Holird REPORT

Total Page:16

File Type:pdf, Size:1020Kb

Holird REPORT CBA HoliRD REPORT: Williams Syndrome Marina Esteban Medina María Peña-Chilet Carlos Loucera Joaquín Dopazo Clinical Bioinformatics Area - FPS Sevilla, January 13, 2020 Collaborators: Dra.Victoria Campuzano’s group - U735 CIBERER Research group at Universidad Pompeu Fabra, Barcelona. CBA Objectives and methodology: The Holistic Rare Disease project (HoliRD) aims to build Diseases Maps for as many Rare Diseases as possible and to model them to systematize research in drug repurposing. In order to achieve this purpose several databases such as ORPHANET, OMIM, HPO, PubMed, KEGG, STRING, as well as the literature is used to collect all the up-to-date knowledge of the diseases under study and defining a Disease Map that contains the functional relationships among the known disease genes, as well as the functional consequences of their activity. Then, a mechanistic model that accounts for the activity of such map is used. The HiPathia algorithm, which has successfully proven to predict cell activities related to cancer hallmarks (Hidalgo et al., Oncotarget 2017; 8:5160-5178; Hidalgo et al., Biol Direct. 2018;13:16) as well as the effect of protein inhibitions on cell survival (Cubuk et al., Cancer Res. 2018; 78:6059-6072) is used to simulate the activity of the disease map. Finally, machine learning algorithms are used to find other proteins, already target of drugs with another indication, which display a potential causal effect on the activity of the previously defined disease map. The drugs that target these proteins are potential candidates for repurposing. Schematic representation of the method used. Examples of the use of this approach can be found in Esteban-Medina et al., BMC Bioinformatics. 2019, 20(1):370. CBA Report This report describes the results of the different steps of the HoliRD approach applied to Williams Syndrome Identification of genes highly related to the rare disease (RD) under study in Orphanet/OMIM A total of 9 genes annotated as Williams Syndrome (WS) were found in the OMIM/ORPHANET database. WS highly related genes Disease ID Entrez ID Gene Symbol OMIM:194050 2006 ELN OMIM:194050 51085 MLXIPL ORPHA:904 26608 TBL2 ORPHA:904 3984 LIMK1 ORPHA:904 9569 GTF2IRD1 ORPHA:904 7461 CLIP2 ORPHA:904 9031 BAZ1B ORPHA:904 2969 GTF2I ORPHA:904 5982 RFC2 CBA Identification of highly related HPO to the RD under study: A total of 143 HPO codes associated to WS with specificity >=7 were selected. WS highly related HPOs HPO ID HPO term Specificity level HP:0000010 Recurrent urinary tract infections 10 HP:0000015 Bladder diverticulum 8 HP:0000023 Inguinal hernia 9 HP:0000025 Functional abnormality of male internal genitalia 7 HP:0000028 Cryptorchidism 10 HP:0000044 Hypogonadotrophic hypogonadism 9 HP:0000075 Renal duplication 8 HP:0000076 Vesicoureteral reflux 11 HP:0000083 Renal insufficiency 9 HP:0000089 Renal hypoplasia 9 HP:0000093 Proteinuria 9 HP:0000121 Nephrocalcinosis 8 HP:0000125 Pelvic kidney 10 HP:0000147 Polycystic ovaries 12 HP:0000154 Wide mouth 10 HP:0000158 Macroglossia 15 HP:0000179 Thick lower lip vermilion 12 HP:0000212 Gingival overgrowth 11 HP:0000232 Everted lower lip vermilion 12 HP:0000252 Microcephaly 19 HP:0000275 Narrow face 8 CBA HP:0000280 Coarse facial features 7 HP:0000286 Epicanthus 10 HP:0000307 Pointed chin 7 HP:0000337 Broad forehead 7 HP:0000343 Long philtrum 12 HP:0000347 Micrognathia 16 HP:0000348 High forehead 7 HP:0000368 Low-set, posteriorly rotated ears 9 HP:0000389 Chronic otitis media 11 HP:0000400 Macrotia 7 HP:0000407 Sensorineural hearing impairment 10 HP:0000411 Protruding ear 7 HP:0000431 Wide nasal bridge 8 HP:0000485 Megalocornea 8 HP:0000486 Strabismus 7 HP:0000518 Cataract 7 HP:0000581 Blepharophimosis 12 HP:0000627 Posterior embryotoxon 8 HP:0000635 Blue irides 9 HP:0000668 Hypodontia 12 HP:0000670 Carious teeth 11 HP:0000682 Abnormality of dental enamel 14 HP:0000689 Dental malocclusion 11 HP:0000691 Microdontia 11 HP:0000716 Depressivity 7 HP:0000717 Autism 7 CBA HP:0000739 Anxiety 8 HP:0000767 Pectus excavatum 8 HP:0000787 Nephrolithiasis 8 HP:0000938 Osteopenia 9 HP:0000939 Osteoporosis 9 HP:0000960 Sacral dimple 14 HP:0001052 Nevus flammeus 9 HP:0001081 Cholelithiasis 9 HP:0001136 Retinal arteriolar tortuosity 20 HP:0001181 Adducted thumb 14 HP:0001249 Intellectual disability 7 HP:0001257 Spasticity 11 HP:0001260 Dysarthria 7 HP:0001297 Stroke 10 HP:0001310 Dysmetria 8 HP:0001337 Tremor 7 HP:0001347 Hyperreflexia 7 HP:0001361 Nystagmus-induced head nodding 8 HP:0001387 Joint stiffness 7 HP:0001531 Failure to thrive in infancy 7 HP:0001537 Umbilical hernia 10 HP:0001582 Redundant skin 9 HP:0001618 Dysphonia 8 HP:0001629 Ventricular septal defect 9 HP:0001631 Atrial septal defect 9 HP:0001634 Mitral valve prolapse 9 CBA HP:0001636 Tetralogy of Fallot 13 HP:0001639 Hypertrophic cardiomyopathy 8 HP:0001642 Pulmonic stenosis 7 HP:0001643 Patent ductus arteriosus 9 HP:0001645 Sudden cardiac death 8 HP:0001647 Bicuspid aortic valve 9 HP:0001653 Mitral regurgitation 8 HP:0001800 Hypoplastic toenails 10 HP:0001822 Hallux valgus 16 HP:0001969 Tubulointerstitial abnormality 10 HP:0002020 Gastroesophageal reflux 11 HP:0002024 Malabsorption 8 HP:0002027 Abdominal pain 8 HP:0002035 Rectal prolapse 11 HP:0002120 Cerebral cortical atrophy 14 HP:0002141 Gait imbalance 7 HP:0002150 Hypercalciuria 10 HP:0002183 Phonophobia 7 HP:0002205 Recurrent respiratory infections 11 HP:0002253 Colonic diverticula 10 HP:0002308 Arnold-Chiari malformation 11 HP:0002575 Tracheoesophageal fistula 13 HP:0002623 Overriding aorta 10 HP:0002637 Cerebral ischemia 15 HP:0002650 Scoliosis 8 HP:0002808 Kyphosis 8 CBA HP:0002857 Genu valgum 19 HP:0002974 Radioulnar synostosis 21 HP:0002999 Patellar dislocation 13 HP:0003028 Abnormality of the ankles 9 HP:0003072 Hypercalcemia 9 HP:0003196 Short nose 8 HP:0003236 Elevated serum creatine kinase 8 HP:0003298 Spina bifida occulta 11 HP:0003307 Hyperlordosis 8 HP:0003312 Abnormal form of the vertebral bodies 8 HP:0003422 Vertebral segmentation defect 8 HP:0004209 Clinodactyly of the 5th finger 19 HP:0004295 Abnormality of the gastric mucosa 8 HP:0004381 Supravalvular aortic stenosis 8 HP:0004398 Peptic ulcer 7 HP:0004428 Elfin facies 7 HP:0004969 Peripheral pulmonary artery stenosis 15 HP:0005113 Aortic arch aneurysm 13 HP:0005344 Abnormal carotid artery morphology 8 HP:0005562 Multiple renal cysts 9 HP:0005692 Joint hyperflexibility 7 HP:0005978 Type II diabetes mellitus 9 HP:0007018 Attention deficit hyperactivity disorder 9 Atrophy/Degeneration involving the corticospinal HP:0007372 9 tracts HP:0007477 Abnormal dermatoglyphics 7 CBA HP:0007495 Prematurely aged appearance 7 HP:0007720 Flat cornea 8 HP:0007957 Corneal opacity 7 HP:0008053 Aplasia/Hypoplasia of the iris 12 HP:0008499 High hypermetropia 7 HP:0008661 Urethral stenosis 13 HP:0008736 Hypoplasia of penis 12 HP:0010526 Dysgraphia 7 HP:0010662 Abnormality of the diencephalon 8 HP:0010669 Hypoplasia of the zygomatic bone 12 HP:0010780 Hyperacusis 7 HP:0010807 Open bite 11 HP:0010880 Increased nuchal translucency 8 HP:0011001 Increased bone mineral density 8 HP:0100025 Overfriendliness 7 HP:0100539 Periorbital edema 13 HP:0100785 Insomnia 7 HP:0100817 Renovascular hypertension 14 HP:0200021 Down-sloping shoulders 9 CBA Identification of genes that shared at least HPO-RD codes Genes with >= 25 WS-HPO codes Gene Symbol Entrez Gene Symbol Entrez Gene Symbol Entrez ACTB 60 COX2 4513 SMC1A 8243 ARVCF 421 COX3 4514 NAA10 8260 RERE 473 ND1 4535 OFD1 8481 ATP6V1A 523 ND4 4538 TP63 8626 ATRX 546 ND5 4540 BAZ1B 9031 BRCA1 672 ND6 4541 SMC3 9126 BRAF 673 TRNF 4558 GTF2IRD1 9569 COMT 1312 TRNH 4564 SEC24C 9632 DHCR7 1717 TRNL1 4567 SEMA3E 9723 DVL1 1855 TRNQ 4572 MED12 9968 DVL3 1857 TRNS1 4574 CPLX1 10815 ELN 2006 TRNS2 4575 POLR3A 11128 ERCC2 2068 TRNW 4578 KAT6B 23522 ERCC3 2071 NOTCH2 4853 PIGN 23556 ERCC4 2072 NOTCH3 4854 RAB3GAP2 25782 ERCC6 2074 NRAS 4893 NIPBL 25836 FBN1 2200 ROR2 4920 SETBP1 26040 FGFR1 2260 OCRL 4952 TBL2 26608 FGFR3 2261 PIK3CA 5290 MLXIPL 51085 FGFR2 2263 MAP2K1 5604 BCOR 54880 FLNA 2316 PTCH1 5727 NSUN2 54888 GABRD 2563 PTEN 5728 SETD5 55209 CBA GATA4 2626 PTPN11 5781 FANCI 55215 GJA1 2697 ALDH18A1 5832 CHD7 55636 GP1BB 2812 RAD21 5885 HDAC8 55869 GTF2E2 2961 RAF1 5894 ARID1B 57492 GTF2I 2969 RFC2 5982 PIEZO2 63895 HRAS 3265 RPS6KA3 6197 PRDM16 63976 HSPG2 3339 RREB1 6239 NSD1 64324 KRAS 3845 SKI 6497 NXN 64359 LETM1 3954 TBX1 6899 MPLKIP 136647 LIG4 3981 HIRA 7290 B3GLCT 145173 LIMK1 3984 UFD1 7353 ARX 170302 LMNA 4000 CLIP2 7461 ARID2 196528 MECP2 4204 NSD2 7468 JMJD1C 221037 KMT2A 4297 RNF113A 7737 GTF2H5 404672 COX1 4512 Genes with >= 50 WS-HPO codes Gene Symbol Entrez Gene Symbol Entrez ELN 2006 CLIP2 7461 GTF2I 2969 BAZ1B 9031 KRAS 3845 GTF2IRD1 9569 LIMK1 3984 TBL2 26608 RFC2 5982 MLXIPL 51085 CBA Genes with >= 143 (all) WS-HPO codes Gene Symbol Entrez ELN 2006 GTF2I 2969 LIMK1 3984 RFC2 5982 CLIP2 7461 BAZ1B 9031 GTF2IRD1 9569 TBL2 26608 In order to maintain the specificity and not over expand the Disease Map of action only genes with >= 50 WS-HPO codes were selected. **Take into account that not all genes can be found in HiPathia pathways. We have selected those genes that expand the affected HiPathia circuits within a certain threshold for the model** Location of the selected disease related genes in KEGG pathways to define the Disease Map of action. After locating the RD associated genes within KEGG pathways, a total of 177 circuits belonging to 36 KEGG pathways were found as part of the disease map. KEGG-pathway KEGG-pathway KEGG pathway KEGG pathway code code Natural
Recommended publications
  • Cognition and Steroidogenesis in the Rhesus Macaque
    Cognition and Steroidogenesis in the Rhesus Macaque Krystina G Sorwell A DISSERTATION Presented to the Department of Behavioral Neuroscience and the Oregon Health & Science University School of Medicine in partial fulfillment of the requirements for the degree of Doctor of Philosophy November 2013 School of Medicine Oregon Health & Science University CERTIFICATE OF APPROVAL This is to certify that the PhD dissertation of Krystina Gerette Sorwell has been approved Henryk Urbanski Mentor/Advisor Steven Kohama Member Kathleen Grant Member Cynthia Bethea Member Deb Finn Member 1 For Lily 2 TABLE OF CONTENTS Acknowledgments ......................................................................................................................................................... 4 List of Figures and Tables ............................................................................................................................................. 7 List of Abbreviations ................................................................................................................................................... 10 Abstract........................................................................................................................................................................ 13 Introduction ................................................................................................................................................................. 15 Part A: Central steroidogenesis and cognition ............................................................................................................
    [Show full text]
  • Gene Expression Profile in Different Age Groups and Its Association With
    cells Article Gene Expression Profile in Different Age Groups and Its Association with Cognitive Function in Healthy Malay Adults in Malaysia Nur Fathiah Abdul Sani 1 , Ahmad Imran Zaydi Amir Hamzah 1, Zulzikry Hafiz Abu Bakar 1 , Yasmin Anum Mohd Yusof 2, Suzana Makpol 1 , Wan Zurinah Wan Ngah 1 and Hanafi Ahmad Damanhuri 1,* 1 Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Center, Jalan Yaacob Latif, Cheras, Kuala Lumpur 56000, Malaysia; [email protected] (N.F.A.S.); [email protected] (A.I.Z.A.H.); zulzikryhafi[email protected] (Z.H.A.B.); [email protected] (S.M.); [email protected] (W.Z.W.N.) 2 Faculty of Medicine and Defence Health, National Defence University of Malaysia, Kem Sungai Besi, Kuala Lumpur 57000, Malaysia; [email protected] * Correspondence: hanafi[email protected] Abstract: The mechanism of cognitive aging at the molecular level is complex and not well under- stood. Growing evidence suggests that cognitive differences might also be caused by ethnicity. Thus, this study aims to determine the gene expression changes associated with age-related cognitive decline among Malay adults in Malaysia. A cross-sectional study was conducted on 160 healthy Malay subjects, aged between 28 and 79, and recruited around Selangor and Klang Valley, Malaysia. Citation: Abdul Sani, N.F.; Amir Gene expression analysis was performed using a HumanHT-12v4.0 Expression BeadChip microarray Hamzah, A.I.Z.; Abu Bakar, Z.H.; kit. The top 20 differentially expressed genes at p < 0.05 and fold change (FC) = 1.2 showed that Mohd Yusof, Y.A.; Makpol, S.; Wan PAFAH1B3, HIST1H1E, KCNA3, TM7SF2, RGS1, and TGFBRAP1 were regulated with increased Ngah, W.Z.; Damanhuri, H.A.
    [Show full text]
  • Gabaergic Signaling Linked to Autophagy Enhances Host Protection Against Intracellular Bacterial Infections
    ARTICLE DOI: 10.1038/s41467-018-06487-5 OPEN GABAergic signaling linked to autophagy enhances host protection against intracellular bacterial infections Jin Kyung Kim1,2,3, Yi Sak Kim1,2,3, Hye-Mi Lee1,3, Hyo Sun Jin4, Chiranjivi Neupane 2,5, Sup Kim1,2,3, Sang-Hee Lee6, Jung-Joon Min7, Miwa Sasai8, Jae-Ho Jeong 9,10, Seong-Kyu Choe11, Jin-Man Kim12, Masahiro Yamamoto8, Hyon E. Choy 9,10, Jin Bong Park 2,5 & Eun-Kyeong Jo1,2,3 1234567890():,; Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the brain; however, the roles of GABA in antimicrobial host defenses are largely unknown. Here we demonstrate that GABAergic activation enhances antimicrobial responses against intracel- lular bacterial infection. Intracellular bacterial infection decreases GABA levels in vitro in macrophages and in vivo in sera. Treatment of macrophages with GABA or GABAergic drugs promotes autophagy activation, enhances phagosomal maturation and antimicrobial responses against mycobacterial infection. In macrophages, the GABAergic defense is mediated via macrophage type A GABA receptor (GABAAR), intracellular calcium release, and the GABA type A receptor-associated protein-like 1 (GABARAPL1; an Atg8 homolog). Finally, GABAergic inhibition increases bacterial loads in mice and zebrafish in vivo, sug- gesting that the GABAergic defense plays an essential function in metazoan host defenses. Our study identified a previously unappreciated role for GABAergic signaling in linking antibacterial autophagy to enhance host innate defense against intracellular bacterial infection. 1 Department of Microbiology, Chungnam National University School of Medicine, Daejeon 35015, Korea. 2 Department of Medical Science, Chungnam National University School of Medicine, Daejeon 35015, Korea.
    [Show full text]
  • Characterisation of GABAA Receptors and Cation-Chloride Cotransporters in the Uterus and Their Role in Pre-Term Labour
    Characterisation of GABAA receptors and cation-chloride cotransporters in the uterus and their role in pre-term labour Melissa Linda Sutherland December 2017 Supervisors: Dr. Amy V. Poole, Dr. Jennifer A. Fraser, Dr. Claire Garden. A thesis submitted in partial fulfilment of the requirements of Edinburgh Napier University, for the award of Master by Research Declaration It is hereby declared that this thesis is the result of the author’s original research. It has been composed by the author and has not been previously submitted for examination, which has led to the award of a degree or professional qualification. Signed: Date: Contents page Abbreviations .............................................................................................. 1 Acknowledgements ................................................................................... 3 Abstract ......................................................................................................... 4 CHAPTER 1. Introduction ......................................................................... 5 1.1-aminobutyric acid (GABA) .............................................................. 5 1.2 GABA receptor structure and function .......................................... 5 Figure 1.1 Schematic diagram of the GABAA subunit and receptor ......................................................................................................... 6 1.3 GABAARs role in development central nervous system ..........................................................................................................
    [Show full text]
  • Ion Channels
    UC Davis UC Davis Previously Published Works Title THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels. Permalink https://escholarship.org/uc/item/1442g5hg Journal British journal of pharmacology, 176 Suppl 1(S1) ISSN 0007-1188 Authors Alexander, Stephen PH Mathie, Alistair Peters, John A et al. Publication Date 2019-12-01 DOI 10.1111/bph.14749 License https://creativecommons.org/licenses/by/4.0/ 4.0 Peer reviewed eScholarship.org Powered by the California Digital Library University of California S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2019/20: Ion channels. British Journal of Pharmacology (2019) 176, S142–S228 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels Stephen PH Alexander1 , Alistair Mathie2 ,JohnAPeters3 , Emma L Veale2 , Jörg Striessnig4 , Eamonn Kelly5, Jane F Armstrong6 , Elena Faccenda6 ,SimonDHarding6 ,AdamJPawson6 , Joanna L Sharman6 , Christopher Southan6 , Jamie A Davies6 and CGTP Collaborators 1School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK 2Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK 3Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK 4Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck, A-6020 Innsbruck, Austria 5School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK 6Centre for Discovery Brain Science, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties.
    [Show full text]
  • SZDB: a Database for Schizophrenia Genetic Research
    Schizophrenia Bulletin vol. 43 no. 2 pp. 459–471, 2017 doi:10.1093/schbul/sbw102 Advance Access publication July 22, 2016 SZDB: A Database for Schizophrenia Genetic Research Yong Wu1,2, Yong-Gang Yao1–4, and Xiong-Jian Luo*,1,2,4 1Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, China; 2Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, China; 3CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China 4YGY and XJL are co-corresponding authors who jointly directed this work. *To whom correspondence should be addressed; Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China; tel: +86-871-68125413, fax: +86-871-68125413, e-mail: [email protected] Schizophrenia (SZ) is a debilitating brain disorder with a Introduction complex genetic architecture. Genetic studies, especially Schizophrenia (SZ) is a severe mental disorder charac- recent genome-wide association studies (GWAS), have terized by abnormal perceptions, incoherent or illogi- identified multiple variants (loci) conferring risk to SZ. cal thoughts, and disorganized speech and behavior. It However, how to efficiently extract meaningful biological affects approximately 0.5%–1% of the world populations1 information from bulk genetic findings of SZ remains a and is one of the leading causes of disability worldwide.2–4 major challenge. There is a pressing
    [Show full text]
  • NIH Public Access Author Manuscript Psychopharmacology (Berl)
    NIH Public Access Author Manuscript Psychopharmacology (Berl). Author manuscript; available in PMC 2010 February 1. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Psychopharmacology (Berl). 2009 September ; 205(4): 529. doi:10.1007/s00213-009-1562-z. The role of GABAA receptors in the acute and chronic effects of ethanol: a decade of progress Sandeep Kumar1, Patrizia Porcu1, David F. Werner1, Douglas B. Matthews3, Jaime L. Diaz- Granados3, Rebecca S. Helfand3, and A. Leslie Morrow1,2 Sandeep Kumar: ; Patrizia Porcu: ; David F. Werner: ; Douglas B. Matthews: ; Jaime L. Diaz-Granados: ; Rebecca S. Helfand: ; A. Leslie Morrow: [email protected] 1 Department of Psychiatry, Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, 3027 Thurston-Bowles Building, CB #7178, Chapel Hill, NC 27599-7178, USA 2 Department of Pharmacology, Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, 3027 Thurston-Bowles Building, CB #7178, Chapel Hill, NC 27599-7178, USA 3 Department of Psychology and Neuroscience, Baylor University, Waco, TX, USA Abstract The past decade has brought many advances in our understanding of GABAA receptor-mediated ethanol action in the central nervous system. We now know that specific GABAA receptor subtypes are sensitive to ethanol at doses attained during social drinking while other subtypes respond to ethanol at doses attained by severe intoxication. Furthermore, ethanol increases GABAergic neurotransmission through indirect effects, including the elevation of endogenous GABAergic neuroactive steroids, presynaptic release of GABA, and dephosphorylation of GABAA receptors promoting increases in GABA sensitivity. Ethanol’s effects on intracellular signaling also influence GABAergic transmission in multiple ways that vary across brain regions and cell types.
    [Show full text]
  • GABA Strikes Down Again in Epilepsy
    57 Editorial Page 1 of 12 GABA strikes down again in epilepsy Milena Guazzi, Pasquale Striano Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, “G. Gaslini” Institute, Genova, Italy Correspondence to: Pasquale Striano, MD, PhD. Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, “G. Gaslini” Institute, Genova, Italy. Email: [email protected]. Provenance: This is an invited Editorial commissioned by Section Editor Zhangyu Zou, MD, PhD (Department of Neurology, Fujian Medical University Union Hospital, Fujian Medical University, Fuzhou, China). Comment on: Butler KM, Moody OA, Schuler E, et al. De novo variants in GABRA2 and GABRA5 alter receptor function and contribute to early- onset epilepsy. Brain 2018. [Epub ahead of print]. Submitted Dec 03, 2018. Accepted for publication Dec 24, 2018. doi: 10.21037/atm.2018.12.55 View this article at: http://dx.doi.org/10.21037/atm.2018.12.55 Disruption of GABA transmission has been associated established epilepsy genes, supporting the link common and with different epilepsy syndromes according to the role rare, severe epilepsies. Moreover, this case-control exome of GABA as the major inhibitory neurotransmitter in the sequencing study revealed an excess of missense variants in central nervous system (CNS) (1). In fact, mutations in genes encoding GABAA receptor subunits through in GGE several genes encoding GABA receptor subunits, including patients and functional assessment of some of these variants GABRA1, GABRA6, GABRB2, GABRB3, GABRG2, and showed loss-of-function mechanism for 4 out of 7 GABRB2 GABRD have been identified in patients ranging from and GABRA5 variants.
    [Show full text]
  • Ligand-Gated Ion Channels
    S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2015/16: Ligand-gated ion channels. British Journal of Pharmacology (2015) 172, 5870–5903 THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: Ligand-gated ion channels Stephen PH Alexander1, John A Peters2, Eamonn Kelly3, Neil Marrion3, Helen E Benson4, Elena Faccenda4, Adam J Pawson4, Joanna L Sharman4, Christopher Southan4, Jamie A Davies4 and CGTP Collaborators L 1 School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK, N 2Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK, 3School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK, 4Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/ doi/10.1111/bph.13350/full. Ligand-gated ion channels are one of the eight major pharmacological targets into which the Guide is divided, with the others being: ligand-gated ion channels, voltage- gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets.
    [Show full text]
  • Haplotype-Based Localization of an Alcohol Dependence Gene to the 5Q34 ³-Aminobutyric Acid Type a Gene Cluster
    ORIGINAL ARTICLE Haplotype-Based Localization of an Alcohol Dependence Gene to the 5q34 ␥-Aminobutyric Acid Type A Gene Cluster Marta Radel, MD, PhD; Roger L. Vallejo, PhD; Nakao Iwata, MD, PhD; Richard Aragon, PhD; Jeffrey C. Long, PhD; Matti Virkkunen, MD; David Goldman, MD Context: Pharmacobehavioral and pharmacogenetic evi- Results: Sib-pair linkage of GABRG2 to alcohol depen- ␥ dence links -aminobutyric acid type A (GABAA) recep- dence was observed in Finns (P=.008). Association of tors and chromosomal regions containing GABAA recep- the GABRB2 1412T allele with alcohol dependence was tor genes to ethanol-related responses. The GABAA gene detected in both populations (Finns, P=.01; Southwest- cluster on chromosome 5q34 is of particular interest in ern Native Americans, P=.008), and the GABRA6 1519T the genetics of alcohol dependence because of the ␥2 sub- allele was associated in both Finns (P=.01) and South- unit requirement for ethanol’s modulatory action on western Native Americans (P=.03). Linkage disequilib- rium mapping with 3-locus haplotypes yielded evi- GABAA receptors, previous linkage findings in mice and humans implicating both GABRA6 and GABRG2, and re- dence for an alcohol-dependence locus at the GABAA gene ported associations of GABRA6, GABRB2, and GABRG2 cluster region in both populations. The most highly sig- nificant signals were at 3-locus haplotypes that in- alleles with alcohol dependence. cluded 1 or more GABRA6 polymorphisms, with the peak signal at a GABRA6 3-locus haplotype (Finns, empirical Objective: To determine whether variation at the 5q34 P=.004; Southwestern Native Americans, empirical GABAA gene cluster is implicated in differential suscep- P=.02).
    [Show full text]
  • Sternum. ^Sympathetic Chain \ to Prevertebral
    Durham E-Theses An electrophysiological study of the interaction between fenamate NSAIDs and the GABA(_A) receptor Patten, Debra How to cite: Patten, Debra (1999) An electrophysiological study of the interaction between fenamate NSAIDs and the GABA(_A) receptor, Durham theses, Durham University. Available at Durham E-Theses Online: http://etheses.dur.ac.uk/4561/ Use policy The full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-prot purposes provided that: • a full bibliographic reference is made to the original source • a link is made to the metadata record in Durham E-Theses • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders. Please consult the full Durham E-Theses policy for further details. Academic Support Oce, Durham University, University Oce, Old Elvet, Durham DH1 3HP e-mail: [email protected] Tel: +44 0191 334 6107 http://etheses.dur.ac.uk 2 An electrophysiological study of the interaction between Fenamate NSAIDs and the GABAA receptor. Debra Patten Submitted for the Degree of Ph.D. The copyright of this thesis rests with the author. No quotation from it should be published without the written consent of the author and information derived from it should be acknowledged. 1 9 JUL 2000 Dept. of Biological Sciences University of Durham March 1999 March 1999 Table of Contents AN ELECTROPHYSIOLOGICAL STUDY OF THE INTERACTION BETWEEN FENAMATE NSAIDs AND THE GABAA RECEPTOR CHAPTER ONE: GENERAL INTRODUCTION 1.1.
    [Show full text]
  • Uterus Carcinosarcoma
    PATIENT TUMOR TYPE QRF# Uterus carcinosarcoma PPAATIENTTIENT PHYPHYSICIANSICIAN SPECIMEN DISEASE ORDERING PHYSICIAN SPECIMEN SITE NAME MEDICAL FACILITY SPECIMEN ID DATE OF BIRTH ADDITIONAL RECIPIENT SPECIMEN TYPE SEX MEDICAL FACILITY ID DATE OF COLLECTION MEDICAL RECORD # PATHOLOGIST SPECIMEN RECEIVED NO REPORTREPORTABLE ALABLE ALTERATERATIONSTIONS WITH CCOMPOMPANIONANION DIADIAGNOGNOSSTIC (TIC (CDCDx)x) CLAIMS See professional services section for additional information OOTHER ALTHER ALTERATERATIONSTIONS & BIOMARKERS IDENTIFIED Results reported in this section are not prescriptive or conclusive for labeled use of any specific therapeutic product. See professional services section for additional information. MicrMicroossatatellitellite se sttatusatus MS-Stable § NT5C2NT5C2 R367Q TTumor Mutumor Mutational Burational Burdenden 53 Muts/Mb § PIK3CPIK3CAA R88Q AATRXTRX E259* PIK3CPIK3CAA M1043I CCAASP8SP8 E36* PPOLEOLE A456P FBFBXXW7W7 R465C PPTENTEN E7* FHFH splice site 1237-1G>T PPTENTEN S179I HSD3B1HSD3B1 T353M PPTENTEN F341V KDKDM5CM5C E448* RB1RB1 E323* MSH6MSH6 E908* TP53TP53 S127F MSH6MSH6 E1023* TP53TP53 Y327* § Refer to appendix for limitation statements related to detection of any copy number alterations, gene rearrangements, MSI or TMB result in this section. Please refer to appendix for Explanation of Clinical Significance Classification and for variants of unknown significance (VUS). FoundationOne CDx™ (F1CDx) is a next generation sequencing based TABLE 1 in vitro diagnostic device for detection of substitutions, insertion and
    [Show full text]