Burden of Rare Variants in ALS and Axonal Hereditary Neuropathy Genes Influence Survival In
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Chapter 7: Monogenic Forms of Diabetes
CHAPTER 7 MONOGENIC FORMS OF DIABETES Mark A. Sperling, MD, and Abhimanyu Garg, MD Dr. Mark A. Sperling is Emeritus Professor and Chair, University of Pittsburgh, Department of Pediatrics, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA. Dr. Abhimanyu Garg is Professor of Internal Medicine and Chief of the Division of Nutrition and Metabolic Diseases at University of Texas Southwestern Medical Center, Dallas, TX. SUMMARY Types 1 and 2 diabetes have multiple and complex genetic influences that interact with environmental triggers, such as viral infections or nutritional excesses, to result in their respective phenotypes: young, lean, and insulin-dependence for type 1 diabetes patients or older, overweight, and often manageable by lifestyle interventions and oral medications for type 2 diabetes patients. A small subset of patients, comprising ~2%–3% of all those diagnosed with diabetes, may have characteristics of either type 1 or type 2 diabetes but have single gene defects that interfere with insulin production, secretion, or action, resulting in clinical diabetes. These types of diabetes are known as MODY, originally defined as maturity-onset diabetes of youth, and severe early-onset forms, such as neonatal diabetes mellitus (NDM). Defects in genes involved in adipocyte development, differentiation, and death pathways cause lipodystrophy syndromes, which are also associated with insulin resistance and diabetes. Although these syndromes are considered rare, more awareness of these disorders and increased availability of genetic testing in clinical and research laboratories, as well as growing use of next generation, whole genome, or exome sequencing for clinically challenging phenotypes, are resulting in increased recognition. A correct diagnosis of MODY, NDM, or lipodystrophy syndromes has profound implications for treatment, genetic counseling, and prognosis. -
Clinical Spectrum and Genetic Landscape for Hereditary Spastic
Dong et al. Molecular Neurodegeneration (2018) 13:36 https://doi.org/10.1186/s13024-018-0269-1 RESEARCH ARTICLE Open Access Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China En-Lin Dong1†, Chong Wang1†, Shuang Wu1†, Ying-Qian Lu1, Xiao-Hong Lin1, Hui-Zhen Su1, Miao Zhao1, Jin He1, Li-Xiang Ma2, Ning Wang1,3, Wan-Jin Chen1,3* and Xiang Lin1* Abstract Background: Hereditary spastic paraplegias (HSP) is a heterogeneous group of rare neurodegenerative disorders affecting the corticospinal tracts. To date, more than 78 HSP loci have been mapped to cause HSP. However, both the clinical and mutational spectrum of Chinese patients with HSP remained unclear. In this study, we aim to perform a comprehensive analysis of clinical phenotypes and genetic distributions in a large cohort of Chinese HSP patients, and to elucidate the primary pathogenesis in this population. Methods: We firstly performed next-generation sequencing targeting 149 genes correlated with HSP in 99 index cases of our cohort. Multiplex ligation-dependent probe amplification testing was further carried out among those patients without known disease-causing gene mutations. We simultaneously performed a retrospective study on the reported patients exhibiting HSP in other Chinese cohorts. All clinical and molecular characterization from above two groups of Chinese HSP patients were analyzed and summarized. Eventually, we further validated the cellular changes in fibroblasts of two major spastic paraplegia (SPG) patients (SPG4 and SPG11) in vitro. Results: Most patients of ADHSP (94%) are pure forms, whereas most patients of ARHSP (78%) tend to be complicated forms. In ADHSP, we found that SPG4 (79%) was the most prevalent, followed by SPG3A (11%), SPG6 (4%) and SPG33 (2%). -
Identification of the Drosophila Melanogaster Homolog of the Human Spastin Gene
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by RERO DOC Digital Library Dev Genes Evol (2003) 213:412–415 DOI 10.1007/s00427-003-0340-x EXPRESSION NOTE Lars Kammermeier · Jrg Spring · Michael Stierwald · Jean-Marc Burgunder · Heinrich Reichert Identification of the Drosophila melanogaster homolog of the human spastin gene Received: 14 April 2003 / Accepted: 5 May 2003 / Published online: 5 June 2003 Springer-Verlag 2003 Abstract The human SPG4 locus encodes the spastin gene encoding spastin. This gene is expressed ubiqui- gene, which is responsible for the most prevalent form tously in fetal and adult human tissues (Hazan et al. of autosomal dominant hereditary spastic paraplegia 1999). The highest expression levels are found in the (AD-HSP), a neurodegenerative disorder. Here we iden- brain, with selective expression in the cortex and striatum. tify the predicted gene product CG5977 as the Drosophila In the spinal cord, spastin is expressed exclusively in homolog of the human spastin gene, with much higher nuclei of motor neurons, suggesting that the strong sequence similarities than any other related AAA domain neurodegenerative defects observed in patients are caused protein in the fly. Furthermore we report a new potential by a primary defect of spastin in neurons (Charvin et al. transmembrane domain in the N-terminus of the two 2003). The human spastin gene encodes a predicted 616- homologous proteins. During embryogenesis, the expres- amino-acid long protein and is a member of the large sion pattern of Drosophila spastin becomes restricted family of proteins with an AAA domain (ATPases primarily to the central nervous system, in contrast to the Associated with diverse cellular Activities). -
Abstracts from the 9Th Biennial Scientific Meeting of The
International Journal of Pediatric Endocrinology 2017, 2017(Suppl 1):15 DOI 10.1186/s13633-017-0054-x MEETING ABSTRACTS Open Access Abstracts from the 9th Biennial Scientific Meeting of the Asia Pacific Paediatric Endocrine Society (APPES) and the 50th Annual Meeting of the Japanese Society for Pediatric Endocrinology (JSPE) Tokyo, Japan. 17-20 November 2016 Published: 28 Dec 2017 PS1 Heritable forms of primary bone fragility in children typically lead to Fat fate and disease - from science to global policy a clinical diagnosis of either osteogenesis imperfecta (OI) or juvenile Peter Gluckman osteoporosis (JO). OI is usually caused by dominant mutations affect- Office of Chief Science Advsor to the Prime Minister ing one of the two genes that code for two collagen type I, but a re- International Journal of Pediatric Endocrinology 2017, 2017(Suppl 1):PS1 cessive form of OI is present in 5-10% of individuals with a clinical diagnosis of OI. Most of the involved genes code for proteins that Attempts to deal with the obesity epidemic based solely on adult be- play a role in the processing of collagen type I protein (BMP1, havioural change have been rather disappointing. Indeed the evidence CREB3L1, CRTAP, LEPRE1, P4HB, PPIB, FKBP10, PLOD2, SERPINF1, that biological, developmental and contextual factors are operating SERPINH1, SEC24D, SPARC, from the earliest stages in development and indeed across generations TMEM38B), or interfere with osteoblast function (SP7, WNT1). Specific is compelling. The marked individual differences in the sensitivity to the phenotypes are caused by mutations in SERPINF1 (recessive OI type obesogenic environment need to be understood at both the individual VI), P4HB (Cole-Carpenter syndrome) and SEC24D (‘Cole-Carpenter and population level. -
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. -
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Supplementary Figure S1. Results of flow cytometry analysis, performed to estimate CD34 positivity, after immunomagnetic separation in two different experiments. As monoclonal antibody for labeling the sample, the fluorescein isothiocyanate (FITC)- conjugated mouse anti-human CD34 MoAb (Mylteni) was used. Briefly, cell samples were incubated in the presence of the indicated MoAbs, at the proper dilution, in PBS containing 5% FCS and 1% Fc receptor (FcR) blocking reagent (Miltenyi) for 30 min at 4 C. Cells were then washed twice, resuspended with PBS and analyzed by a Coulter Epics XL (Coulter Electronics Inc., Hialeah, FL, USA) flow cytometer. only use Non-commercial 1 Supplementary Table S1. Complete list of the datasets used in this study and their sources. GEO Total samples Geo selected GEO accession of used Platform Reference series in series samples samples GSM142565 GSM142566 GSM142567 GSM142568 GSE6146 HG-U133A 14 8 - GSM142569 GSM142571 GSM142572 GSM142574 GSM51391 GSM51392 GSE2666 HG-U133A 36 4 1 GSM51393 GSM51394 only GSM321583 GSE12803 HG-U133A 20 3 GSM321584 2 GSM321585 use Promyelocytes_1 Promyelocytes_2 Promyelocytes_3 Promyelocytes_4 HG-U133A 8 8 3 GSE64282 Promyelocytes_5 Promyelocytes_6 Promyelocytes_7 Promyelocytes_8 Non-commercial 2 Supplementary Table S2. Chromosomal regions up-regulated in CD34+ samples as identified by the LAP procedure with the two-class statistics coded in the PREDA R package and an FDR threshold of 0.5. Functional enrichment analysis has been performed using DAVID (http://david.abcc.ncifcrf.gov/) -
Microtubule-Severing Enzymes at the Cutting Edge
Commentary 2561 Microtubule-severing enzymes at the cutting edge David J. Sharp1,* and Jennifer L. Ross2 1Department of Physiology and Biophysics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA 2Department of Physics, University of Massachusetts-Amherst, 302 Hasbrouck Laboratory, Amherst, MA 01003, USA *Author for correspondence ([email protected]) Journal of Cell Science 125, 2561–2569 ß 2012. Published by The Company of Biologists Ltd doi: 10.1242/jcs.101139 Summary ATP-dependent severing of microtubules was first reported in Xenopus laevis egg extracts in 1991. Two years later this observation led to the purification of the first known microtubule-severing enzyme, katanin. Katanin homologs have now been identified throughout the animal kingdom and in plants. Moreover, members of two closely related enzyme subfamilies, spastin and fidgetin, have been found to sever microtubules and might act alongside katanins in some contexts (Roll-Mecak and McNally, 2010; Yu et al., 2008; Zhang et al., 2007). Over the past few years, it has become clear that microtubule-severing enzymes contribute to a wide range of cellular activities including mitosis and meiosis, morphogenesis, cilia biogenesis and disassembly, and migration. Thus, this group of enzymes is revealing itself to be among the most important of the microtubule regulators. This Commentary focuses on our growing understanding of how microtubule-severing enzymes contribute to the organization and dynamics of diverse microtubule arrays, as well as the structural and biophysical characteristics that afford them the unique capacity to catalyze the removal of tubulin from the interior microtubule lattice. Our goal is to provide a broader perspective, focusing on a limited number of particularly informative, representative and/or timely findings. -
Proteomic and Metabolomic Analyses of Mitochondrial Complex I-Deficient
THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 287, NO. 24, pp. 20652–20663, June 8, 2012 © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A. Proteomic and Metabolomic Analyses of Mitochondrial Complex I-deficient Mouse Model Generated by Spontaneous B2 Short Interspersed Nuclear Element (SINE) Insertion into NADH Dehydrogenase (Ubiquinone) Fe-S Protein 4 (Ndufs4) Gene*□S Received for publication, November 25, 2011, and in revised form, April 5, 2012 Published, JBC Papers in Press, April 25, 2012, DOI 10.1074/jbc.M111.327601 Dillon W. Leong,a1 Jasper C. Komen,b1 Chelsee A. Hewitt,a Estelle Arnaud,c Matthew McKenzie,d Belinda Phipson,e Melanie Bahlo,e,f Adrienne Laskowski,b Sarah A. Kinkel,a,g,h Gayle M. Davey,g William R. Heath,g Anne K. Voss,a,h René P. Zahedi,i James J. Pitt,j Roman Chrast,c Albert Sickmann,i,k Michael T. Ryan,l Gordon K. Smyth,e,f,h b2 a,h,m,n3 David R. Thorburn, and Hamish S. Scott Downloaded from From the aMolecular Medicine Division, gImmunology Division, and eBioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia, the bMurdoch Childrens Research Institute, Royal Children’s Hospital and Department of Paediatrics, University of Melbourne, Parkville, Victoria 3052, Australia, the cDépartement de Génétique Médicale, Université de Lausanne, 1005 Lausanne, Switzerland, the dCentre for Reproduction and Development, Monash Institute of Medical Research, Clayton, Victoria 3168, Australia, the hDepartment of Medical Biology -
A Deficiency Screen for Genetic Interactions with Spastin Overexpression Reveals a Role for P21-Activated Kinase 3
Genetics:Genetics: PublishedPublished ArticlesArticles AheadAhead ofof Print,Print, publishedpublished onon JuneJuly 29,24, 20112011 asas 10.1534/genetics.111.13083110.1534/genetics.111.130831 1 Loss of Drosophila melanogaster p21-activated kinase 3 (pak3) suppresses defects in synapse structure and function caused by spastin mutations Emily F. Ozdowski*, Sophia Gayle*, Hong Bao§, Bing Zhang§, Nina T. Sherwood* *Department of Biology / Institute for Genome Sciences and Policy Duke University Durham, NC 27710 §Department of Zoology University of Oklahoma Norman, OK 73019 Copyright 2011. E. F. Ozdowski, et al. 2 Running Title: pak3 and spastin in synapse development Keywords: spastin (CG5977) pak3 (CG14895) Microtubule Actin Neuromuscular junction Corresponding Author: Nina Tang Sherwood Duke University Medical Center CARL Bldg Box 3577 Durham, NC 27710 Office phone: (919) 684-8658 Lab phone: (919) 668-3656 Fax: (919) 681-9193 Email: [email protected] E. F. Ozdowski, et al. 3 ABSTRACT Microtubules are dynamic structures that must elongate, disassemble, and be cleaved into smaller pieces for proper neuronal development and function. The AAA ATPase Spastin severs microtubules along their lengths and is thought to regulate the balance between long, stable filaments and shorter fragments that seed extension or are transported. In both Drosophila and humans, loss of Spastin function results in reduction of synaptic connections and disabling motor defects. To gain insight into how spastin is regulated, we screened the Drosophila melanogaster genome for deletions that modify a spastin overexpression phenotype, eye size reduction. One suppressor region deleted p21-activated kinase 3 (pak3), which encodes a member of the Pak family of actin-regulatory enzymes, but whose in vivo function is unknown. -
Role of Senataxin in RNA: DNA Hybrids Resolution at DNA Double
Role of senataxin in RNA : DNA hybrids resolution at DNA double strand breaks Sarah Cohen To cite this version: Sarah Cohen. Role of senataxin in RNA : DNA hybrids resolution at DNA double strand breaks. Cellular Biology. Université Paul Sabatier - Toulouse III, 2019. English. NNT : 2019TOU30125. tel-02930730 HAL Id: tel-02930730 https://tel.archives-ouvertes.fr/tel-02930730 Submitted on 4 Sep 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. ����� ���� ������������������ ������������������������������������ ��������� ���!������"������ �� "��#�$�% ��� � ���� %��"���������"� ��� ��� � � � &������ ������������ ������� ����'������"�� � (����� �"�� ���"�� �������"�&)�����"����*���� (�+ "" ��"��� ��������"�����!��� ������������������,�,�$�,����-��.�� ���.�,����+&����-��" �������������,����/�������������� �������������������� �,�0�%�$�� ��� ���������,����-������� � �������0���+ � ����� ������'������� ������'������������ %����1�� ����� ����������������� /��������/�,�� ��� ���������� ������������������� ������������������������������ �� ����������������� -
Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase -
Myopathy Genes (HGNC) Neuropathy (HGNC) Neuromuscular Disease
Myopathy Genes Neuropathy Neuromuscular Disease (HGNC) (HGNC) (HGNC) ABHD5 ABCA1 ADCK3 ACTG2 ACO2 AGRN AGK AGXT ALS2 ALDOA AIFM1 ANG AMER1 ALAD AP4B1 ANO5 AMACR AP4E1 AR AP1S1 AP4M1 AUH APTX AP4S1 B4GALT1 AR AP5Z1 CACNA1S ATL3 ATM CASQ1 B4GALNT1 ATXN10 CCDC78 BAG3 ATXN7 CHCHD10 BRP44L BEAN1 CHRNA1 C12orf65 C9orf72 CHRNB1 C19orf12 CACNB4 CHRND C1NH CAPN3 CHRNE CECR1 CHAT CLPB CISD2 CHKB COL6A1 CLCF1 CHMP2B COL6A2 CLCN2 CHRNG COL6A3 CLP1 CLCN1 COLQ CMT2G COL9A3 CTNS CMT2H COQ2 DGUOK CMTDIA COQ6 DNA2 CMTX2 COQ9 DNAJB6 CMTX3 COX15 DNAJC19 COASY CPT1A DNM2 COX6A1 CYP7B1 DPM2 CPOX DAG1 DYSF CYP27A1 DDHD2 EMD CYP2U1 DOK7 EPG5 DARS2 DPAGT1 FAM111B DCAF8 DPM3 FBXL4 DDHD1 DUX4 FKBP14 DFNX5 ECEL1 FKRP DHTKD1 ERBB3 FLH1 DIAPH3 ERLIN2 FLNC DNAJB2 FA2H HNRNPA1 DNAJC3 FKTN HNRNPDL ELOVL5 FUS HNRPA2B1 ERCC8 G6PC KLHL40 FAH GFPT1 KLHL41 FAM126A GLE1 LAMA2 FBN1 GYS2 LDB3 FMR1 HSPD1 LMOD3 FXN IFRD1 MEGF10 GALC INF2 MGME1 GBE1 ISPD MTAP GJC2 ITGA7 MTMR14 GP1BA ITPR1 MYF6 HADHA KCNA1 MYH14 HADHB KCNC3 MYLK2 HFE KCNE3 NARS2 HINT1 KCNJ18 NEB HK1 KCNJ2 ORAI1 HMBS KIAA0196 PRKAG2 HSD17B4 KIF21A PTEN HSN1B L1CAM RBCK1 IARS2 LAMB2 RET IGHMBP2 LARGE RMND1 KCNJ10 MCCC2 SCN4A KIF5A MRE11A SERAC1 LRSAM1 MRPL3 SGCA LYST MTO1 SIL1 MANBA MTPAP SPEG MARS MTTP STAC3 MTATP6 MUSK STIM1 MYH14 MYBPC3 SYNE1 MYOT MYH3 SYNE2 NAMSD MYH8 TAZ NF2 NF1 TIA1 NGLY1 NIPA1 TMEM43 NMSR NOP56 TNPO3 NOTCH3 OPTN TNXB OPA1 PDSS2 TPM2 OPA3 PDYN TRPV4 OTOF PFN1 UBA1 PDK3 PHKA2 VCP PDSS1 PHKG2 XDH PEX10 PHOX2A ACADS PEX2 PIP5K1C ACADVL PMM2 PLEC ACTA1 PNPLA6 PLP1 AGL PPOX POMGNT1 AMPD1 PRICKLE1