New IBD Genes? Gut: First Published As 10.1136/Gut.2004.062406 on 11 July 2005

Total Page:16

File Type:pdf, Size:1020Kb

New IBD Genes? Gut: First Published As 10.1136/Gut.2004.062406 on 11 July 2005 1060 CLINICAL @LERT New IBD genes? Gut: first published as 10.1136/gut.2004.062406 on 11 July 2005. Downloaded from D McGovern, T Ahmad ............................................................................................................................... New reports of potential novel inflammatory bowel disease (IBD) genes further advance our understanding of the genetic basis of IBD rohn’s disease (CD) and ulcerative colitis result from an inappropri- Peltekova VD, Wintle RF, Rubin LA, et al. Functional variants of OCTN cation transporter Cate response of the mucosal genes are associated with Crohn disease. Nat Genet 2004;36:471–5. immune system to the normal enteric flora in a genetically susceptible indivi- Crohn disease is a chronic, inflammatory disease of the gastrointestinal tract. A locus dual. The importance of genetic predis- of approximately 250 kb at 5q31 (IBD5) was previously associated with suscept- position was firmly established in 2001 ibility to Crohn disease, as indicated by increased prevalence of a risk haplotype of by the identification of the first CD 11 single-nucleotide polymorphisms among individuals with Crohn disease, but the susceptibility gene NOD2 (CARD15)on pathogenic lesion in the region has not yet been identified. We report here that two chromosome 16q12 (IBD1).12 It is now variants in the organic cation transporter cluster at 5q31 (a missense substitution in clear that NOD2 variants contribute only SLC22A4 and a GRC transversion in the SLC22A5 promoter) form a haplotype a small part to genetic susceptibility, associated with susceptibility to Crohn disease. These variants alter transcription and suggesting the existence of other, as yet transporter functions of the organic cation transporters and interact with variants in unidentified, genes. Although these another gene associated with Crohn disease, CARD15, to increase risk of Crohn have remained elusive, linkage studies disease. These results suggest that SLC22A4, SLC22A5 and CARD15 act in a have provided important clues to their common pathogenic pathway to cause Crohn disease. location, implicating at least seven other regions of the human genome. Two recent studies report the cloning Stoll M, Corneliussen B, Costello CM, et al. Genetic variation in DLG5 is associated with of potential novel inflammatory bowel inflammatory bowel disease. Nat Genet 2004;36:476–80. disease (IBD) genes within linkage areas 3 4 on chromosomes 5 and 10. Linkage Crohn disease and ulcerative colitis are two subphenotypes of inflammatory bowel between CD and chromosome 5q31-33 disease (IBD), a complex disorder resulting from gene-environment interaction. We 5 (IBD5) was first demonstrated in 1999 refined our previously defined linkage region for IBD on chromosome 10q23 and and further characterisation of this locus used positional cloning to identify genetic variants in DLG5 associated with IBD. refined the region to a highly conserved DLG5 encodes a scaffolding protein involved in the maintenance of epithelial 6 http://gut.bmj.com/ 250 kb haplotype. Identifying the IBD5 integrity. We identified two distinct haplotypes with a replicable distortion in causal mutation(s) has been hampered transmission (P = 0.000023 and P = 0.004 for association with IBD, P = 0.00012 and by the degree of linkage disequilibrium P = 0.04 for association with Crohn disease). One of the risk-associated DLG5 and the density of immunoregulatory haplotypes is distinguished from the common haplotype by a nonsynonymous single- genes on this haplotype. A Canadian nucleotide polymorphism 113GRA, resulting in the amino acid substitution R30Q in 3 group now suggest that the true IBD5 the DUF622 domain of DLG5. This mutation probably impedes scaffolding of DLG5. disease causing mutations occur in We stratified the study sample according to the presence of risk-associated CARD15 SLC22A4 and SLC22A5, encoding OCTN1 variants to study potential gene-gene interaction. We found a significant difference on September 24, 2021 by guest. Protected copyright. and OCTN2 respectively, members of the in association of the 113A DLG5 variant with Crohn disease in affected individuals organic cationic transporter subfamily. carrying the risk-associated CARD15 alleles versus those carrying non-risk- These proteins are involved in the elim- associated CARD15 alleles. This is suggestive of a complex pattern of gene-gene ination of toxins and the uptake of interaction between DLG5 and CARD15, reflecting the complex nature of polygenic various physiological substrates, includ- diseases. Further functional studies will evaluate the biological significance of DLG5 ing carnitine (required for oxygen burst variants. mediated pathogen killing). OCTN1 and OCTN2 are widely expressed, including in intestinal epithelial cells, macro- phages, and T cells. Two putatively the risk haplotype is associated with a Precisely how these SNPs might interact functional single nucleotide polymorph- 3–4-fold risk of disease, similar to that with NOD2 to increase the risk of CD isms (SNPs), one in SLC22A4 and the for possession of CARD15 mutations. remains unclear. However, tantalising other in SLC22A5, form a risk haplotype Interestingly, the risk was much greater clues are provided by the suggestion that enriched in individuals with CD. The in the presence of both the risk haplotype a-defensins are potential substrates of L503F (leucine to phenylalanine at codon and CD associated CARD15 alleles, con- OCTN1 and 2, and by a recent report 503) polymorphism maps to a region of sistent with an interaction between IBD5 suggesting that NOD2 variants may actu- SLC22A4, important for cellular transport, and CARD15. The strong linkage ally increase susceptibility to CD, through and functional data presented by the disequilibrium across IBD5 makes inter- adefectina-defensin production.7 The authors suggest the variant allele may pretation of association data from indivi- same group has published a study in an affect uptake of carnitine, various xeno- dual SNPs difficult. This region is rich in independent cohort confirming their biotics, and toxins. The SLC22A5 SNP is genes, many of which are attractive findings. Analyses in this cohort have located in the gene promoter where it candidates for disease pathogenesis. It revealed particular association with ileal appears to disrupt a predicted heat shock therefore remains possible that other CD8 in contrast to a previous study element required for the binding of heat ‘‘functional’’ SNPs, expressed in tissues suggesting an association between IBD5 shock transcription factors. Possession of relevant to IBD, exist on this haplotype. and perianal CD.9 www.gutjnl.com CLINICAL @LERT 1061 A second study reports an association The rapid advances in our under- with susceptibility to Crohn’s disease. Nature between SNPs in DLG5, a member of the 2001;411:599–603. standing of the genetic basis of IBD 2 Ogura Y, Bonen DK, Inohara N, et al. A membrane associated guanylate kinase are yet to impact on routine clinical frameshift mutation in NOD2 associated with Gut: first published as 10.1136/gut.2004.062406 on 11 July 2005. Downloaded from gene family, and IBD. A German group4 practice although recent discoveries susceptibility to Crohn’s disease. Nature performed linkage disequilibrium map- have provided considerable insights for 2001;411:603–6. 3 Peltekova VD, Wintle RF, Rubin LA, et al. ping of a locus on chromosome 10 and investigators. There is considerable opti- Functional variants of OCTN cation transporter demonstrated association with variants mism that as IBD genes are identified genes are associated with Crohn disease. Nat in DLG5. Four common haplotypes and their environmental interactions Genet 2004;36:471–5. 4 Stoll M, Corneliussen B, Costello CM, et al. across DLG5 were identified. Haplotype unravelled that we may be able to better Genetic variation in DLG5 is associated with D (containing the unique SNP 113A) define the heterogeneous group of inflammatory bowel disease. Nat Genet conferred a modest risk of CD while patients with IBD, aid understanding 2004;36:476–80. haplotype A was protective. The results of the molecular mechanisms specific to 5 Ma Y, Ohmen JD, Li Z, et al. A genome-wide search identifies potential new susceptibility loci were replicated in a case control study subgroups of disease, and provide a for Crohn’s disease. Inflamm Bowel Dis (but not in an independent family based framework to predict clinical phenotype 1999;5:271–8. association study) and once again pos- and response to therapy. These novel 6 Rioux JD, Daly MJ, Silverberg MS, et al. Genetic variation in the 5q31 cytokine gene cluster confers sible interaction with the CD associated findings reported by the Canadian and susceptibility to Crohn disease. Nat Genet CARD15 alleles was noted. DLG5 is German make an important contribu- 2001;29:223–8. expressed in the colon and small intes- tion towards this goal. 7 Wehkamp J, Harder J, Weichenthal M, et al. NOD2 (CARD15) mutations in Crohn’s disease tine where it acts as a multifunctional are associated with diminished mucosal alpha- adapter and scaffold protein involved in Gut 2005;54:1060–1061. defensin expression. Gut 2004;53:1658–64. the regulation of epithelial cell growth, doi: 10.1136/gut.2004.048918 8 Newman B, Gu X, Wintle R, et al. A risk shape, and polarity. Computer predic- haplotype in the Solute Carrier Family 22A4/ .................. 22A5 gene cluster influences phenotypic tion programs suggest that the IBD Authors’ affiliations expression of Crohn’s
Recommended publications
  • Roles and Mechanisms of Kinesin-6 KIF20A in Spindle Organization During Cell Division T ⁎ Wen-Da Wu, Kai-Wei Yu, Ning Zhong, Yu Xiao, Zhen-Yu She
    European Journal of Cell Biology 98 (2019) 74–80 Contents lists available at ScienceDirect European Journal of Cell Biology journal homepage: www.elsevier.com/locate/ejcb Review Roles and mechanisms of Kinesin-6 KIF20A in spindle organization during cell division T ⁎ Wen-Da Wu, Kai-Wei Yu, Ning Zhong, Yu Xiao, Zhen-Yu She Department of Cell Biology and Genetics/Center for Cell and Developmental Biology, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350108, China ARTICLE INFO ABSTRACT Keywords: Mitotic kinesin is crucial for spindle assembly and chromosome segregation in cell division. KIF20A/MKlp2, a Kinesin-6 member of kinesin-6 subfamily, plays important roles in the central spindle organization at anaphase and cy- KIF20A tokinesis. In this review, we briefly introduce the discovery and classification of kinesin-6 motors in model Microtubule organisms, and summarize the biochemical features and mechanics of KIF20A proteins. We emphasize the Anaphase complicated interactions of KIF20A with partner proteins, including MKlp1, Plk1 and Rab6. Particularly, we Spindle assembly highlight the regulation of Cdk1 and chromosomal passenger complex on kinesin-6 KIF20A at late stage of Mitosis mitosis. We summarized the multiple functions of KIF20A in central spindle assembly and the formation of cleavage furrow in both mitosis and meiosis. In addition, we conclude the expression patterns of KIF20A in tumorigenesis and its applications in tumor therapy. 1. Introduction kinesin superfamily proteins (Miki et al., 2005). Kinesin-6 subfamily is comprised of KIF20A (Lawrence et al., 2004), KIF20B (MPP1) Kinesin superfamily proteins (KIFs) are molecular motors that (Kamimoto et al., 2001; Matsumoto-Taniura et al., 1996; Westendorf mediate the transport of various cargos, including the newly synthe- et al., 1994) and MKlp1 (Lawrence et al., 2004; Nislow et al., 1990; sized protein complexes, vesicles and mRNAs along the microtubule Sellitto and Kuriyama, 1988).
    [Show full text]
  • 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.
    [Show full text]
  • Organ of Corti Size Is Governed by Yap/Tead-Mediated Progenitor Self-Renewal
    Organ of Corti size is governed by Yap/Tead-mediated progenitor self-renewal Ksenia Gnedevaa,b,1, Xizi Wanga,b, Melissa M. McGovernc, Matthew Bartond,2, Litao Taoa,b, Talon Treceka,b, Tanner O. Monroee,f, Juan Llamasa,b, Welly Makmuraa,b, James F. Martinf,g,h, Andrew K. Grovesc,g,i, Mark Warchold, and Neil Segila,b,1 aDepartment of Stem Cell Biology and Regenerative Medicine, Keck Medicine of University of Southern California, Los Angeles, CA 90033; bCaruso Department of Otolaryngology–Head and Neck Surgery, Keck Medicine of University of Southern California, Los Angeles, CA 90033; cDepartment of Neuroscience, Baylor College of Medicine, Houston, TX 77030; dDepartment of Otolaryngology, Washington University in St. Louis, St. Louis, MO 63130; eAdvanced Center for Translational and Genetic Medicine, Lurie Children’s Hospital of Chicago, Chicago, IL 60611; fDepartment of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030; gProgram in Developmental Biology, Baylor College of Medicine, Houston, TX 77030; hCardiomyocyte Renewal Laboratory, Texas Heart Institute, Houston, TX 77030 and iDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030; Edited by Marianne E. Bronner, California Institute of Technology, Pasadena, CA, and approved April 21, 2020 (received for review January 6, 2020) Precise control of organ growth and patterning is executed However, what initiates this increase in Cdkn1b expression re- through a balanced regulation of progenitor self-renewal and dif- mains unclear. In addition, conditional ablation of Cdkn1b in the ferentiation. In the auditory sensory epithelium—the organ of inner ear is not sufficient to completely relieve the block on Corti—progenitor cells exit the cell cycle in a coordinated wave supporting cell proliferation (9, 10), suggesting the existence of between E12.5 and E14.5 before the initiation of sensory receptor additional repressive mechanisms.
    [Show full text]
  • DLG5 Variants Do Not Influence Susceptibility to Inflammatory Bowel
    1416 INFLAMMATORY BOWEL DISEASE DLG5 variants do not influence susceptibility to Gut: first published as 10.1136/gut.2005.066621 on 20 April 2005. Downloaded from inflammatory bowel disease in the Scottish population C L Noble, E R Nimmo, H Drummond, L Smith, I D R Arnott, J Satsangi ............................................................................................................................... Gut 2005;54:1416–1420. doi: 10.1136/gut.2005.066621 Introduction: Recent data have suggested that specific haplotypic variants of the DLG5 gene on chromosome 10q23 may be associated with susceptibility to inflammatory bowel disease (IBD) in Germany. Haplotype D, notably characterised by the presence of a GRA substitution at nucleotide 113, was associated with susceptibility to Crohn’s disease (CD) whereas an extended haplotype A conferred protection. Aims: Association of DLG5 haplotypic variants with disease susceptibility, genotype-phenotype relation- ships, and epistasis with CARD15 was investigated in the Scottish population. See end of article for authors’ affiliations Patients and methods: A total of 374 CD, 305 ulcerative colitis (UC), and 294 healthy controls (HC) were ....................... studied. Genotyping for the variants rs1248696 (113A, representing haplotype D) and the single nucleotide polymorphism tag rs2289311 (representing haplotype A) were typed using the Taqman Correspondence to: Professor J Satsangi, system. Gastrointestinal Unit, Results: On analysis of the DLG5 variant 113A, there were no associations with IBD when allelic frequency Western General Hospital, (11.4% IBD v 13.2% HC; p = 0.30) and carrier frequency (19.2% IBD v 24.6% HC; p = 0.069) were Edinburgh, EH4 2XU, UK; analysed. No associations were observed between 113A variant allelic frequency (p = 0.37), carrier [email protected] frequency (p = 0.057), and CD.
    [Show full text]
  • Whole-Exome Sequencing Identifies Causative Mutations in Families
    BASIC RESEARCH www.jasn.org Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract Amelie T. van der Ven,1 Dervla M. Connaughton,1 Hadas Ityel,1 Nina Mann,1 Makiko Nakayama,1 Jing Chen,1 Asaf Vivante,1 Daw-yang Hwang,1 Julian Schulz,1 Daniela A. Braun,1 Johanna Magdalena Schmidt,1 David Schapiro,1 Ronen Schneider,1 Jillian K. Warejko,1 Ankana Daga,1 Amar J. Majmundar,1 Weizhen Tan,1 Tilman Jobst-Schwan,1 Tobias Hermle,1 Eugen Widmeier,1 Shazia Ashraf,1 Ali Amar,1 Charlotte A. Hoogstraaten,1 Hannah Hugo,1 Thomas M. Kitzler,1 Franziska Kause,1 Caroline M. Kolvenbach,1 Rufeng Dai,1 Leslie Spaneas,1 Kassaundra Amann,1 Deborah R. Stein,1 Michelle A. Baum,1 Michael J.G. Somers,1 Nancy M. Rodig,1 Michael A. Ferguson,1 Avram Z. Traum,1 Ghaleb H. Daouk,1 Radovan Bogdanovic,2 Natasa Stajic,2 Neveen A. Soliman,3,4 Jameela A. Kari,5,6 Sherif El Desoky,5,6 Hanan M. Fathy,7 Danko Milosevic,8 Muna Al-Saffar,1,9 Hazem S. Awad,10 Loai A. Eid,10 Aravind Selvin,11 Prabha Senguttuvan,12 Simone Sanna-Cherchi,13 Heidi L. Rehm,14 Daniel G. MacArthur,14,15 Monkol Lek,14,15 Kristen M. Laricchia,15 Michael W. Wilson,15 Shrikant M. Mane,16 Richard P. Lifton,16,17 Richard S. Lee,18 Stuart B. Bauer,18 Weining Lu,19 Heiko M. Reutter ,20,21 Velibor Tasic,22 Shirlee Shril,1 and Friedhelm Hildebrandt1 Due to the number of contributing authors, the affiliations are listed at the end of this article.
    [Show full text]
  • A Systematic Genome-Wide Association Analysis for Inflammatory Bowel Diseases (IBD)
    A systematic genome-wide association analysis for inflammatory bowel diseases (IBD) Dissertation zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Fakultät der Christian-Albrechts-Universität zu Kiel vorgelegt von Dipl.-Biol. ANDRE FRANKE Kiel, im September 2006 Referent: Prof. Dr. Dr. h.c. Thomas C.G. Bosch Koreferent: Prof. Dr. Stefan Schreiber Tag der mündlichen Prüfung: Zum Druck genehmigt: der Dekan “After great pain a formal feeling comes.” (Emily Dickinson) To my wife and family ii Table of contents Abbreviations, units, symbols, and acronyms . vi List of figures . xiii List of tables . .xv 1 Introduction . .1 1.1 Inflammatory bowel diseases, a complex disorder . 1 1.1.1 Pathogenesis and pathophysiology. .2 1.2 Genetics basis of inflammatory bowel diseases . 6 1.2.1 Genetic evidence from family and twin studies . .6 1.2.2 Single nucleotide polymorphisms (SNPs) . .7 1.2.3 Linkage studies . .8 1.2.4 Association studies . 10 1.2.5 Known susceptibility genes . 12 1.2.5.1 CARD15. .12 1.2.5.2 CARD4. .15 1.2.5.3 TNF-α . .15 1.2.5.4 5q31 haplotype . .16 1.2.5.5 DLG5 . .17 1.2.5.6 TNFSF15 . .18 1.2.5.7 HLA/MHC on chromosome 6 . .19 1.2.5.8 Other proposed IBD susceptibility genes . .20 1.2.6 Animal models. 21 1.3 Aims of this study . 23 2 Methods . .24 2.1 Laboratory information management system (LIMS) . 24 2.2 Recruitment. 25 2.3 Sample preparation. 27 2.3.1 DNA extraction from blood. 27 2.3.2 Plate design .
    [Show full text]
  • Diploid Genome Architecture Revealed by Multi-Omic Data of Hybrid Mice
    Downloaded from genome.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Research Diploid genome architecture revealed by multi-omic data of hybrid mice Zhijun Han,1,2 Kairong Cui,3 Katarzyna Placek,3 Ni Hong,1 Chengqi Lin,2 Wei Chen,1 Keji Zhao,3 and Wenfei Jin1 1Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China; 2Institute of Life Sciences, Southeast University, Nanjing, Jiangsu 210096, China; 3Systems Biology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA Although mammalian genomes are diploid, previous studies extensively investigated the average chromatin architectures without considering the differences between homologous chromosomes. We generated Hi-C, ChIP-seq, and RNA-seq data sets from CD4 T cells of B6, Cast, and hybrid mice, to investigate the diploid chromatin organization and epigenetic regulation. Our data indicate that inter-chromosomal interaction patterns between homologous chromosomes are similar, and the similarity is highly correlated with their allelic coexpression levels. Reconstruction of the 3D nucleus revealed that distances of the homologous chromosomes to the center of nucleus are almost the same. The inter-chromosomal interac- tions at centromere ends are significantly weaker than those at telomere ends, suggesting that they are located in different regions within the chromosome territories. The majority of A|B compartments or topologically associated domains (TADs) are consistent between B6 and Cast. We found 58% of the haploids in hybrids maintain their parental compartment status at B6/Cast divergent compartments owing to cis effect. About 95% of the trans-effected B6/Cast divergent compartments con- verge to the same compartment status potentially because of a shared cellular environment.
    [Show full text]
  • Systematic Analysis, Comparison, and Integration of Disease Based Human
    Zhang et al. BMC Medical Genomics 2010, 3:1 http://www.biomedcentral.com/1755-8794/3/1 RESEARCH ARTICLE Open Access Systematic analysis, comparison, and integration of disease based human genetic association data and mouse genetic phenotypic information Yonqing Zhang1†, Supriyo De1†, John R Garner1, Kirstin Smith1, S Alex Wang2, Kevin G Becker1* Abstract Background: The genetic contributions to human common disorders and mouse genetic models of disease are complex and often overlapping. In common human diseases, unlike classical Mendelian disorders, genetic factors generally have small effect sizes, are multifactorial, and are highly pleiotropic. Likewise, mouse genetic models of disease often have pleiotropic and overlapping phenotypes. Moreover, phenotypic descriptions in the literature in both human and mouse are often poorly characterized and difficult to compare directly. Methods: In this report, human genetic association results from the literature are summarized with regard to replication, disease phenotype, and gene specific results; and organized in the context of a systematic disease ontology. Similarly summarized mouse genetic disease models are organized within the Mammalian Phenotype ontology. Human and mouse disease and phenotype based gene sets are identified. These disease gene sets are then compared individually and in large groups through dendrogram analysis and hierarchical clustering analysis. Results: Human disease and mouse phenotype gene sets are shown to group into disease and phenotypically relevant groups at both a coarse and fine level based on gene sharing. Conclusion: This analysis provides a systematic and global perspective on the genetics of common human disease as compared to itself and in the context of mouse genetic models of disease.
    [Show full text]
  • Strategies for Mapping and Cloning Quantitative Trait Genes in Rodents
    REVIEWS STRATEGIES FOR MAPPING AND CLONING QUANTITATIVE TRAIT GENES IN RODENTS Jonathan Flint, William Valdar, Sagiv Shifman and Richard Mott Abstract | Over the past 15 years, more than 2,000 quantitative trait loci (QTLs) have been identified in crosses between inbred strains of mice and rats, but less than 1% have been characterized at a molecular level. However, new resources, such as chromosome substitution strains and the proposed Collaborative Cross, together with new analytical tools, including probabilistic ancestral haplotype reconstruction in outbred mice, Yin–Yang crosses and in silico analysis of sequence variants in many inbred strains, could make QTL cloning tractable. We review the potential of these strategies to identify genes that underlie QTLs in rodents. In the 1990s, when it first became possible to map the Collaborative Cross), techniques (such as in silico chromosomal locations of quantitative trait loci (QTLs) mapping and whole-genome expression studies) and in rodents, it looked as if QTL discovery would soon analytical tools (such as quantitative complementa- lead to the identification of genes involved in any med- tion tests and Yin–Yang crosses, see below for more ically important phenotype that could be modelled in information). mice or rats1–4. In this review, we discuss the realized or potential More than 10 years later, the field of QTL analysis is success of new approaches to identify genes that under- heading towards a crisis. The National Center for lie QTLs.We focus on methods to identify genetic vari- Biotechnology Information (NCBI) lists 700 QTLs that ants that have only a small effect on the phenotype (by are found in rats (see the Entrez Gene web site in the which we mean that the variants account for 10% or Online links box), and the mouse genome database cur- less of the phenotypic variation of a quantitative rently contains 2,050 mouse QTLs (see the Mouse trait).
    [Show full text]
  • Exploring the Mechanism of Berberine Intervention in Ulcerative Colitis from the Perspective of Inflammation and Immunity Based on Systemic Pharmacology
    Hindawi Evidence-Based Complementary and Alternative Medicine Volume 2021, Article ID 9970240, 11 pages https://doi.org/10.1155/2021/9970240 Research Article Exploring the Mechanism of Berberine Intervention in Ulcerative Colitis from the Perspective of Inflammation and Immunity Based on Systemic Pharmacology Yan Jiang,1,2 Li Zhao,2 Qing Chen,2 and Lihong Zhou 1 1School of Medicine, Hunan Normal University, Changsha, Hunan, China 2e First Affiliated Hospital, University of South China, Hengyang, Hunan, China Correspondence should be addressed to Lihong Zhou; [email protected] Received 11 March 2021; Revised 3 April 2021; Accepted 9 May 2021; Published 9 June 2021 Academic Editor: Guang Chen Copyright © 2021 Yan Jiang et al. )is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Ulcerative colitis (UC) is a chronic nonspecific inflammatory disease of the colon and rectum. Recent studies found that berberine had effects on inflammatory diseases and immune diseases. Methods. )e PharmMapper database was used to predict the berberine potential target and GeneCards database and OMIM database were utilized to collect UC genes. )e Cytoscape software was used to construct and analyze the networks and DAVID was utilized to perform enrichment analysis. )en, animal experiments were performed to validate the prediction results. )e experimental rats were randomly divided into normal group (control group), model group, and berberine group. )e general condition, body weight, gross morphology of colon tissue, and colonic mucosal damage index (CMDI) score were observed.
    [Show full text]
  • © Copyright 2015 Anna K. Sczaniecka
    © Copyright 2015 Anna K. Sczaniecka The Role and Mechanisms of Dlg5 in the Regulation of the Hippo Signaling Pathway Anna K. Sczaniecka A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Washington 2015 Reading Committee: Valeri Vasioukhin, Chair Cecilia Moens Susan Parkhurst Program Authorized to Offer Degree: Molecular and Cellular Biology University of Washington ABSTRACT The Role and Mechanisms of Dlg5 in the Regulation of the Hippo Signaling Pathway Anna K. Sczaniecka Chair of the Supervisory Committee: Affiliate Associate Professor Valeri Vasioukhin Molecular and Cellular Biology Program The Hippo signal transduction pathway plays a pivotal role in regulation of normal development, adult organ homeostasis, and cancer. At the core of the Hippo pathway, MST1/2 kinases phosphorylate and activate LATS1/2 kinases, which in turn phosphorylate and inactivate transcriptional co-activators YAP1 and TAZ. Phosphorylated YAP1 and TAZ are inhibited from entering the nucleus and are instead cytoplasmically retained or degraded. Cells monitor their microenvironment, by sensing local cell density and cellular polarity, and use Hippo signaling to regulate the maintenance of normal cell numbers necessary for tissue function. The mechanisms responsible for the connection between the cellular microenvironment and Hippo pathway are poorly understood. In this study, in collaboration with Dr. Andrew Emili’s laboratory in the University of Toronto, I reveal a novel mechanistic connection between the Hippo signaling pathway and the apical-basal cell polarity protein DLG5. I found that DLG5 binds to MST1/2 kinases of the core Hippo pathway. Inactivation of Dlg5 in mice in vivo and in primary cells ex vivo results in increased Hippo pathway activity and decreased levels and activity of YAP1 and TAZ.
    [Show full text]
  • The Glomerular Transcriptome and a Predicted Protein–Protein Interaction Network
    BASIC RESEARCH www.jasn.org The Glomerular Transcriptome and a Predicted Protein–Protein Interaction Network Liqun He,* Ying Sun,* Minoru Takemoto,* Jenny Norlin,* Karl Tryggvason,* Tore Samuelsson,† and Christer Betsholtz*‡ *Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, and ‡Department of Medicine, Karolinska Institutet, Stockholm, and †Department of Medical Biochemistry, Go¨teborg University, Go¨teborg, Sweden ABSTRACT To increase our understanding of the molecular composition of the kidney glomerulus, we performed a meta-analysis of available glomerular transcriptional profiles made from mouse and man using five different methodologies. We generated a combined catalogue of glomerulus-enriched genes that emerged from these different sources and then used this to construct a predicted protein–protein interaction network in the glomerulus (GlomNet). The combined glomerulus-enriched gene catalogue provides the most comprehensive picture of the molecular composition of the glomerulus currently available, and GlomNet contributes an integrative systems biology approach to the understanding of glomerular signaling networks that operate during development, function, and disease. J Am Soc Nephrol 19: 260–268, 2008. doi: 10.1681/ASN.2007050588 Many kidney diseases and, importantly, approxi- nins have been shown to be mutated in Alport syn- mately two thirds of all cases of ESRD originate with drome and Pierson congenital nephrotic syndromes, glomerular disease. Most cases of glomerular disease respectively.11,12 Genetic studies in mice have further are caused by systemic disorders (e.g., diabetes, hyper- revealed genes and proteins of importance for glomer- tension, lupus, obesity) for which the molecular ulus development and function, such as podoca- pathogeneses of the glomerular complications are un- lyxin,13 CD2AP,14 NEPH1,15 FAT1,16 forkhead box known.
    [Show full text]