An Allelic Variant in the Intergenic Region Between ERAP1 and ERAP2
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Download.Cse.Ucsc.Edu/ Early Age of Onset (~2.5 Years) of This PRA Form in Goldenpath/Canfam2/Database/) Using Standard Settings
Kropatsch et al. Canine Genetics and Epidemiology (2016) 3:7 DOI 10.1186/s40575-016-0037-x RESEARCH Open Access A large deletion in RPGR causes XLPRA in Weimaraner dogs Regina Kropatsch1*, Denis A. Akkad1, Matthias Frank2, Carsten Rosenhagen3, Janine Altmüller4,5, Peter Nürnberg4,6,7, Jörg T. Epplen1,8 and Gabriele Dekomien1 Abstract Background: Progressive retinal atrophy (PRA) belongs to a group of inherited retinal disorders associated with gradual vision impairment due to degeneration of retinal photoreceptors in various dog breeds. PRA is highly heterogeneous, with autosomal dominant, recessive or X-linked modes of inheritance. In this study we used exome sequencing to investigate the molecular genetic basis of a new type of PRA, which occurred spontaneously in a litter of German short-hair Weimaraner dogs. Results: Whole exome sequencing in two PRA-affected Weimaraner dogs identified a large deletion comprising the first four exons of the X-linked retinitis pigmentosa GTPase regulator (RPGR) gene known to be involved in human retinitis pigmentosa and canine PRA. Screening of 16 individuals in the corresponding pedigree of short-hair Weimaraners by qPCR, verified the deletion in hemizygous or heterozygous state in one male and six female dogs, respectively. The mutation was absent in 88 additional unrelated Weimaraners. The deletion was not detectable in the parents of one older female which transmitted the mutation to her offspring, indicating that the RPGR deletion represents a de novo mutation concerning only recent generations of the Weimaraner breed in Germany. Conclusion: Our results demonstrate the value of an existing DNA biobank combined with exome sequencing to identify the underlying genetic cause of a spontaneously occurring inherited disease. -
ERAP2 Facilitates a Subpeptidome of Birdshot Uveitis-Associated HLA-A29
bioRxiv preprint doi: https://doi.org/10.1101/2020.08.14.250654; this version posted August 14, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Title: 2 ERAP2 facilitates a subpeptidome of Birdshot Uveitis-associated 3 HLA-A29 4 5 W.J. Venema 1,2, S. Hiddingh1,2 , J.H. de Boer 1, F.H.J. Claas 3, A Mulder3 , A.I. Den Hollander4 , 6 E. Stratikos 5, S. Sarkizova 6,7, G.M.C. Janssen 8, P.A. van Veelen 8, J.J.W. Kuiper 1,2* 7 8 1. Department of Ophthalmology, University Medical Center Utrecht, University of 9 Utrecht, Utrecht, Netherlands. 10 2. Center for Translational Immunology, University Medical Center Utrecht, University of 11 Utrecht, Utrecht, Netherlands. 12 3. Department of Immunology, Leiden University Medical Center, Leiden, the 13 Netherlands 14 4. Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, 15 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The 16 Netherlands. 17 5. National Centre for Scientific Research Demokritos, Agia Paraskevi 15341, Greece 18 6. Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. 19 7. Broad Institute of MIT and Harvard, Cambridge, MA, USA. 20 8. Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, 21 the Netherlands. 22 23 * Corresponding author; email: [email protected] 24 25 ABSTRACT (words: 199): 26 27 Birdshot Uveitis (BU) is a blinding inflammatory eye condition that only affects 28 HLA-A29-positive individuals. -
Identifying Novel Disease-Associated Variants and Understanding The
Identifying Novel Disease-variants and Understanding the Role of the STAT1-STAT4 Locus in SLE A dissertation submitted to the Graduate School of University of Cincinnati In partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Immunology Graduate Program of the College of Medicine by Zubin H. Patel B.S., Worcester Polytechnic Institute, 2009 John B. Harley, M.D., Ph.D. Committee Chair Gurjit Khurana Hershey, M.D., Ph.D Leah C. Kottyan, Ph.D. Harinder Singh, Ph.D. Matthew T. Weirauch, Ph.D. Abstract Systemic Lupus Erythematosus (SLE) or lupus is an autoimmune disorder caused by an overactive immune system with dysregulation of both innate and adaptive immune pathways. It can affect all major organ systems and may lead to inflammation of the serosal and mucosal surfaces. The pathogenesis of lupus is driven by genetic factors, environmental factors, and gene-environment interactions. Heredity accounts for a substantial proportion of SLE risk, and the role of specific genetic risk loci has been well established. Identifying the specific causal genetic variants and the underlying molecular mechanisms has been a major area of investigation. This thesis describes efforts to develop an analytical approach to identify candidate rare variants from trio analyses and a fine-mapping analysis at the STAT1-STAT4 locus, a well-replicated SLE-risk locus. For the STAT1-STAT4 locus, subsequent functional biological studies demonstrated genotype dependent gene expression, transcription factor binding, and DNA regulatory activity. Rare variants are classified as variants across the genome with an allele-frequency less than 1% in ancestral populations. -
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. -
An Overview on ERAP Roles in Infectious Diseases
cells Review An Overview on ERAP Roles in Infectious Diseases 1,2, , 1, 2,3 1 Irma Saulle * y, Chiara Vicentini y, Mario Clerici and Mara Biasin 1 Cattedra di Immunologia, Dipartimento di Scienze Biomediche e Cliniche L. Sacco”, Università degli Studi di Milano, 20157 Milan, Italy; [email protected] (C.V.); [email protected] (M.B.) 2 Cattedra di Immunologia, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti Università degli Studi di Milano, 20122 Milan, Italy; [email protected] 3 IRCCS Fondazione Don Carlo Gnocchi, 20157 Milan, Italy * Correspondence: [email protected]; Tel.: +39-0250319679 These authors equally contributed to this work. y Received: 13 February 2020; Accepted: 12 March 2020; Published: 14 March 2020 Abstract: Endoplasmic reticulum (ER) aminopeptidases ERAP1 and ERAP2 (ERAPs) are crucial enzymes shaping the major histocompatibility complex I (MHC I) immunopeptidome. In the ER, these enzymes cooperate in trimming the N-terminal residues from precursors peptides, so as to generate optimal-length antigens to fit into the MHC class I groove. Alteration or loss of ERAPs function significantly modify the repertoire of antigens presented by MHC I molecules, severely affecting the activation of both NK and CD8+ T cells. It is, therefore, conceivable that variations affecting the presentation of pathogen-derived antigens might result in an inadequate immune response and onset of disease. After the first evidence showing that ERAP1-deficient mice are not able to control Toxoplasma gondii infection, a number of studies have demonstrated that ERAPs are control factors for several infectious organisms. In this review we describe how susceptibility, development, and progression of some infectious diseases may be affected by different ERAPs variants, whose mechanism of action could be exploited for the setting of specific therapeutic approaches. -
Influence of ERAP1 and ERAP2 Gene Polymorphisms on Disease
Human Immunology 80 (2019) 325–334 Contents lists available at ScienceDirect Human Immunology journal homepage: www.elsevier.com/locate/humimm Influence of ERAP1 and ERAP2 gene polymorphisms on disease T susceptibility in different populations ⁎ Yufeng Yaoa,b, Nannan Liua, Ziyun Zhoua, Li Shia,b, a Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, China b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, Kunming 650118, China ARTICLE INFO ABSTRACT Keywords: The endoplasmic reticulum aminopeptidases (ERAPs), ERAP1 and ERAP2, makes a role in shaping the HLA class ERAP1 I peptidome by trimming peptides to the optimal size in MHC-class I-mediated antigen presentation and edu- ERAP2 cating the immune system to differentiate between self-derived and foreign antigens. Association studies have Polymorphism shown that genetic variations in ERAP1 and ERAP2 genes increase susceptibility to autoimmune diseases, in- Disease association fectious diseases, and cancers. Both ERAP1 and ERAP2 genes exhibit diverse polymorphisms in different po- Population genetic background pulations, which may influence their susceptibly to the aforementioned diseases. In this article, we reviewthe distribution of ERAP1 and ERAP2 gene polymorphisms in various populations; discuss the risk or protective influence of these gene polymorphisms in autoimmune diseases, infectious diseases, and cancers; and highlight how ERAP genetic variations can influence disease associations. 1. ERAP gene introduction to CD8+ T cells [1,2]. ERAPs have been found to trim peptides to the optimal size for MHC-I binding [3,4] but can also over-trim and destroy 1.1. ERAPs play an important role in the antigen presentation process MHC-I ligands. -
The Physiological Functions of Mammalian Endoplasmic Oxidoreductin 1: on Disulfides and More
ANTIOXIDANTS & REDOX SIGNALING Volume 16, Number 10, 2012 FORUM REVIEW ARTICLE ª Mary Ann Liebert, Inc. DOI: 10.1089/ars.2011.4475 The Physiological Functions of Mammalian Endoplasmic Oxidoreductin 1: On Disulfides and More Thomas Ramming and Christian Appenzeller-Herzog Abstract Significance: The oxidative process of disulfide-bond formation is essential for the folding of most secretory and membrane proteins in the endoplasmic reticulum (ER). It is driven by electron relay pathways that transfer two electrons derived from the fusion of two adjacent cysteinyl side chains onto various types of chemical oxidants. The conserved, ER-resident endoplasmic oxidoreductin 1 (Ero1) sulfhydryl oxidases that reduce molecular oxygen to generate an active-site disulfide represent one of these pathways. In mammals, two family members exist, Ero1a and Ero1b. Recent Advances: The two mammalian Ero1 enzymes differ in transcriptional and post- translational regulation, tissue distribution, and catalytic turnover. A specific protein–protein interaction be- tween either isoform and protein disulfide isomerase (PDI) facilitates the propagation of disulfides from Ero1 via PDI to nascent polypeptides, and inbuilt oxidative shutdown mechanisms in Ero1a and Ero1b prevent excessive oxidation of PDI. Critical Issues: Besides disulfide-bond generation, Ero1a also regulates calcium release from the ER and the secretion of disulfide-linked oligomers through its reversible association with the chaperone ERp44. This review explores the functional repertoire and possible redundancy of mammalian Ero1 enzymes. Future Directions: Systematic analyses of different knockout mouse models will be the most promising strategy to shed new light on unique and tissue-specific roles of Ero1a and Ero1b. Moreover, in-depth characterization of the known physical interactions of Ero1 with peroxidases and PDI family members will help broaden our functional and mechanistic understanding of Ero1 enzymes. -
Identification of Novel Mouse Delta1 Target Genes: Combination of Transcriptomics and Proteomics
Institut für Experimentelle Genetik GSF – Forschungszentrum für Umwelt und Gesundheit Identification of novel mouse Delta1 target genes: Combination of transcriptomics and proteomics Christine Hutterer Vollständiger Abdruck der von der Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigten Dissertation. Vorsitzender: Univ.-Prof. Dr. A. Gierl Prüfer der Dissertation: 1. apl. Prof. Dr. J. Adamski 2. Univ.-Prof. Dr. W. Wurst Die Dissertation wurde am 31.01.2005 bei der Technischen Universität München eingereicht und durch die Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt am 13.05.2005 angenommen. DANKSAGUNG Besonderer Dank gebührt Prof. Dr. Martin Hrabé de Angelis, Leiter des Instituts für experimentelle Genetik. Unter anderem durch seine Leidenschaft für die Wissenschaft wollte ich am IEG arbeiten. Ich möchte mich jedoch nicht nur für die wissenschaftlichen Ratschläge und Diskussionen bedanken, sondern auch für viele interessante nicht-wissenschaftliche Gespräche. Ebenfalls besonders bedanke ich mich bei meinem Doktorvater Dr. Jurek Adamski, dessen fachliche Meinung und positive Einstellung mich sehr motivierte. Großen Dank möchte ich der gesamten „Beckers-Arbeitsgruppe“ aussprechen. Allen voran Dr. Johannes Beckers, Leiter der Genregulation und Expression Profiling Arbeitsgruppe, für die Überlassung des Themas und die Betreuung meiner Doktorarbeit, die mir viel Entscheidungsfreiraum ließ, sowie für zahlreiche gute Ideen und lehrreiche Gespräche. Bei Tomek Mijalski möchte ich mich für seine stetige Hilfsbereitschaft und die entstandene Freundschaft besonders bedanken. Weiterhin bedanke ich mich ganz herzlich bei Dr. Sonja Becker für wertvolle Labortricks und Kniffe, die Durchsicht des Manuskripts und ihre herzliche Art. Vielen Dank an dieser Stelle auch an Kathrin Seidel für die gute technische Unterstützung im Labor und mit der Mausarbeit. -
Association of ERAP2 Polymorphisms in Colombian HLA-B27+ Or HLA-B15+ Patients with Spa and Its Relationship with Clinical Presen
RMD Open: first published as 10.1136/rmdopen-2020-001250 on 10 September 2020. Downloaded from Spondyloarthritis Original research Association of ERAP2 polymorphisms in Colombian HLA-B27+ or HLA-B15+ patients with SpA and its relationship with clinical presentation: axial or peripheral predominance John Londono ,1,2 Ana M Santos,1 Juan C Rueda,1 Enrique Calvo-Paramo,3 Ruben Burgos-Vargas,4 Gilberto Vargas-Alarcon,5 Nancy Martinez-Rodriguez,6 Sofia Arias-Correal,1 Guisselle-Nathalia Muñoz,1 Diana Padilla,1 Francy Cuervo,1 Viviana Reyes-Martinez,1 Santiago Bernal-Macías ,1 Catalina Villota-Eraso,1 Luz M Avila-Portillo,1,2 Consuelo Romero,2 Juan F Medina7 To cite: Londono J, Santos AM, ABSTRACT Key messages Rueda JC, et al. Association of Objective To determine the association between ERAP2 polymorphisms in endoplasmic reticulum aminopeptidase (ERAP)1 and ERAP2 Colombian HLA-B27+ or HLA- What is already known about this subject? single-nucleotide polymorphisms (SNPs) and human B15+ patients with SpA and its ► ERAP1 and ERAP2 polymorphisms have been leukocyte antigens (HLA)-B27+ or HLA-B15+ patients with relationship with clinical associated with SpA: ERAP1 SNPs preferentially spondyloarthritis (SpA). presentation: axial or peripheral with HLA-B27+ patients and ERAP2 SNPs with HLA- Methods predominance. RMD Open 104 patients with SpA according to B27− patients. 2020;6:e001250. doi:10.1136/ Assessment of Spondyloarthritis International Society rmdopen-2020-001250 criteria were included in the study. HLA typing was What does this study add? performed by PCR. The polymorphisms were determined ► In this study, conducted on a group of Latin American Received 24 March 2020 Revised 23 July 2020 by real-time PCR on genomic DNA using customised patients with SpA, particular ERAP2 but not ERAP1 Accepted 1 August 2020 probes for SNPs rs27044, rs17482078, rs10050860 and SNP haplotypes were found to be associated with http://rmdopen.bmj.com/ rs30187 in ERAP1, and rs2910686, rs2248374 and either HLA-B27+ or HLA-B15+ patients with SpA. -
Sex-Specific Differences in Endoplasmic Reticulum Aminopeptidase 1 Modulation Influence Blood Pressure and Renin-Angiotensin System Responses
Sex-specific differences in endoplasmic reticulum aminopeptidase 1 modulation influence blood pressure and renin-angiotensin system responses Sanjay Ranjit, … , Gordon H. Williams, Jose R. Romero JCI Insight. 2019;4(21):e129615. https://doi.org/10.1172/jci.insight.129615. Research Article Endocrinology Salt sensitivity of blood pressure (SSBP) and hypertension are common, but the underlying mechanisms remain unclear. Endoplasmic reticulum aminopeptidase 1 (ERAP1) degrades angiotensin II (ANGII). We hypothesized that decreasing ERAP1 increases BP via ANGII-mediated effects on aldosterone (ALDO) production and/or renovascular function. Compared with WT littermate mice, ERAP1-deficient (ERAP1+/–) mice had increased tissue ANGII, systolic and diastolic BP, and SSBP, indicating that ERAP1 deficiency leads to volume expansion. However, the mechanisms underlying the volume expansion differed according to sex. Male ERAP1+/– mice had increased ALDO levels and normal renovascular responses to volume expansion (decreased resistive and pulsatility indices and increased glomerular volume). In contrast, female ERAP1+/– mice had normal ALDO levels but lacked normal renovascular responses. In humans,E RAP1 rs30187, a loss-of-function gene variant that reduces ANGII degradation in vitro, is associated with hypertension. In our cohort from the Hypertensive Pathotype (HyperPATH) Consortium, there was a significant dose-response association between rs30187 risk alleles and systolic and diastolic BP as well as renal plasma flow in men, but not in women. Thus, lowering ERAP1 led to volume expansion and increased BP. In males, the volume expansion was due to elevated ALDO with normal renovascular function, whereas in females the volume expansion was due to impaired renovascular function with normal ALDO levels. Find the latest version: https://jci.me/129615/pdf RESEARCH ARTICLE Sex-specific differences in endoplasmic reticulum aminopeptidase 1 modulation influence blood pressure and renin- angiotensin system responses Sanjay Ranjit, Jian Yao Wong, Jia W. -
Laser Capture Microdissection of Human Pancreatic Islets Reveals Novel Eqtls Associated with Type 2 Diabetes
Original Article Laser capture microdissection of human pancreatic islets reveals novel eQTLs associated with type 2 diabetes Amna Khamis 1,2,11, Mickaël Canouil 2,11, Afshan Siddiq 1, Hutokshi Crouch 1, Mario Falchi 1, Manon von Bulow 3, Florian Ehehalt 4,5,6, Lorella Marselli 7, Marius Distler 4,5,6, Daniela Richter 5,6, Jürgen Weitz 4,5,6, Krister Bokvist 8, Ioannis Xenarios 9, Bernard Thorens 10, Anke M. Schulte 3, Mark Ibberson 9, Amelie Bonnefond 2, Piero Marchetti 7, Michele Solimena 5,6, Philippe Froguel 1,2,* ABSTRACT Objective: Genome wide association studies (GWAS) for type 2 diabetes (T2D) have identified genetic loci that often localise in non-coding regions of the genome, suggesting gene regulation effects. We combined genetic and transcriptomic analysis from human islets obtained from brain-dead organ donors or surgical patients to detect expression quantitative trait loci (eQTLs) and shed light into the regulatory mechanisms of these genes. Methods: Pancreatic islets were isolated either by laser capture microdissection (LCM) from surgical specimens of 103 metabolically phe- notyped pancreatectomized patients (PPP) or by collagenase digestion of pancreas from 100 brain-dead organ donors (OD). Genotyping (> 8.7 million single nucleotide polymorphisms) and expression (> 47,000 transcripts and splice variants) analyses were combined to generate cis- eQTLs. Results: After applying genome-wide false discovery rate significance thresholds, we identified 1,173 and 1,021 eQTLs in samples of OD and PPP, e respectively. Among the strongest eQTLs shared between OD and PPP were CHURC1 (OD p-value¼1.71 Â 10-24;PPPp-value ¼ 3.64 Â 10 24)and À À PSPH (OD p-value ¼ 3.92 Â 10 26;PPPp-value ¼ 3.64 Â 10 24). -
Genome-Wide Association and Gene Enrichment Analyses of Meat Sensory Traits in a Crossbred Brahman-Angus
Proceedings of the World Congress on Genetics Applied to Livestock Production, 11. 124 Genome-wide association and gene enrichment analyses of meat tenderness in an Angus-Brahman cattle population J.D. Leal-Gutíerrez1, M.A. Elzo1, D. Johnson1 & R.G. Mateescu1 1 University of Florida, Department of Animal Sciences, 2250 Shealy Dr, 32608 Gainesville, Florida, United States. [email protected] Summary The objective of this study was to identify genomic regions associated with meat tenderness related traits using a whole-genome scan approach followed by a gene enrichment analysis. Warner-Bratzler shear force (WBSF) was measured on 673 steaks, and tenderness and connective tissue were assessed by a sensory panel on 496 steaks. Animals belong to the multibreed Angus-Brahman herd from University of Florida and range from 100% Angus to 100% Brahman. All animals were genotyped with the Bovine GGP F250 array. Gene enrichment was identified in two pathways; the first pathway is involved in negative regulation of transcription from RNA polymerase II, and the second pathway groups several cellular component of the endoplasmic reticulum membrane. Keywords: tenderness, gene enrichment, regulation of transcription, cell growth, cell proliferation Introduction Identification of quantitative trait loci (QTL) for any complex trait, including meat tenderness, is the first most important step in the process of understanding the genetic architecture underlying the phenotype. Given a large enough population and a dense coverage of the genome, a genome-wide association study (GWAS) is usually successful in uncovering major genes and QTLs with large and medium effect on these type of traits. Several GWA studies on Bos indicus (Magalhães et al., 2016; Tizioto et al., 2013) or crossbred beef cattle breeds (Bolormaa et al., 2011b; Hulsman Hanna et al., 2014; Lu et al., 2013) were successful at identifying QTL for meat tenderness; and most of them include the traditional candidate genes µ-calpain and calpastatin.