab, a copy of the relative’s report is required. Please attach detailed medical records and family history information Specimen Type: Date sample obtained: __________ /__________ /__________ 9 Whole Blood 9 Serum 9 CSF 9 Muscle 9 CVS: Cultured 9 Amniotic Fluid: Cultured 9 Saliva (Not available for all tests) 9 DNA** - tissue source: Concentration ug/ml Was DNA extracted at a CLIA-certified laboratory or a laboratory meeting equivalent requirements (as determined by CAP and/or CMS)? 9 Yes 9 No 9 Other*: If not collected same day as shipped, how was sample stored? 9 Room temp 9 Refrigerated 9 Frozen (-20) 9 Frozen (-80) History of blood transfusion? 9 Yes 9 No Most recent transfusion: __________ /__________ /__________ *Please contact us at 1.800.394.4493, option 2 prior to sending specimens. -
An Unusual Case of Cowden Syndrome Associated With
Pistorius et al. Hereditary Cancer in Clinical Practice (2016) 14:11 DOI 10.1186/s13053-016-0051-8 CASE REPORT Open Access An unusual case of Cowden syndrome associated with ganglioneuromatous polyposis Steffen Pistorius1,6*†, Barbara Klink2,7*†, Jessica Pablik3, Andreas Rump2, Daniela Aust3,7, Marlene Garzarolli4, Evelin Schröck2,7 and Hans K. Schackert5,6,7 Abstract Background: Ganglioneuromatous polyposis (GP) is a very rare disorder which may be associated with other clinical manifestations and syndromes, such as Cowden syndrome, multiple endocrine neoplasia (MEN) type II and neurofibromatosis (NF) 1. The risk for malignant transformation of ganglioneuromas is unknown, and the combination of GP with colon cancer has been only very seldom reported. Methods and results: We report the case of a 60-year old male patient with adenocarcinoma, adenomas and lipomas of the colon and multiple gastroduodenal lesions combined with generalised lipomatosis and macrocephaly. Based on the initial endoscopic and histological findings, a (restorative) proctocolectomy was recommended but declined by the patient. Instead, a colectomy was performed. The histological examination revealed an unforeseen GP in addition to the colon cancer. Extensive molecular diagnostics allowed for the differential diagnosis of the causes of the clinical manifestations, and the clinical suspicion of Cowden syndrome could not be confirmed using Sanger Sequencing and MLPA for the analysis of PTEN. Finally, a pathogenic germline mutation in PTEN (heterozygous stop mutation in exon 2: NM_000314 (PTEN):c.138C > A; p.Tyr46*) could be detected by next-generation sequencing (NGS), confirming an unusual presentation of Cowden syndrome with GP. Conclusions: Cowden syndrome should be considered in cases of GP with extracolonic manifestation and verified by combined clinical and molecular diagnostics.