DOCSLIB.ORG

Production Role Murine TLR9 Plays in Autoantibody Signal Strength

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Production Role Murine TLR9 Plays in Autoantibody Signal Strength Unbiased Modifier Screen Reveals That Signal Strength Determines the Regulatory Role Murine TLR9 Plays in Autoantibody Production This information is current as of September 28, 2021. Robyn E. Mills, Viola C. Lam, Allison Tan, Nicole Cresalia, Nir Oksenberg, Julie Zikherman, Mark Anderson, Arthur Weiss and Michelle L. Hermiston J Immunol 2015; 194:3675-3686; Prepublished online 13 March 2015; Downloaded from doi: 10.4049/jimmunol.1500026 http://www.jimmunol.org/content/194/8/3675 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2015/03/13/jimmunol.150002 Material 6.DCSupplemental References This article cites 46 articles, 12 of which you can access for free at: http://www.jimmunol.org/content/194/8/3675.full#ref-list-1 Why The JI? Submit online. by guest on September 28, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Unbiased Modifier Screen Reveals That Signal Strength Determines the Regulatory Role Murine TLR9 Plays in Autoantibody Production Robyn E. Mills,*,† Viola C. Lam,* Allison Tan,*,‡ Nicole Cresalia,* Nir Oksenberg,* Julie Zikherman,x Mark Anderson,x,{ Arthur Weiss,‡,x and Michelle L. Hermiston* The autoimmune disease systemic lupus erythematosus has a complex environmental and multifactorial genetic basis. Genome-wide association studies have recently identified numerous disease-associated polymorphisms, but it remains unclear in which cells and during which step of pathogenesis specific polymorphisms interact to cause disease. Using a mouse model in which the same ac- tivating mutation (CD45E613R) causes distinct genetic background–dependent disease phenotypes, we performed a screen for genetic modifiers of autoreactivity between anti-nuclear Ab (ANA)–resistant CD45E613R.B6 and ANA-permissive CD45E613R. Downloaded from BALB/c mice. Within a novel autoreactivity-associated locus on chromosome 9, we identify a putative modifier, TLR9. Validating a role for TLR9 in modifying autoreactivity in the context of the CD45E613R mutation, manipulation of TLR9 gene dosage eliminates ANA in CD45E613R.BALB/c mice, but confoundingly permits ANA in CD45E613R.B6 mice. We demonstrate that sensitivity to ANA is modulated by strength of TLR9 signal, because stronger TLR9B6 signals, but not weaker TLR9BALB/c signals, negatively regulate CD45E613R B cell development during competitive reconstitution at the central tolerance checkpoint. Our results identify a novel autoreactivity-associated locus and validate Tlr9 as a candidate gene within the locus. We further http://www.jimmunol.org/ demonstrate a novel role for TLR9 signal strength in central tolerance, providing insight into the interplay of disease- associated polymorphisms at a discrete step of systemic lupus erythematosus pathogenesis. The Journal of Immunology, 2015, 194: 3675–3686. athogenesis of the clinically heterogeneous autoimmune SLE pathogenesis. Furthermore, the variability of clinical presen- disease systemic lupus erythematous (SLE) is a multistep tation has made studying relative contributions of individual loci to P process that is heavily influenced by both genetics and the pathogenesis of SLE in patients difficult. Murine models of SLE environment (1–3). A hallmark of SLE is the presence of circu- have been essential for dissecting the multistep pathogenesis of SLE lating anti-nuclear Abs (ANAs), which can form immune com- in a controlled environment (2). These models provide a tractable by guest on September 28, 2021 plexes with self nucleic acids and associated proteins (4). These genetic framework for dissecting the perturbations in signaling immune complexes can deposit in tissues, trigger inflammation, networks and cell types responsible for disease. and cause end organ damage (1). Recent advances have identified Regulators and mediators of lymphocyte Ag receptor signaling numerous candidate genes via genome-wide association studies are commonly dysregulated in SLE (5). However, despite well- that may contribute to SLE pathogenesis (3). However, it remains documented evidence that perturbations of Ag receptor signaling incompletely understood how these disease-associated loci coop- can alter the developmental tolerance checkpoints and determine erate with each other or environmental triggers at various stages of cell fate upon activation (5), it remains unclear how genetic context influences whether these lymphocytes will break toler- ance. The phosphatase CD45 is an essential regulator of Ag *Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143; †Biomedical Sciences Graduate Program, University of California San receptor signaling, and its absence impairs lymphocyte devel- Francisco, San Francisco, CA 94143; ‡Howard Hughes Medical Institute, University opment, causing a SCID phenotype in both mice and humans (6). of California San Francisco, San Francisco, CA 94143; xDepartment of Medicine, University of California San Francisco, San Francisco, CA 94143; and {Diabetes CD45 is expressed on all nucleated hematopoietic cells, and its Center, University of California San Francisco, San Francisco, CA 94143 dysregulation has been associated with increased susceptibility to Received for publication January 6, 2015. Accepted for publication February 13, autoimmune disease. We previously demonstrated that a single 2015. amino acid substitution, E613R, in the juxtamembrane wedge This work was supported by National Science Foundation Grant GRFP1144247 and domain of CD45 results in a lupus-like phenotype in ∼40% of National Institutes of Health Grant T32AI007334 (to R.E.M.), National Institutes of mice on a mixed 129/Sv and C57BL/6 (B6) genetic background Health Grant K08 AR059723 and a Rosalind Russell Medical Research Foundation Bechtel Award (to J.Z.), National Institutes of Health Grant P01 AI355297 (to A.W.), (7). Mirroring the variable presentation of human SLE, the and the Campini Foundation, the Pepp Family Foundation, the St. Baldrick’s Foun- phenotype of CD45E613R mice is extremely sensitive to ge- dation, and National Institutes of Health Grant R01 AI089831 (M.L.H.). netic context. Despite hyperresponsive Ag receptor signaling, Address correspondence and reprint requests to Dr. Michelle L. Hermiston, Depart- CD45E613R mice fully backcrossed to B6 or 129/Sv genetic ment of Pediatrics, University of California San Francisco, 1450 Third Street, San Francisco, CA 94143. E-mail address: [email protected] backgrounds fail to develop autoantibodies or end organ damage 3 The online version of this article contains supplemental material. (8–11). However, true B6 129/Sv CD45E613R F1 mice reca- Abbreviations used in this article: ANA, anti-nuclear Ab; B6, C57BL/6; LOD, pitulate the original lupus phenotype with 100% penetrance (12). logarithm of the odds; QTL, quantitative trait locus; SLE, systemic lupus erythema- Further validating this model, the CD45E613R mutation cooperates tosus; SNP, single nucleotide polymorphism; Wam, wedge-associated modifier; WT, with established lupus risk alleles to exacerbate disease in the wild-type. autoimmune-resistant B6 genetic background (9, 10). These data Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 indicate that the phenotypic consequences of CD45E613R-induced www.jimmunol.org/cgi/doi/10.4049/jimmunol.1500026 3676 TLR9 REGULATION OF ANAs DEPENDS ON SIGNAL STRENGTH Ag receptor hyperresponsiveness require additional genetic pertur- Biotechnology Information m36 mouse assembly. Experimental p values bations to mediate loss of tolerance and systemic autoimmunity. were established by permutation testing (1000 permutations). In silico In this study, we further investigate the interplay of alterations in mapping of potentially interesting genes in candidate loci and SNP anal- yses were performed using mouse Ensembl (http://www.ensembl.org/ Ag receptor signaling and genetic modifiers on the development of Mus_musculus/index.html), the University of California Santa Cruz ge- ANA. We demonstrate that the CD45E613R mutation on a BALB/c nome browser (http://genome.ucsc.edu/), and The Jackson Laboratory genetic background results in production of ANA, specifically anti- Mouse Genome Informatics database (http://www.informatics.jax.org/). dsDNA Abs, without concomitant end organ disease. This provides Autoantibody assays a tractable system to interrogate a key step in the multistep path- ogenesis of SLE, loss of self-tolerance, without the interference of ANAs were performed as previously described (9). Briefly, HEp-2 slides immune complex–mediated tissue damage. We leverage this phe- (Inova Diagnostics) were stained with a 1:40 or 1:100 serum dilution, washed, and detected with FITC-conjugated donkey anti-mouse IgG sec- notype to screen
Load more

Recommended publications
  • Uwaterloo Latex Thesis Template
    New Algorithms for Predicting Conformational Polymorphism and Inferring Direct Couplings for Side Chains of Proteins by Laleh Soltan Ghoraie A thesis presented to the University of Waterloo in fulfillment of the thesis requirement for the degree of Doctor of Philosophy in Computer Science Waterloo, Ontario, Canada, 2015 c Laleh Soltan Ghoraie 2015 I hereby declare that I am the sole author of this thesis. This is a true copy of the thesis, including any required final revisions, as accepted by my examiners. I understand that my thesis may be made electronically available to the public. ii Abstract Protein crystals populate diverse conformational ensembles. Despite much evidence that there is widespread conformational polymorphism in protein side chains, most of the x- ray crystallography data are modelled by single conformations in the Protein Data Bank. The ability to extract or to predict these conformational polymorphisms is of crucial im- portance, as it facilitates deeper understanding of protein dynamics and functionality. This dissertation describes a computational strategy capable of predicting side-chain poly- morphisms. The applied approach extends a particular class of algorithms for side-chain prediction by modelling the side-chain dihedral angles more appropriately as continuous rather than discrete variables. Employing a new inferential technique known as particle belief propagation (PBP), we predict residue-specific distributions that encode informa- tion about side-chain polymorphisms. The predicted polymorphisms are in relatively close agreement with results from a state-of-the-art approach based on x-ray crystallography data. This approach characterizes the conformational polymorphisms of side chains us- ing electron density information, and has successfully discovered previously unmodelled conformations.
    [Show full text]
  • High-Throughput Discovery of Novel Developmental Phenotypes
    High-throughput discovery of novel developmental phenotypes The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Dickinson, M. E., A. M. Flenniken, X. Ji, L. Teboul, M. D. Wong, J. K. White, T. F. Meehan, et al. 2016. “High-throughput discovery of novel developmental phenotypes.” Nature 537 (7621): 508-514. doi:10.1038/nature19356. http://dx.doi.org/10.1038/nature19356. Published Version doi:10.1038/nature19356 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:32071918 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 Nature. Manuscript Author Author manuscript; Manuscript Author available in PMC 2017 March 14. Published in final edited form as: Nature. 2016 September 22; 537(7621): 508–514. doi:10.1038/nature19356. High-throughput discovery of novel developmental phenotypes A full list of authors and affiliations appears at the end of the article. Abstract Approximately one third of all mammalian genes are essential for life. Phenotypes resulting from mouse knockouts of these genes have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5000 knockout mouse lines, we have identified 410 Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms #Corresponding author: [email protected].
    [Show full text]
  • GENETIC STUDY of RENAL DISEASES (Nephroref Global®) by MASSIVE SEQUENCING (NGS)
    Pablo Iglesias, 57 – Polígono Gran Via Sur 08908 L'Hospitalet de Llobregat (Barcelona) Tel. 932 593 700 – Fax. 932 845 000 GENETIC STUDY OF RENAL DISEASES (NephroRef Global®) BY MASSIVE SEQUENCING (NGS) Request No.: 000 Client: - Analysis code: 55580 Patient Name: xxx Date of Birth: N/A Patient Ref.: xxx Gender: Female Sample Type: Blood EDTA Sample Arrival Date: DD/MM/AAAA Date of Result: DD/MM/AAAA Clinical information: A 9-year-old patient with a nephrotic syndrome without response to corticosteroid therapy. She has nephrotic-range proteinuria with microhematuria, hypoalbuminemia with hypercholesterolemia and normal glomerular filtration. Paternal aunt with cortico-resistant nephrotic syndrome with evolution to end-stage renal failure that required renal transplantation at age 13. RESULT AND INTERPRETATION The presence of a heterozygous likely pathogenic variant has been identified. In addition, the presence of a heterozygous variant of uncertain clinical significance (VUS) has been identified.(See Interpretation and recommendations) The complete list of studied genes is available in Annex 1. (Methodology) The list of reported genes and coverage details is available in Table 1. (Methodology) Gene Variant* Zygosity Inheritance pattern Classification^ NPHS2 NM_014625.3: c.842A>C Heterozygosis Autosomal Recessive Likely Patogénica p.(Glu281Ala) INF2 NM_022489.3: c.67T>A Heterozygosis Autosomal Recessive VUS p.(Ser23Thr) * Nomenclature according to HGVS v15.11 ^ Based on the recommendations of the American College of Medical Genetics and Genomics (ACMG) Physician, technical specialist responsible for Clinical Analysis: Jaime Torrents Pont. The results relate to samples received and analysed. This report may not be reproduced in part without permission. This document is addressed to the addressee and contains confidential information.
    [Show full text]
  • RAB6B Polyclonal Antibody
    For Research Use Only RAB6B Polyclonal antibody Catalog Number:10340-1-AP 2 Publications www.ptgcn.com Catalog Number: GenBank Accession Number: Recommended Dilutions: Basic Information 10340-1-AP BC002510 WB 1:500-1:2000 Size: GeneID (NCBI): IP 0.5-4.0 ug for IP and 1:500-1:2000 450 μg/ml 51560 for WB IHC 1:20-1:200 Source: Full Name: IF 1:10-1:100 Rabbit RAB6B, member RAS oncogene family Isotype: Calculated MW: IgG 23 kDa Purification Method: Observed MW: Antigen affinity purification 24 kDa Immunogen Catalog Number: AG0322 Applications Tested Applications: Positive Controls: IF, IHC, IP, WB,ELISA WB : mouse brain tissue; C6 cells, rat brain tissue Cited Applications: IP : mouse brain tissue; IF, WB IHC : human gliomas tissue; Species Specificity: human, mouse, rat IF : C6 cells; Cited Species: mouse, rat Note-IHC: suggested antigen retrieval with TE buffer pH 9.0; (*) Alternatively, antigen retrieval may be performed with citrate buffer pH 6.0 The human RAB genes share structural and biochemical properties with the Ras gene superfamily. Accumulating Background Information data suggests an important role for RAB proteins either in endocytosis or in biosynthetic protein transport. The transport of newly synthesized proteins from endoplasmic reticulum to the Golgi complex and to secretory vesicles involves the movement of carrier vesicles, a process that appears to involve RAB protein function. Rab6A has been shown to be a regulator of membrane traffic from the Golgi apparatus towards the endoplasmic reticulum (ER). Rab6B is encoded by an independent gene which is located on chromosome 3 region q21-q23.
    [Show full text]
  • 1 Supplementary Materials and Methods Gene Set Enrichment Analysis for Gene Expression Data We Compared the Gene Expression Leve
    Supplementary Materials and Methods Gene set enrichment analysis for gene expression data We compared the gene expression levels from 2 different phenotypes (i.e., drug sensitive versus resistant) and picked up the genes which had significant different expression for Gene set enrichment analysis (GSEA) by using Molecular Signatures Database(V3.0). Gene set enrichment analysis was carried out by computing overlaps with canonical pathways(CP) and gene ontology (GO) gene sets(C5), obtained from the Broad Institute [1]. Genes in Gene Set (K), Genes in Overlap (k), k/K and P value were used to rank the pathways enriched in each phenotype. We used with 10363 genes in 2334 pathways as the gene set in this study. Supplementary References 1.Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 2005;102:15545– 50. 1 Supplementary Results Other drug response-genotype associations in this study Cells with wild genotype were more sensitive to irinotecan than those with TGFβR2 mutation and deletion together (P=0.03) (Supplementary Table S6). PC cells with wild genotype in ADAM gene family were more sensitive to gemcitabine and docetaxel than those with mutation in this family (p<0.05) (Supplementary Table S6). PC cells with wild genotype were more sensitive to docetaxel than those with DEPDC or TTN mutation (p<0.05) (Supplementary Table S6). PC cells with BAI3 mutation were more sensitive to cisplatin than those with wild genotype (p=0.02) (Supplementary Table S6).
    [Show full text]
  • Evidence of Oligogenic Inheritance in Nephronophthisis
    JASN Express. Published on September 12, 2007 as doi: 10.1681/ASN.2007020243 CLINICAL RESEARCH www.jasn.org Evidence of Oligogenic Inheritance in Nephronophthisis Julia Hoefele,*† Matthias T.F. Wolf,* John F. O’Toole,* Edgar A. Otto,* Ulla Schultheiss,* Georges Deˆschenes,‡ Massimo Attanasio,* Boris Utsch,* Corinne Antignac,§ and ʈ Friedhelm Hildebrandt* ʈ Departments of *Pediatrics and Human Genetics, University of Michigan, Ann Arbor, Michigan; †Department of Pediatrics, University Children’s Hospital, University of Munich, Munich, Germany; and ‡Hoˆpital Robert Debre´, Pediatric Nephrology, AP-HP, and §INSERM, U574, Universite´ Paris Descartes, Faculte de Me´dicine Rene´ Descartes, and Hoˆpital Necker-Enfants Malades, AP-HP, Department of Genetics, Paris, France ABSTRACT Nephronophthisis is a recessive cystic renal disease that leads to end-stage renal failure in the first two decades of life. Twenty-five percent of nephronophthisis cases are caused by large homozygous deletions of NPHP1, but six genes responsible for nephronophthisis have been identified. Because oligogenic inheritance has been described for the related Bardet-Biedl syndrome, we evaluated whether mutations in more than one gene may also be detected in cases of nephronophthisis. Because the nephrocystins 1 to 4 are known to interact, we examined patients with nephronophthisis from 94 different families and sequenced all exons of the NPHP1, NPHP2, NPHP3, and NPHP4 genes. In our previous studies involving 44 families, we detected two mutations in one of the NPHP1–4 genes. Here, we detected in six families two mutations in either NPHP1, NPHP3, or NPHP4, and identified a third mutation in one of the other NPHP genes. Furthermore, we found possible digenic disease by detecting one individual who carried one mutation in NPHP2 and a second mutation in NPHP3.
    [Show full text]
  • 1847.Full-Text.Pdf
    Published OnlineFirst January 29, 2016; DOI: 10.1158/0008-5472.CAN-15-1752 Cancer Molecular and Cellular Pathobiology Research RASSF1A Directly Antagonizes RhoA Activity through the Assembly of a Smurf1-Mediated Destruction Complex to Suppress Tumorigenesis Min-Goo Lee, Seong-In Jeong, Kyung-Phil Ko, Soon-Ki Park, Byung-Kyu Ryu, Ick-Young Kim, Jeong-Kook Kim, and Sung-Gil Chi Abstract RASSF1A is a tumor suppressor implicated in many tumorigenic as Rhotekin. As predicted on this basis, RASSF1A competed with processes; however, the basis for its tumor suppressor functions are Rhotekin to bind RhoA and to block its activation. RASSF1A not fully understood. Here we show that RASSF1A is a novel mutants unable to bind RhoA or Smurf1 failed to suppress antagonist of protumorigenic RhoA activity. Direct interaction RhoA-induced tumor cell proliferation, drug resistance, epitheli- between the C-terminal amino acids (256–277) of RASSF1A and al–mesenchymal transition, migration, invasion, and metastasis. active GTP-RhoA was critical for this antagonism. In addition, Clinically, expression levels of RASSF1A and RhoA were inversely interaction between the N-terminal amino acids (69-82) of correlated in many types of primary and metastatic tumors and RASSF1A and the ubiquitin E3 ligase Smad ubiquitination regu- tumor cell lines. Collectively, our findings showed how RASSF1A latory factor 1 (Smurf1) disrupted GTPase activity by facilitating may suppress tumorigenesis by intrinsically inhibiting the tumor- Smurf1-mediated ubiquitination of GTP-RhoA. We noted that the promoting activity of RhoA, thereby illuminating the potential RhoA-binding domain of RASSF1A displayed high sequence mechanistic consequences of RASSF1A inactivation in many can- homology with Rho-binding motifs in other RhoA effectors, such cers.
    [Show full text]
  • Prognostic Significance of Autophagy-Relevant Gene Markers in Colorectal Cancer
    ORIGINAL RESEARCH published: 15 April 2021 doi: 10.3389/fonc.2021.566539 Prognostic Significance of Autophagy-Relevant Gene Markers in Colorectal Cancer Qinglian He 1, Ziqi Li 1, Jinbao Yin 1, Yuling Li 2, Yuting Yin 1, Xue Lei 1 and Wei Zhu 1* 1 Department of Pathology, Guangdong Medical University, Dongguan, China, 2 Department of Pathology, Dongguan People’s Hospital, Southern Medical University, Dongguan, China Background: Colorectal cancer (CRC) is a common malignant solid tumor with an extremely low survival rate after relapse. Previous investigations have shown that autophagy possesses a crucial function in tumors. However, there is no consensus on the value of autophagy-associated genes in predicting the prognosis of CRC patients. Edited by: This work screens autophagy-related markers and signaling pathways that may Fenglin Liu, Fudan University, China participate in the development of CRC, and establishes a prognostic model of CRC Reviewed by: based on autophagy-associated genes. Brian M. Olson, Emory University, United States Methods: Gene transcripts from the TCGA database and autophagy-associated gene Zhengzhi Zou, data from the GeneCards database were used to obtain expression levels of autophagy- South China Normal University, China associated genes, followed by Wilcox tests to screen for autophagy-related differentially Faqing Tian, Longgang District People's expressed genes. Then, 11 key autophagy-associated genes were identified through Hospital of Shenzhen, China univariate and multivariate Cox proportional hazard regression analysis and used to Yibing Chen, Zhengzhou University, China establish prognostic models. Additionally, immunohistochemical and CRC cell line data Jian Tu, were used to evaluate the results of our three autophagy-associated genes EPHB2, University of South China, China NOL3, and SNAI1 in TCGA.
    [Show full text]
  • Renal Cystic Disorders Infosheet 6-14-19
    Next Generation Sequencing Panel for Renal Cystic Disorders Clinical Features: Renal cystic diseases are a genetically heterogeneous group of conditions characterized By isolated renal disease or renal cysts in conjunction with extrarenal features (1). Age of onset of renal cystic disease ranges from neonatal to adult onset. Common features of renal cystic diseases include renal insufficiency and progression to end stage renal disease (ESRD). Identification of the genetic etiology of renal cystic disease can aid in appropriate clinical management of the affected patient. Our Renal Cystic Disorders Panel includes sequence and deletion/duplicaton analysis of all 79 genes listed below. Renal Cystic Disorders Sequencing Panel AHI1 BMPER HNF1B NEK8 TCTN3 WDPCP ANKS6 C5orf42 IFT27 NOTCH2 TFAP2A WDR19 ARL13B CC2D2A IFT140 NPHP1 TMEM107 XPNPEP3 ARL6 CDC73 IFT172 NPHP3 TMEM138 ZNF423 B9D1 CEP104 INPP5E NPHP4 TMEM216 B9D2 CEP120 INVS OFD1 TMEM231 BBIP1 CEP164 IQCB1 PDE6D TMEM237 BBS1 CEP290 JAG1 PKD2 TMEM67 BBS10 CEP41 KIAA0556 PKHD1 TRIM32 BBS12 CEP83 KIAA0586 REN TSC1 BBS2 CRB2 KIF14 RPGRIP1L TSC2 BBS4 CSPP1 KIF7 SALL1 TTC21B BBS5 DCDC2 LZTFL1 SDCCAG8 TTC8 BBS7 GLIS2 MKKS TCTN1 UMOD BBS9 GLIS3 MKS1 TCTN2 VHL Disorder Genes Inheritance Clinical features/molecular genetics Bardet Biedl ARL6 AR Bardet-Biedl syndrome (BBS) is an autosomal syndrome BBS1 recessive multi-systemic ciliopathy characterized By BBS10 retinal dystrophy, oBesity, postaxial polydactyly, BBS12 leaning difficulties, renal involvement and BBS2 genitourinary abnormalities (2). Visual prognosis is BBS4 poor, and the mean age of legal Blindness is 15.5 BBS5 years. Birth weight is typically normal But significant BBS7 weight gain Begins within the first year. Renal BBS9 disease is a major cause of morBidity and mortality.
    [Show full text]
  • Inhibition of Mitochondrial Complex II in Neuronal Cells Triggers Unique
    www.nature.com/scientificreports OPEN Inhibition of mitochondrial complex II in neuronal cells triggers unique pathways culminating in autophagy with implications for neurodegeneration Sathyanarayanan Ranganayaki1, Neema Jamshidi2, Mohamad Aiyaz3, Santhosh‑Kumar Rashmi4, Narayanappa Gayathri4, Pulleri Kandi Harsha5, Balasundaram Padmanabhan6 & Muchukunte Mukunda Srinivas Bharath7* Mitochondrial dysfunction and neurodegeneration underlie movement disorders such as Parkinson’s disease, Huntington’s disease and Manganism among others. As a corollary, inhibition of mitochondrial complex I (CI) and complex II (CII) by toxins 1‑methyl‑4‑phenylpyridinium (MPP+) and 3‑nitropropionic acid (3‑NPA) respectively, induced degenerative changes noted in such neurodegenerative diseases. We aimed to unravel the down‑stream pathways associated with CII inhibition and compared with CI inhibition and the Manganese (Mn) neurotoxicity. Genome‑wide transcriptomics of N27 neuronal cells exposed to 3‑NPA, compared with MPP+ and Mn revealed varied transcriptomic profle. Along with mitochondrial and synaptic pathways, Autophagy was the predominant pathway diferentially regulated in the 3‑NPA model with implications for neuronal survival. This pathway was unique to 3‑NPA, as substantiated by in silico modelling of the three toxins. Morphological and biochemical validation of autophagy markers in the cell model of 3‑NPA revealed incomplete autophagy mediated by mechanistic Target of Rapamycin Complex 2 (mTORC2) pathway. Interestingly, Brain Derived Neurotrophic Factor
    [Show full text]
  • Viewed and Published Immediately Upon Acceptance Cited in Pubmed and Archived on Pubmed Central Yours — You Keep the Copyright
    BMC Genomics BioMed Central Research article Open Access Differential gene expression in ADAM10 and mutant ADAM10 transgenic mice Claudia Prinzen1, Dietrich Trümbach2, Wolfgang Wurst2, Kristina Endres1, Rolf Postina1 and Falk Fahrenholz*1 Address: 1Johannes Gutenberg-University, Institute of Biochemistry, Mainz, Johann-Joachim-Becherweg 30, 55128 Mainz, Germany and 2Helmholtz Zentrum München – German Research Center for Environmental Health, Institute for Developmental Genetics, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany Email: Claudia Prinzen - [email protected]; Dietrich Trümbach - [email protected]; Wolfgang Wurst - [email protected]; Kristina Endres - [email protected]; Rolf Postina - [email protected]; Falk Fahrenholz* - [email protected] * Corresponding author Published: 5 February 2009 Received: 19 June 2008 Accepted: 5 February 2009 BMC Genomics 2009, 10:66 doi:10.1186/1471-2164-10-66 This article is available from: http://www.biomedcentral.com/1471-2164/10/66 © 2009 Prinzen et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: In a transgenic mouse model of Alzheimer disease (AD), cleavage of the amyloid precursor protein (APP) by the α-secretase ADAM10 prevented amyloid plaque formation, and alleviated cognitive deficits. Furthermore, ADAM10 overexpression increased the cortical synaptogenesis. These results suggest that upregulation of ADAM10 in the brain has beneficial effects on AD pathology. Results: To assess the influence of ADAM10 on the gene expression profile in the brain, we performed a microarray analysis using RNA isolated from brains of five months old mice overexpressing either the α-secretase ADAM10, or a dominant-negative mutant (dn) of this enzyme.
    [Show full text]
  • Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
    BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in
    [Show full text]