DOCSLIB.ORG

Evaluation of the Genetic Architecture of Cystic Fibrosis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Evaluation of the Genetic Architecture of Cystic Fibrosis EVALUATION OF THE GENETIC ARCHITECTURE OF CYSTIC FIBROSIS by Melis Atalar Aksit A dissertation submitted to Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland March 2020 © 2020 Melis Atalar Aksit All rights reserved Abstract Cystic fibrosis (CF) is an autosomal recessive disease caused by variants in CFTR. Individuals with CF show a high degree of variability in disease severity, complications and survival. This phenotypic variability is influenced by a combination of the allelic heterogeneity in CFTR, genetic modifiers outside of CFTR, environmental factors, and stochastic (random) factors. In this study, I evaluate genetic modifiers that influence the age of onset of diabetes occurring as a complication of CF (cystic fibrosis- related diabetes, or CFRD), and the impact of one of the most common CF-causing mutations in CFTR, W1282X. In Chapter 2, in a genome-wide association study for CFRD, I obtained genome- wide significance for variants at a novel locus (PTMA) and two known CFRD genetic modifiers (TCF7L2 and SLC26A9). Furthermore, I determined CFRD and T2D have more etiologic and mechanistic overlap than previously known, aligning along pathways involving β-cell function rather than insulin sensitivity. In Chapter 3, I identified a variant in a well-studied locus, CDKN2B-AS1, that is associated with markedly earlier onset of cystic fibrosis-related diabetes in females. This finding could partially explain why females with cystic fibrosis develop diabetes at a younger age than males, and provides new information on disease etiology that could affect future risk-assessment strategies. In Chapter 4, I demonstrated how W1282X, one of the most common CF- causing mutations, results in a premature termination codon which induces nonsense- mediated mRNA decay. This finding indicates transcripts with this mutation will not generate any protein, and hence treatment with CFTR modulators (which act on expressed protein) would not be beneficial. ii Taken together, these findings highlight the importance of understanding the genetic etiology of each individual’s disease for appropriate treatment. The nature of the CF-causing mutation in CFTR will inform proper treatment, and genetic risk factors outside of CFTR influences disease severity may be used to adjust disease surveillance strategies such as adjusting the age or frequency of diabetes screening tests. Furthermore, this work provides a better understanding of the genetic architecture of cystic fibrosis- related diabetes, which gives us insight into the mechanism of this disease. iii Thesis Committee Advisor & 1st Reader: Garry R. Cutting, MD Professor of Pediatrics and Medicine McKusick-Nathans Institute of the Department of Genetic Medicine Johns Hopkins School of Medicine Advisor & 2nd Reader: Scott M. Blackman, MD, PhD Associate Professor of Pediatrics McKusick-Nathans Institute of the Department of Genetic Medicine Johns Hopkins School of Medicine Chair & 3rd Reader: Terri H. Beaty, PhD Professor Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Loyal A. Goff, PhD Assistant Professor of Neuroscience McKusick-Nathans Institute of the Department of Genetic Medicine Johns Hopkins School of Medicine Dan E. Arking, PhD Professor of Medicine McKusick-Nathans Institute of the Department of Genetic Medicine Johns Hopkins School of Medicine iv Dedication To my parents, whom I owe this PhD to. Their unconditional support and selfless sacrifices has brought me to where I am today. To my sister, who has been by my side since day one, and has brought so much joy into my life. To my husband, who has brought out the best in me. I would not have been able to get through my thesis without him, and I know I can get through anything because he is by my side. v Acknowledgements My thesis would not have been possible without the support of many people I am so lucky to have in my life. First and foremost, I’d like to thank my thesis advisors, Dr. Garry Cutting and Dr. Scott Blackman. I am very lucky to be mentored by these two amazing physician scientists. Dr. Cutting has provided a great lab environment with a lot of support. He keeps all of us motivated and provides us with all the resources we need to be successful. Dr. Blackman patiently guided me on how to do better analyses, payed attention to the detail, and helped perfect my work. Together, the two of them provided the perfect balance which made my doctoral thesis work very enjoyable. I am very grateful for all of their help and guidance. In addition, I would like to thank my colleagues in the lab, who have made me look forward to coming in to lab every day. Dr. Neeraj Sharma has been an unofficial third mentor to me. He is extremely hard working, very knowledgeable, and always happy to answer all of my questions. I am very grateful for all of the opportunities and support he gave me along the way. In addition, the upper year PhD students, Dr Briana Vecchio-Pagan, Dr. Melissa Lee, Dr. Ted Han, Dr. Allison McCague, and Dr. Anh-Thu Lam have been a great example for me and provided me advice that allowed my thesis work to go much more smoothly. I am especially grateful for Dr. Anh-Thu Lam, my “kitten pair”, who is always on top of things, has patiently listened and helped me prepare for all of my presentations and exams, and most importantly has become a great, lifelong friend. In addition, I am grateful for Karen Raraigh, who has been a great resource for me; she knows all of the details of all of the genetic variants in CFTR by heart, and always helps put things into perspective from a patient stand point. I would also like to thank all of the other past and present lab members; Anya Joynt, Alyssa Bowling, Matthew Pellicore, Taylor Evans, Emily Marcisak, Corey Lu, Yasmin Akhtar, Kathleen Paul and Derek Osorio, for the countless great memories and making my time as a doctoral thesis student so enjoyable. In addition, I am very grateful for Patricia Cornwall, who has made sure that everything goes very smoothly, and has always known how to make me laugh in the process. vi I would also like to thank our collaborators at the Center for Inherited Disease Research (CIDR) of JHMI. Dr. Hua Ling, Dr. Peng Zhang, Dr. Elizabeth Pugh, and Kurt Hetrick have been extremely helpful and undoubtedly significantly improved my thesis work. Lastly, I would like to thank the human genetics program. I am grateful for Dr. Barbara Migeon for founding this PhD program which provided me with so many opportunities. I am also very grateful for Dr. David Valle and Sandy Muscelli for providing an environment filled with so many opportunities and making sure everything goes smoothly in the process. Finally, I would like to thank my fellow doctoral students in the program, for their support and friendship. I owe my thesis to all of these people, whom together provided me with this incredible support system. I am very grateful for all of their support, advice, and encouragement. vii Table of Contents Abstract ii Thesis Committee iv Dedication v Acknowledgements vi Table of Contents viii List of Tables x List of Figures xii Chapter 1: Introduction 1 1.1 Cystic Fibrosis 2 1.2 Phenotypic heterogeneity in CF 2 1.3 Cystic Fibrosis-Related Diabetes 4 1.4 Genetic Modifiers of Cystic Fibrosis-Related Diabetes 6 1.5 Nonsense-mediated mRNA Decay and W1282X 8 Chapter 2: Genetic modifiers of cystic fibrosis-related diabetes 9 have extensive overlap with type 2 diabetes and related traits 2.1 Introduction 10 2.2 Results 12 2.3 Discussion 22 2.4 Methods 28 Chapter 3: Common variants in CDKN2B-AS1 delay onset of 68 CFRD in females 3.1 Introduction 69 viii 3.2 Results 70 3.3 Discussion 74 3.4 Methods 76 Chapter 4: Decreased mRNA and protein stability of W1282X 84 limits response to modulator therapy 4.1 Introduction 85 4.2 Results 87 4.3 Discussion 93 4.4 Materials and Methods 97 Chapter 5: Conclusions 114 Reference 118 Curriculum Vitae 132 ix List of Tables Chapter 2: Table 2.1 Characteristics of patients enrolled by the studies 41 comprising the International Cystic Fibrosis Gene Modifier Consortium. Table 2.2 Association statistics for top variant at each genome-wide 42 significant locus. Table S2.1 Associations of potential covariates with CFRD onset. 50 Table S2.2 Association statistics of variants that exceeded genome-wide 51 significance. Table S2.3 Association statistics for all variants that exceeded suggestive 52 significance. Table S2.4 Association statistics of T2D risk variants previously identified as 54 CFRD modifiers other than TCF7L2. Table S2.5 Associations of variants with T2D and CFRD that were 55 genome-wide significant in either study. Table S2.6 Variants included in each polygenic risk score. 60 Table S2.7 Polygenic Risk Score (PRS) association statistics. 65 Table S2.8 Variants included in the CFRD PRS. 66 Table S2.9 Table S2.11. Association summary statistics for F508del only, non F508del homozygotes, and F508del homozygosity * SNP interaction term analyses in variants that exceeded genome-wide significance. x Chapter 4: Table S4.1 EMGs containing full-length CFTR cDNA and flanking introns 113 faithfully reproduce splicing patterns observed in affected tissues. xi List of Figures Chapter 2: Figure 2.1 Manhattan plot of Phase 1 + 2 combined association analysis. 36 Figure 2.2 LocusZoom and Forest Plots of genome-wide significant loci, 37 TCF7L2 (A-B), PTMA (C-D), and SLC26A9 (E-F). Figure 2.3 Comparison of the genetic risk architectures of CFRD and T2D. 38 Figure 2.4 Cumulative incidence (A-B) and prevalence (C-D) plots by CFRD PRS 40 in test and replication populations.
Load more

Recommended publications
  • Cellular and Molecular Signatures in the Disease Tissue of Early
    Cellular and Molecular Signatures in the Disease Tissue of Early Rheumatoid Arthritis Stratify Clinical Response to csDMARD-Therapy and Predict Radiographic Progression Frances Humby1,* Myles Lewis1,* Nandhini Ramamoorthi2, Jason Hackney3, Michael Barnes1, Michele Bombardieri1, Francesca Setiadi2, Stephen Kelly1, Fabiola Bene1, Maria di Cicco1, Sudeh Riahi1, Vidalba Rocher-Ros1, Nora Ng1, Ilias Lazorou1, Rebecca E. Hands1, Desiree van der Heijde4, Robert Landewé5, Annette van der Helm-van Mil4, Alberto Cauli6, Iain B. McInnes7, Christopher D. Buckley8, Ernest Choy9, Peter Taylor10, Michael J. Townsend2 & Costantino Pitzalis1 1Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Departments of 2Biomarker Discovery OMNI, 3Bioinformatics and Computational Biology, Genentech Research and Early Development, South San Francisco, California 94080 USA 4Department of Rheumatology, Leiden University Medical Center, The Netherlands 5Department of Clinical Immunology & Rheumatology, Amsterdam Rheumatology & Immunology Center, Amsterdam, The Netherlands 6Rheumatology Unit, Department of Medical Sciences, Policlinico of the University of Cagliari, Cagliari, Italy 7Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK 8Rheumatology Research Group, Institute of Inflammation and Ageing (IIA), University of Birmingham, Birmingham B15 2WB, UK 9Institute of
    [Show full text]
  • Supplemental Information
    Supplemental information Dissection of the genomic structure of the miR-183/96/182 gene. Previously, we showed that the miR-183/96/182 cluster is an intergenic miRNA cluster, located in a ~60-kb interval between the genes encoding nuclear respiratory factor-1 (Nrf1) and ubiquitin-conjugating enzyme E2H (Ube2h) on mouse chr6qA3.3 (1). To start to uncover the genomic structure of the miR- 183/96/182 gene, we first studied genomic features around miR-183/96/182 in the UCSC genome browser (http://genome.UCSC.edu/), and identified two CpG islands 3.4-6.5 kb 5’ of pre-miR-183, the most 5’ miRNA of the cluster (Fig. 1A; Fig. S1 and Seq. S1). A cDNA clone, AK044220, located at 3.2-4.6 kb 5’ to pre-miR-183, encompasses the second CpG island (Fig. 1A; Fig. S1). We hypothesized that this cDNA clone was derived from 5’ exon(s) of the primary transcript of the miR-183/96/182 gene, as CpG islands are often associated with promoters (2). Supporting this hypothesis, multiple expressed sequences detected by gene-trap clones, including clone D016D06 (3, 4), were co-localized with the cDNA clone AK044220 (Fig. 1A; Fig. S1). Clone D016D06, deposited by the German GeneTrap Consortium (GGTC) (http://tikus.gsf.de) (3, 4), was derived from insertion of a retroviral construct, rFlpROSAβgeo in 129S2 ES cells (Fig. 1A and C). The rFlpROSAβgeo construct carries a promoterless reporter gene, the β−geo cassette - an in-frame fusion of the β-galactosidase and neomycin resistance (Neor) gene (5), with a splicing acceptor (SA) immediately upstream, and a polyA signal downstream of the β−geo cassette (Fig.
    [Show full text]
  • NICU Gene List Generator.Xlsx
    Neonatal Crisis Sequencing Panel Gene List Genes: A2ML1 - B3GLCT A2ML1 ADAMTS9 ALG1 ARHGEF15 AAAS ADAMTSL2 ALG11 ARHGEF9 AARS1 ADAR ALG12 ARID1A AARS2 ADARB1 ALG13 ARID1B ABAT ADCY6 ALG14 ARID2 ABCA12 ADD3 ALG2 ARL13B ABCA3 ADGRG1 ALG3 ARL6 ABCA4 ADGRV1 ALG6 ARMC9 ABCB11 ADK ALG8 ARPC1B ABCB4 ADNP ALG9 ARSA ABCC6 ADPRS ALK ARSL ABCC8 ADSL ALMS1 ARX ABCC9 AEBP1 ALOX12B ASAH1 ABCD1 AFF3 ALOXE3 ASCC1 ABCD3 AFF4 ALPK3 ASH1L ABCD4 AFG3L2 ALPL ASL ABHD5 AGA ALS2 ASNS ACAD8 AGK ALX3 ASPA ACAD9 AGL ALX4 ASPM ACADM AGPS AMELX ASS1 ACADS AGRN AMER1 ASXL1 ACADSB AGT AMH ASXL3 ACADVL AGTPBP1 AMHR2 ATAD1 ACAN AGTR1 AMN ATL1 ACAT1 AGXT AMPD2 ATM ACE AHCY AMT ATP1A1 ACO2 AHDC1 ANK1 ATP1A2 ACOX1 AHI1 ANK2 ATP1A3 ACP5 AIFM1 ANKH ATP2A1 ACSF3 AIMP1 ANKLE2 ATP5F1A ACTA1 AIMP2 ANKRD11 ATP5F1D ACTA2 AIRE ANKRD26 ATP5F1E ACTB AKAP9 ANTXR2 ATP6V0A2 ACTC1 AKR1D1 AP1S2 ATP6V1B1 ACTG1 AKT2 AP2S1 ATP7A ACTG2 AKT3 AP3B1 ATP8A2 ACTL6B ALAS2 AP3B2 ATP8B1 ACTN1 ALB AP4B1 ATPAF2 ACTN2 ALDH18A1 AP4M1 ATR ACTN4 ALDH1A3 AP4S1 ATRX ACVR1 ALDH3A2 APC AUH ACVRL1 ALDH4A1 APTX AVPR2 ACY1 ALDH5A1 AR B3GALNT2 ADA ALDH6A1 ARFGEF2 B3GALT6 ADAMTS13 ALDH7A1 ARG1 B3GAT3 ADAMTS2 ALDOB ARHGAP31 B3GLCT Updated: 03/15/2021; v.3.6 1 Neonatal Crisis Sequencing Panel Gene List Genes: B4GALT1 - COL11A2 B4GALT1 C1QBP CD3G CHKB B4GALT7 C3 CD40LG CHMP1A B4GAT1 CA2 CD59 CHRNA1 B9D1 CA5A CD70 CHRNB1 B9D2 CACNA1A CD96 CHRND BAAT CACNA1C CDAN1 CHRNE BBIP1 CACNA1D CDC42 CHRNG BBS1 CACNA1E CDH1 CHST14 BBS10 CACNA1F CDH2 CHST3 BBS12 CACNA1G CDK10 CHUK BBS2 CACNA2D2 CDK13 CILK1 BBS4 CACNB2 CDK5RAP2
    [Show full text]
  • Targeting Oncogenic Notch Signaling with SERCA Inhibitors Luca Pagliaro, Matteo Marchesini and Giovanni Roti*
    Pagliaro et al. J Hematol Oncol (2021) 14:8 https://doi.org/10.1186/s13045-020-01015-9 REVIEW Open Access Targeting oncogenic Notch signaling with SERCA inhibitors Luca Pagliaro, Matteo Marchesini and Giovanni Roti* Abstract P-type ATPase inhibitors are among the most successful and widely prescribed therapeutics in modern pharmacol- ogy. Clinical transition has been safely achieved for H+/K+ ATPase inhibitors such as omeprazole and Na+/K+-ATPase 2 inhibitors like digoxin. However, this is more challenging for Ca +-ATPase modulators due to the physiological role of 2 2 Ca + in cardiac dynamics. Over the past two decades, sarco-endoplasmic reticulum Ca +-ATPase (SERCA) modula- 2 tors have been studied as potential chemotherapy agents because of their Ca +-mediated pan-cancer lethal efects. Instead, recent evidence suggests that SERCA inhibition suppresses oncogenic Notch1 signaling emerging as an alternative to γ-secretase modulators that showed limited clinical activity due to severe side efects. In this review, we focus on how SERCA inhibitors alter Notch1 signaling and show that Notch on-target-mediated antileukemia proper- 2 ties of these molecules can be achieved without causing overt Ca + cellular overload. Keywords: SERCA , T cell acute lymphoblastic leukemia, Thapsigargin, Notch signaling, NOTCH1, CAD204520, T-ALL Background metalloprotease (ADAM-10 or TACE/ADAM-17). Te NOTCH receptors are transmembrane cell-surface pro- resulting short-lived protein fragments are substrates teins that control cell to cell communication, embryo-
    [Show full text]
  • 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
    [Show full text]
  • Transcriptomic Profiling of Ca Transport Systems During
    cells Article Transcriptomic Profiling of Ca2+ Transport Systems during the Formation of the Cerebral Cortex in Mice Alexandre Bouron Genetics and Chemogenomics Lab, Université Grenoble Alpes, CNRS, CEA, INSERM, Bâtiment C3, 17 rue des Martyrs, 38054 Grenoble, France; [email protected] Received: 29 June 2020; Accepted: 24 July 2020; Published: 29 July 2020 Abstract: Cytosolic calcium (Ca2+) transients control key neural processes, including neurogenesis, migration, the polarization and growth of neurons, and the establishment and maintenance of synaptic connections. They are thus involved in the development and formation of the neural system. In this study, a publicly available whole transcriptome sequencing (RNA-Seq) dataset was used to examine the expression of genes coding for putative plasma membrane and organellar Ca2+-transporting proteins (channels, pumps, exchangers, and transporters) during the formation of the cerebral cortex in mice. Four ages were considered: embryonic days 11 (E11), 13 (E13), and 17 (E17), and post-natal day 1 (PN1). This transcriptomic profiling was also combined with live-cell Ca2+ imaging recordings to assess the presence of functional Ca2+ transport systems in E13 neurons. The most important Ca2+ routes of the cortical wall at the onset of corticogenesis (E11–E13) were TACAN, GluK5, nAChR β2, Cav3.1, Orai3, transient receptor potential cation channel subfamily M member 7 (TRPM7) non-mitochondrial Na+/Ca2+ exchanger 2 (NCX2), and the connexins CX43/CX45/CX37. Hence, transient receptor potential cation channel mucolipin subfamily member 1 (TRPML1), transmembrane protein 165 (TMEM165), and Ca2+ “leak” channels are prominent intracellular Ca2+ pathways. The Ca2+ pumps sarco/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) and plasma membrane Ca2+ ATPase 1 (PMCA1) control the resting basal Ca2+ levels.
    [Show full text]
  • Isolation and Characterization of a Novel Gene CLUAP1 Whose Expression Is Frequently Upregulated in Colon Cancer
    Oncogene (2004) 23, 9289–9294 & 2004 Nature Publishing Group All rights reserved 0950-9232/04 $30.00 www.nature.com/onc SHORT REPORT Isolation and characterization of a novel gene CLUAP1 whose expression is frequently upregulated in colon cancer Meiko Takahashi1, Yu-Min Lin2, Yusuke Nakamura1 and Yoichi Furukawa*,1 1Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai Minato-ku, Tokyo 108-8639, Japan; 2Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, 95 Wen Chang Road, Taipei 11160, Taiwan To disclose mechanisms of colorectal carcinogenesis and appear to be upregulated frequently in the cancer tissues identify novel diagnostic markers and drug targets for compared with the corresponding noncancerous cells. treatment of these tumors, we previously analysed the Since carcinogenesis involves activation of oncogenes expression profiles of 11 colorectal cancers using a and/or inactivation of tumor suppressor genes, en- genome-wide cDNA microarray containing 23 040 genes. hanced expression of at least some of these upregulated Among the genes commonly transactivated in the cancers, genes may reflect oncogenic properties. we identified a novel human gene, which we termed Among the genes with frequently elevated expression CLUAP1 (clusterin-associated protein 1). It encodes a in cancer tissues in our microarray data, an EST with an nuclear protein of 413 amino acids containing a coiled-coil in-house accession number of B9223 corresponding to domain. To investigate its function, we searched for KIAA0643, Hs. 155995 in UniGene cluster (http:// CLUAP1-interacting proteins using yeast two-hybrid www.ncbi.nlm.nih.gov/UniGene/), was upregulated in system and identified nuclear Clusterin.
    [Show full text]
  • ATP2A1 Gene Atpase Sarcoplasmic/Endoplasmic Reticulum Ca2+ Transporting 1
    ATP2A1 gene ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 1 Normal Function The ATP2A1 gene provides instructions for making an enzyme called sarco(endo) plasmic reticulum calcium-ATPase 1 (SERCA1). This enzyme belongs to a family of ATPase enzymes that help control the level of positively charged calcium atoms ( calcium ions) inside cells. The SERCA1 enzyme is found in skeletal muscle cells. ( Skeletal muscles are the muscles used for movement.) Within muscle cells, the SERCA1 enzyme is located in the membrane of a structure called the sarcoplasmic reticulum. This structure plays a major role in muscle contraction and relaxation by storing and releasing calcium ions. When calcium ions are transported out of the sarcoplasmic reticulum, muscles contract; when calcium ions are transported into the sarcoplasmic reticulum, muscles relax. The SERCA1 enzyme transports calcium ions from the cell into the sarcoplasmic reticulum, triggering muscle relaxation. Health Conditions Related to Genetic Changes Brody myopathy At least 10 mutations in the ATP2A1 gene have been found to cause Brody myopathy, a muscle disorder characterized by muscle cramping after exercise. Most ATP2A1 gene mutations lead to a premature stop signal in the instructions for making the SERCA1 enzyme, resulting in a nonfunctional enzyme. Other mutations lead to the production of a SERCA1 enzyme with decreased function. As a result, calcium ions are slow to enter the sarcoplasmic reticulum and muscle relaxation is delayed. After exercise or other strenuous activity, during which the muscles rapidly contract and relax, people with Brody myopathy develop muscle cramps because their muscles cannot fully relax. Scientists believe that other proteins or other pathways may function in the absence of a fully functional SERCA1 enzyme to transport calcium ions into the sarcoplasmic reticulum and help with muscle relaxation.
    [Show full text]
  • Dissection of the Corticotroph Transcriptome in a Mouse Model Of
    bioRxiv preprint doi: https://doi.org/10.1101/2020.07.29.227330; this version posted July 30, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Dissection of the corticotroph transcriptome in a mouse model of 2 glucocorticoid-induced suppression of the HPA axis 3 Romanò N1, Duncan PJ1, McClafferty H1, Nolan O1, Ding Q1, Homer NZ2, Le Tissier 4 P1, Walker BR2,3, Shipston MJ1, Chambers TJG1,4. 5 6 1. Centre for Discovery Brain Sciences, Hugh Robson Building, 15 George 7 Square, University of Edinburgh, Edinburgh, EH8 9XD, UK 8 2. Centre for Cardiovascular Science, Queen’s Medical Research Institute, 47 9 Little France Crescent, Edinburgh EH16 4TJ 10 3. Translational & Clinical Research Institute, Newcastle University, Newcastle 11 upon Tyne, NE1 7RU 12 4. Edinburgh Centre for Endocrinology and Diabetes, Royal Infirmary of 13 Edinburgh, Little France, Edinburgh EH16 4SA 14 15 Corresponding author: [email protected] 16 17 Word count: 6316 18 19 Key words: Chronic, Glucocorticoid, Recovery, HPA axis bioRxiv preprint doi: https://doi.org/10.1101/2020.07.29.227330; this version posted July 30, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 20 ABSTRACT 21 Glucocorticoids (GC) are prescribed for periods >3 months to 1-3% of the UK 22 population; 10-50% of these patients develop hypothalamus- pituitary-adrenal (HPA) 23 axis suppression, which may last over 6 months and is associated with morbidity and 24 mortality.
    [Show full text]
  • Drosophila and Human Transcriptomic Data Mining Provides Evidence for Therapeutic
    Drosophila and human transcriptomic data mining provides evidence for therapeutic mechanism of pentylenetetrazole in Down syndrome Author Abhay Sharma Institute of Genomics and Integrative Biology Council of Scientific and Industrial Research Delhi University Campus, Mall Road Delhi 110007, India Tel: +91-11-27666156, Fax: +91-11-27662407 Email: [email protected] Nature Precedings : hdl:10101/npre.2010.4330.1 Posted 5 Apr 2010 Running head: Pentylenetetrazole mechanism in Down syndrome 1 Abstract Pentylenetetrazole (PTZ) has recently been found to ameliorate cognitive impairment in rodent models of Down syndrome (DS). The mechanism underlying PTZ’s therapeutic effect is however not clear. Microarray profiling has previously reported differential expression of genes in DS. No mammalian transcriptomic data on PTZ treatment however exists. Nevertheless, a Drosophila model inspired by rodent models of PTZ induced kindling plasticity has recently been described. Microarray profiling has shown PTZ’s downregulatory effect on gene expression in fly heads. In a comparative transcriptomics approach, I have analyzed the available microarray data in order to identify potential mechanism of PTZ action in DS. I find that transcriptomic correlates of chronic PTZ in Drosophila and DS counteract each other. A significant enrichment is observed between PTZ downregulated and DS upregulated genes, and a significant depletion between PTZ downregulated and DS dowwnregulated genes. Further, the common genes in PTZ Nature Precedings : hdl:10101/npre.2010.4330.1 Posted 5 Apr 2010 downregulated and DS upregulated sets show enrichment for MAP kinase pathway. My analysis suggests that downregulation of MAP kinase pathway may mediate therapeutic effect of PTZ in DS. Existing evidence implicating MAP kinase pathway in DS supports this observation.
    [Show full text]
  • Clinical Significance of P‑Class Pumps in Cancer (Review)
    ONCOLOGY LETTERS 22: 658, 2021 Clinical significance of P‑class pumps in cancer (Review) SOPHIA C. THEMISTOCLEOUS1*, ANDREAS YIALLOURIS1*, CONSTANTINOS TSIOUTIS1, APOSTOLOS ZARAVINOS2,3, ELIZABETH O. JOHNSON1 and IOANNIS PATRIKIOS1 1Department of Medicine, School of Medicine; 2Department of Life Sciences, School of Sciences, European University Cyprus, 2404 Nicosia, Cyprus; 3College of Medicine, Member of Qatar University Health, Qatar University, 2713 Doha, Qatar Received January 25, 2021; Accepted Apri 12, 2021 DOI: 10.3892/ol.2021.12919 Abstract. P‑class pumps are specific ion transporters involved Contents in maintaining intracellular/extracellular ion homeostasis, gene transcription, and cell proliferation and migration in all 1. Introduction eukaryotic cells. The present review aimed to evaluate the 2. Methodology role of P‑type pumps [Na+/K+ ATPase (NKA), H+/K+ ATPase 3. NKA (HKA) and Ca2+‑ATPase] in cancer cells across three fronts, 4. SERCA pump namely structure, function and genetic expression. It has 5. HKA been shown that administration of specific P‑class pumps 6. Clinical studies of P‑class pump modulators inhibitors can have different effects by: i) Altering pump func‑ 7. Concluding remarks and future perspectives tion; ii) inhibiting cell proliferation; iii) inducing apoptosis; iv) modifying metabolic pathways; and v) induce sensitivity to chemotherapy and lead to antitumor effects. For example, 1. Introduction the NKA β2 subunit can be downregulated by gemcitabine, resulting in increased apoptosis of cancer cells. The sarco‑ The movement of ions across a biological membrane is a endoplasmic reticulum calcium ATPase can be inhibited by crucial physiological process necessary for maintaining thapsigargin resulting in decreased prostate tumor volume, cellular homeostasis.
    [Show full text]
  • The Ciliopathy-Associated CPLANE Proteins Direct Basal Body Recruitment of Intraflagellar Transport Machinery
    The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Toriyama, M., C. Lee, S. P. Taylor, I. Duran, D. H. Cohn, A. Bruel, J. M. Tabler, et al. 2016. “The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery.” Nature genetics 48 (6): 648-656. doi:10.1038/ng.3558. http:// dx.doi.org/10.1038/ng.3558. Published Version doi:10.1038/ng.3558 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:29626113 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Nat Genet Manuscript Author . Author manuscript; Manuscript Author available in PMC 2016 November 09. Published in final edited form as: Nat Genet. 2016 June ; 48(6): 648–656. doi:10.1038/ng.3558. The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery Michinori Toriyama1, Chanjae Lee1, S. Paige Taylor2, Ivan Duran2, Daniel H. Cohn3, Ange- Line Bruel4, Jacqueline M. Tabler1, Kevin Drew1, Marcus R. Kelley5, Sukyoung Kim1, Tae Joo Park1,**, Daniella Braun6, Ghislaine Pierquin7, Armand Biver8, Kerstin Wagner9, Anne Malfroot10, Inusha Panigrahi11, Brunella Franco12,13, Hadeel Adel Al-lami14, Yvonne Yeung14, Yeon Ja Choi15, University of Washington Center for Mendelian Genomics16, Yannis Duffourd4, Laurence Faivre4,17, Jean-Baptiste Rivière4,18, Jiang Chen15, Karen J.
    [Show full text]