DOCSLIB.ORG

Prevalence of Monogenic Causes in Pediatric Patients with Nephrolithiasis Or Nephrocalcinosis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Prevalence of Monogenic Causes in Pediatric Patients with Nephrolithiasis Or Nephrocalcinosis Article Prevalence of Monogenic Causes in Pediatric Patients with Nephrolithiasis or Nephrocalcinosis Daniela Anne Braun,* Jennifer Ashley Lawson,* Heon Yung Gee,*† Jan Halbritter,*‡ Shirlee Shril,* Weizhen Tan,* | Deborah Stein,* Ari J. Wassner,§ Michael A. Ferguson,* Zoran Gucev, Brittany Fisher,* Leslie Spaneas,* | Jennifer Varner,* John A. Sayer,¶ Danko Milosevic,** Michelle Baum,* Velibor Tasic, and Friedhelm Hildebrandt*†† Abstract Background and objectives Nephrolithiasis is a prevalent condition that affects 10%–15% of adults in their *Division of Nephrology, lifetime. It is associated with high morbidity due to colicky pain, the necessity for surgical intervention, and Department of sometimes progression to CKD. In recent years, multiple monogenic causes of nephrolithiasis and Medicine and §Division nephrocalcinosis have been identified. However, the prevalence of each monogenic gene in a pediatric renal of Endocrinology, stone cohort has not yet been extensively studied. Department of Medicine, Boston Children’s Hospital, Design, setting, participants, & measurements To determine the percentage of cases that can be explained Harvard Medical molecularly by mutations in one of 30 known nephrolithiasis/nephrocalcinosis genes, we conducted a School, Boston, high-throughput exon sequencing analysis in an international cohort of 143 individuals ,18 years of age, Massachusetts; † with nephrolithiasis (n=123) or isolated nephrocalcinosis (n=20). Over 7 months, all eligible individuals at Department of Pharmacology, Brain three renal stone clinics in the United States and Europe were approached for study participation. Korea 21 PLUS Project for Medical Sciences, Results We detected likely causative mutations in 14 of 30 analyzed genes, leading to a molecular diagnosis in Yon sei University 16.8% (24 of 143) of affected individuals; 12 of the 27 detected mutations were not previously described as disease College of Medicine, Seoul, Republic of causing (44.4%). We observed that in our cohort all individuals with infantile manifestation of nephrolithiasis or ‡ Korea; Division of nephrocalcinosis had causative mutations in recessive rather than dominant monogenic genes. In individuals Endocrinology/ who manifested later in life, causative mutations in dominant genes were more frequent. Nephrology, Department of Internal Conclusions We present the first exclusively pediatric cohort examined for monogenic causes of nephrolithiasis/ Medicine, University Clinic Leipzig, Leipzig, ║ nephrocalcinosis, and suggest that important therapeutic and preventative measures may result from Germany; Department mutational analysis in individuals with early manifestation of nephrolithiasis or nephrocalcinosis. of Pediatric Nephrology, Clin J Am Soc Nephrol 11: 664–672, 2016. doi: 10.2215/CJN.07540715 Medical Faculty Skopje, University Children’s Hospital, Skopje, Macedonia; ¶Institute of Introduction pediatric patients are more likely to have a monogenic Genetic Medicine, International Centre for The incidence of pediatric nephrolithiasis and nephro- cause of disease, mutational analysis is particularly Life, Newcastle calcinosis (NL/NC) has significantly increased over the relevant in this cohort. Furthermore, early detection of University, Newcastle last several decades (1). Furthermore, this condition is disease-causing mutations is of great importance in upon Tyne, United associated with high morbidity due to episodes of col- early-onset NL/NC because genetic diagnoses allow Kingdom; **Department icky pain, the necessity for surgical intervention, and fi of Pediatric Nephrology, nely tailored treatment plans that may prevent Dialysis and sometimes progression to CKD. Nephrolithiasis (NL) recurrent disease or progression to ESRD. Transplantation, Clinical and nephrocalcinosis (NC) share a recognized degree Until recently, mutation analysis for individuals Hospital Center Zagreb, of heritability. In twin studies, heritability accounted with NL/NC has not been widely accessible. How- University of Zagreb for nearly half of all NL/NC prevalence (2,3). Accord- ever, through the availability of high-throughput Medical School, Zagreb, Croatia; and ††Howard ing to the Online Mendelian Inheritance in Man multiplex PCR and next-generation sequencing, rapid Hughes Medical (OMIM) database, mutations in at least 30 genes can mutation analysis of multiple genes in large cohorts Institute, Chevy Chase, cause monogenic forms of NL/NC by autosomal re- has become an efficient and cost-effective screening Maryland cessive, autosomal dominant, or X-linked transmission. method (5–7). Recently, we studied 166 adults and 106 children with To identify the prevalence of monogenic causes in Correspondence: Dr. Friedhelm NC or NL and detected causative mutations in 11.4% early-onset NL/NC (onset before 18 years of age), we Hildebrandt, Division of of adult and 20.8% of early-onset cases (4). This result analyzed all coding exons and adjacent splice sites of Nephrology, Boston confirmed a significant occurrence of heritable NL/NC, 30 known NL/NC-causing genes with a defined Children’s Hospital, while also indicating that there are additional uniden- OMIM phenotype in a cohort of 143 children re- 300 Longwood Avenue, fi Boston, MA 02115. ti ed monogenic causes of NL/NC. cruited at three renal stone clinics with at least one Email: friedhelm. However, the contribution of monogenic causes of episode of NL or the presence of NC upon renal ul- hildebrandt@childrens. NL/NC has yet to be extensively studied. Because trasound before 18 years of age. This patient cohort harvard.edu 664 Copyright © 2016 by the American Society of Nephrology www.cjasn.org Vol 11 April, 2016 Clin J Am Soc Nephrol 11: 664–672, April, 2016 Monogenetic Genes in Early-Onset Urinary Stone Disease, Braun et al. 665 had no patient overlap with the previously published All variants that were present in the homozygous state in cohort (4). healthy control cohorts (Exome Aggregation Consortium and Exome Variant Server) were excluded. The remaining variants were confirmed in original patient DNA by Sanger Materials and Methods sequencing. Whenever parental DNA was available, segre- Study Cohort gation analysis was performed. Final calling of variant This study was approved by the Institutional Review pathogenicity was performed by geneticists together with ’ Board of Boston Children s Hospital. Study inclusion cri- physician scientists, who had knowledge of the clinical fi fi teria were de ned as: rst clinical manifestation of NL phenotypes and pedigree structure. and/or presence of NC on renal ultrasound before 18 years of age. Individuals with conditions or medication Coverage Statistics that might have caused secondary renal stone disease were We achieved a median sequencing coverage of 1943 per excluded. To avoid selection bias, all patients seen at three 3 ’ individual, and 197 per amplicon. As previously pub- renal stone clinics (Boston Children s Hospital, University lished, median coverage values .203 are sufficient to ex- Clinic Skopje, and University Clinic Zagreb) over a finite – clude false-negative results in high-throughput exon period (February August 2014) were approached for sequencing (5,6). In this study, only eight of 143 individ- study participation. The exact percentage of individuals uals (5.7%), and 37 of 518 amplicons (7.1%) had a median who declined study participation was not recorded. After coverage ,203. This value is average for next-generation obtaining informed consent, clinical data, pedigree infor- sequencing; hence, this experiment fulfilled the necessary mation, and DNA samples were collected from 143 indi- quality criteria. viduals. All individuals were recruited after the conclusion of the study of Halbritter et al. (4), thereby excluding en- rollment overlap between the two studies. The cohort con- Web Resources Online resources used were as follows: sisted of 72 male and 71 female participants. Of these individuals, 123 had NL, 20 had NC based on renal ultra- UCSC Genome Browser, http://genome.ucsc.edu/cgi-bin/ sound, and three with NC also had reported NL. hgGateway; 1000 Genomes Browser, http://browser.1000genomes.org; Mutation Analysis Ensembl Genome Browser, http://www.ensembl.org; Mutation analysis was performed using a barcoded Exome Variant Server, http://evs.gs.washington.edu/EVS; multiplex PCR-based approach, as previously described Exome Aggregation Consortium, exac.broadinstitute.org; fi (5,6). We designed 518 target-speci c primers for 381 cod- OMIM, http://www.omim.org; ing exons and the adjacent splice sites of 30 genes that are PolyPhen-2, http://genetics.bwh.harvard.edu/pph2 (8); fi known monogenic causes of NL/NC (de ned by OMIM; SIFT, http://sift.jcvi.org (9); and www.ncbi.nlm.nih.gov/omim). The genes screened were: MutationTaster http://www.mutationtaster.org (10). ADCY10, AGXT, PRT, ATP6V0A4, ATP6V1B1, CA2, CASR, CLCN5, CLCNKB, CLDN16, CLDN19, CYP24A1, FAM20A, GRHPR, HNF4A, HOGA1, HPRT1, KCNJ1, OCRL, Results SLC12A1, SLC22A12, SLC2A9, SLC34A1, SLC34A3, We examined an international cohort of 143 individuals SLC3A1, SLC4A1, SLC7A9, SLC9A3R1, VDR,andXDH with early-onset NL or NC for the presence of mutations (Supplemental Tables 1 and 2). Amplicon sizes were chosen in 30 genes that cause NL/NC if mutated. We detected to range from 250 to 300 bp (primer sequences are avail- mutations in 14 of these 30 genes and established a able from the authors). The use of barcoded multiplex PCR molecular diagnosis likely to explain the disease phenotype (Fluidigm 48.48-Access
Load more

Recommended publications
  • Structural Basis for Disruption of Claudin Assembly in Tight Junctions
    www.nature.com/scientificreports OPEN Structural basis for disruption of claudin assembly in tight junctions by an enterotoxin Received: 11 May 2016 Takehiro Shinoda1,2, Naoko Shinya1,2, Kaori Ito1,2, Noboru Ohsawa1,2, Takaho Terada1,3, Accepted: 01 September 2016 Kunio Hirata4, Yoshiaki Kawano4, Masaki Yamamoto4, Tomomi Kimura-Someya1,2, Published: 20 September 2016 Shigeyuki Yokoyama1,3 & Mikako Shirouzu1,2 The food-poisoning bacterium Clostridium perfringens produces an enterotoxin (~35 kDa) that specifically targets human claudin-4, among the 26 human claudin proteins, and causes diarrhea by fluid accumulation in the intestinal cavity. The C-terminal domain of the Clostridium perfringens enterotoxin (C-CPE, ~15 kDa) binds tightly to claudin-4, and disrupts the intestinal tight junction barriers. In this study, we determined the 3.5-Å resolution crystal structure of the cell-free synthesized human claudin- 4•C-CPE complex, which is significantly different from the structure of the off-target complex of an engineered C-CPE with mouse claudin-19. The claudin-4•C-CPE complex structure demonstrated the mechanism underlying claudin assembly disruption. A comparison of the present C-CPE-bound structure of claudin-4 with the enterotoxin-free claudin-15 structure revealed sophisticated C-CPE- induced conformation changes of the extracellular segments, induced on the foundation of the rigid four-transmembrane-helix bundle structure. These conformation changes provide a mechanistic model for the disruption of the lateral assembly of claudin molecules. Furthermore, the present novel structural mechanism for selecting a specific member of the claudin family can be used as the foundation to develop novel medically important technologies to selectively regulate the tight junctions formed by claudin family members in different organs.
    [Show full text]
  • Supplementary Table 1: Adhesion Genes Data Set
    Supplementary Table 1: Adhesion genes data set PROBE Entrez Gene ID Celera Gene ID Gene_Symbol Gene_Name 160832 1 hCG201364.3 A1BG alpha-1-B glycoprotein 223658 1 hCG201364.3 A1BG alpha-1-B glycoprotein 212988 102 hCG40040.3 ADAM10 ADAM metallopeptidase domain 10 133411 4185 hCG28232.2 ADAM11 ADAM metallopeptidase domain 11 110695 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 195222 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 165344 8751 hCG20021.3 ADAM15 ADAM metallopeptidase domain 15 (metargidin) 189065 6868 null ADAM17 ADAM metallopeptidase domain 17 (tumor necrosis factor, alpha, converting enzyme) 108119 8728 hCG15398.4 ADAM19 ADAM metallopeptidase domain 19 (meltrin beta) 117763 8748 hCG20675.3 ADAM20 ADAM metallopeptidase domain 20 126448 8747 hCG1785634.2 ADAM21 ADAM metallopeptidase domain 21 208981 8747 hCG1785634.2|hCG2042897 ADAM21 ADAM metallopeptidase domain 21 180903 53616 hCG17212.4 ADAM22 ADAM metallopeptidase domain 22 177272 8745 hCG1811623.1 ADAM23 ADAM metallopeptidase domain 23 102384 10863 hCG1818505.1 ADAM28 ADAM metallopeptidase domain 28 119968 11086 hCG1786734.2 ADAM29 ADAM metallopeptidase domain 29 205542 11085 hCG1997196.1 ADAM30 ADAM metallopeptidase domain 30 148417 80332 hCG39255.4 ADAM33 ADAM metallopeptidase domain 33 140492 8756 hCG1789002.2 ADAM7 ADAM metallopeptidase domain 7 122603 101 hCG1816947.1 ADAM8 ADAM metallopeptidase domain 8 183965 8754 hCG1996391 ADAM9 ADAM metallopeptidase domain 9 (meltrin gamma) 129974 27299 hCG15447.3 ADAMDEC1 ADAM-like,
    [Show full text]
  • Mutations in the Tight-Junction Gene Claudin 19 (CLDN19) Are Associated with Renal Magnesium Wasting, Renal Failure, and Severe Ocular Involvement
    Mutations in the Tight-Junction Gene Claudin 19 (CLDN19) Are Associated with Renal Magnesium Wasting, Renal Failure, and Severe Ocular Involvement Martin Konrad, Andre´ Schaller, Dominik Seelow, Amit V. Pandey, Siegfried Waldegger, Annegret Lesslauer, Helga Vitzthum, Yoshiro Suzuki, John M. Luk, Christian Becker, Karl P. Schlingmann, Marcel Schmid, Juan Rodriguez-Soriano, Gema Ariceta, Francisco Cano, Ricardo Enriquez, Harald Ju¨ppner, Sevcan A. Bakkaloglu, Matthias A. Hediger, Sabina Gallati, Stephan C. F. Neuhauss, Peter Nu¨rnberg, and Stefanie Weber Claudins are major components of tight junctions and contribute to the epithelial-barrier function by restricting free diffusion of solutes through the paracellular pathway. We have mapped a new locus for recessive renal magnesium loss on chromosome 1p34.2 and have identified mutations in CLDN19, a member of the claudin multigene family, in patients affected by hypomagnesemia, renal failure, and severe ocular abnormalities. CLDN19 encodes the tight-junction protein claudin-19, and we demonstrate high expression of CLDN19 in renal tubules and the retina. The identified mutations interfere severely with either cell-membrane trafficking or the assembly of the claudin-19 protein. The identification of CLDN19 mutations in patients with chronic renal failure and severe visual impairment supports the fundamental role of claudin-19 for normal renal tubular function and undisturbed organization and development of the retina. Tight junctions constitute cell-cell contacts by forming cir- calcium reabsorption
    [Show full text]
  • Single Cell Transcriptional and Chromatin Accessibility Profiling Redefine Cellular Heterogeneity in the Adult Human Kidney
    ARTICLE https://doi.org/10.1038/s41467-021-22368-w OPEN Single cell transcriptional and chromatin accessibility profiling redefine cellular heterogeneity in the adult human kidney Yoshiharu Muto 1,7, Parker C. Wilson 2,7, Nicolas Ledru 1, Haojia Wu1, Henrik Dimke 3,4, ✉ Sushrut S. Waikar 5 & Benjamin D. Humphreys 1,6 1234567890():,; The integration of single cell transcriptome and chromatin accessibility datasets enables a deeper understanding of cell heterogeneity. We performed single nucleus ATAC (snATAC- seq) and RNA (snRNA-seq) sequencing to generate paired, cell-type-specific chromatin accessibility and transcriptional profiles of the adult human kidney. We demonstrate that snATAC-seq is comparable to snRNA-seq in the assignment of cell identity and can further refine our understanding of functional heterogeneity in the nephron. The majority of differ- entially accessible chromatin regions are localized to promoters and a significant proportion are closely associated with differentially expressed genes. Cell-type-specific enrichment of transcription factor binding motifs implicates the activation of NF-κB that promotes VCAM1 expression and drives transition between a subpopulation of proximal tubule epithelial cells. Our multi-omics approach improves the ability to detect unique cell states within the kidney and redefines cellular heterogeneity in the proximal tubule and thick ascending limb. 1 Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA. 2 Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, USA. 3 Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark. 4 Department of Nephrology, Odense University Hospital, Odense, Denmark.
    [Show full text]
  • Differences in Gene Expression Profiles and Carcinogenesis Pathways Involved in Cisplatin Resistance of Four Types of Cancer
    596 ONCOLOGY REPORTS 30: 596-614, 2013 Differences in gene expression profiles and carcinogenesis pathways involved in cisplatin resistance of four types of cancer YONG YANG1,2, HUI LI1,2, SHENGCAI HOU1,2, BIN HU1,2, JIE LIU1,3 and JUN WANG1,3 1Beijing Key Laboratory of Respiratory and Pulmonary Circulation, Capital Medical University, Beijing 100069; 2Department of Thoracic Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020; 3Department of Physiology, Capital Medical University, Beijing 100069, P.R. China Received December 23, 2012; Accepted March 4, 2013 DOI: 10.3892/or.2013.2514 Abstract. Cisplatin-based chemotherapy is the standard Introduction therapy used for the treatment of several types of cancer. However, its efficacy is largely limited by the acquired drug Cisplatin is primarily effective through DNA damage and is resistance. To date, little is known about the RNA expression widely used for the treatment of several types of cancer, such changes in cisplatin-resistant cancers. Identification of the as testicular, lung and ovarian cancer. However, the ability RNAs related to cisplatin resistance may provide specific of cancer cells to become resistant to cisplatin remains a insight into cancer therapy. In the present study, expression significant impediment to successful chemotherapy. Although profiling of 7 cancer cell lines was performed using oligo- previous studies have identified numerous mechanisms in nucleotide microarray analysis data obtained from the GEO cisplatin resistance, it remains a major problem that severely database. Bioinformatic analyses such as the Gene Ontology limits the usefulness of this chemotherapeutic agent. Therefore, (GO) and KEGG pathway were used to identify genes and it is crucial to examine more elaborate mechanisms of cisplatin pathways specifically associated with cisplatin resistance.
    [Show full text]
  • CLDN19 Monoclonal Antibody (M02), Clone 2F2
    CLDN19 monoclonal antibody (M02), clone 2F2 Catalog # : H00149461-M02 規格 : [ 100 ug ] List All Specification Application Image Product Mouse monoclonal antibody raised against a full-length recombinant Western Blot (Recombinant protein) Description: CLDN19. Sandwich ELISA (Recombinant Immunogen: CLDN19 (AAH30524, 1 a.a. ~ 211 a.a) full-length recombinant protein protein) with GST tag. MW of the GST tag alone is 26 KDa. Sequence: MANSGLQLLGYFLALGGWVGIIASTALPQWKQSSYAGDAIITAVGLYEGL WMSCASQSTGQVQCKLYDSLLALDGHIQSARALMVVAVLLGFVAMVLS VVGMKCTRVGDSNPIAKGRVAIAGGALFILAGLCTLTAVSWYATLVTQEF FNPSTPVNARYEFGPALFVGWASAGLAVLGGSFLCCTCPEPERPNSSP QPYRPGPSAAAREYV enlarge Host: Mouse ELISA Reactivity: Human Isotype: IgG2a Kappa Quality Control Antibody Reactive Against Recombinant Protein. Testing: Western Blot detection against Immunogen (48.95 KDa) . Storage Buffer: In 1x PBS, pH 7.4 Storage Store at -20°C or lower. Aliquot to avoid repeated freezing and thawing. Instruction: MSDS: Download Datasheet: Download Applications Western Blot (Recombinant protein) Protocol Download Sandwich ELISA (Recombinant protein) Page 1 of 2 2018/11/27 Detection limit for recombinant GST tagged CLDN19 is 0.1 ng/ml as a capture antibody. Protocol Download ELISA Gene Information Entrez GeneID: 149461 GeneBank BC030524 Accession#: Protein AAH30524 Accession#: Gene Name: CLDN19 Gene Alias: - Gene claudin 19 Description: Omim ID: 248190, 610036 Gene Ontology: Hyperlink Gene Summary: The product of this gene belongs to the claudin family. It plays a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity. Defects in this gene are the cause of hypomagnesemia renal with ocular involvement (HOMGO). HOMGO is a progressive renal disease characterized by primary renal magnesium wasting with hypomagnesemia, hypercalciuria and nephrocalcinosis associated with severe ocular abnormalities such as bilateral chorioretinal scars, macular colobomata, significant myopia and nystagmus.
    [Show full text]
  • Notate Human RPE-Specific Gene Expression
    UvA-DARE (Digital Academic Repository) Function and pathology of the human retinal pigment epithelium Booij, J.C. Publication date 2010 Link to publication Citation for published version (APA): Booij, J. C. (2010). Function and pathology of the human retinal pigment epithelium. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:25 Sep 2021 A new strategy to identify and an- notate human RPE-specific gene expression 3 Judith C Booij, Jacoline B ten Brink, Sigrid MA Swagemakers, Annemieke JMH Verkerk, Anke HW Essing, Peter J van der Spek, Arthur AB Bergen. PlosOne 2010, 5(3) e9341 Chapter 3 Abstract Background: The aim of the study was to identify and functionally annotate cell type-spe- cific gene expression in the human retinal pigment epithelium (RPE), a key tissue involved in age-related macular degeneration and retinitis pigmentosa.
    [Show full text]
  • In-Depth Bioinformatic Study of the CLDN16 Gene and Protein: Prediction of Subcellular Localization to Mitochondria
    medicina Article In-Depth Bioinformatic Study of the CLDN16 Gene and Protein: Prediction of Subcellular Localization to Mitochondria Erasmia Rouka 1,*, Vassilios Liakopoulos 2 , Konstantinos I. Gourgoulianis 3, Chrissi Hatzoglou 4 and Sotirios G. Zarogiannis 4 1 Department of Transfusion Medicine, University Hospital of Larissa, Biopolis, 41334 Larissa, Greece 2 Peritoneal Dialysis Unit, 1st Department of Medicine, Ahepa Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece 3 Department of Respiratory Medicine, Faculty of Medicine, University of Thessaly, Biopolis, 41334 Larissa, Greece 4 Department of Physiology, Faculty of Medicine, University of Thessaly, Biopolis, 41500 Larissa, Greece * Correspondence: [email protected]; Tel.: +30-6977-690-694 Received: 16 April 2019; Accepted: 22 July 2019; Published: 26 July 2019 Abstract: Background and Objectives: The defects in the CLDN16 gene are a cause of primary hypomagnesemia (FHHNC), which is characterized by massive renal magnesium wasting, resulting in nephrocalcinosis and renal failure. The mutations occur throughout the gene’s coding region and can impact on intracellular trafficking of the protein or its paracellular pore forming function. To gain more understanding about the mechanisms by which CLDN16 mutations can induce FHHNC, we performed an in-depth computational analysis of the CLDN16 gene and protein, focusing specifically on the prediction of the latter’s subcellular localization. Materials and Methods: The complete nucleotide or amino acid sequence of CLDN16 in FASTA format was entered and processed in 14 databases. Results: One CpG island was identified. Twenty five promoters/enhancers were predicted. The CLDN16 interactome was found to consist of 20 genes, mainly involved in kidney diseases. No signal peptide cleavage site was identified.
    [Show full text]
  • Gene Modules Associated with Human Diseases Revealed by Network
    bioRxiv preprint doi: https://doi.org/10.1101/598151; this version posted June 15, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Gene modules associated with human diseases revealed by network analysis Shisong Ma1,2*, Jiazhen Gong1†, Wanzhu Zuo1†, Haiying Geng1, Yu Zhang1, Meng Wang1, Ershang Han1, Jing Peng1, Yuzhou Wang1, Yifan Wang1, Yanyan Chen1 1. Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China 2. School of Data Science, University of Science and Technology of China, Hefei, Anhui 230027, China * To whom correspondence should be addressed. Email: [email protected] † These authors contribute equally. 1 bioRxiv preprint doi: https://doi.org/10.1101/598151; this version posted June 15, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. ABSTRACT Despite many genes associated with human diseases have been identified, disease mechanisms often remain elusive due to the lack of understanding how disease genes are connected functionally at pathways level. Within biological networks, disease genes likely map to modules whose identification facilitates etiology studies but remains challenging. We describe a systematic approach to identify disease-associated gene modules.
    [Show full text]
  • Disease-Associated Mutations of Claudin-19 Disrupt Retinal Neurogenesis and Visual Function
    ARTICLE https://doi.org/10.1038/s42003-019-0355-0 OPEN Disease-associated mutations of claudin-19 disrupt retinal neurogenesis and visual function Shao-Bin Wang1,2,4, Tao Xu1,2,3, Shaomin Peng3, Deepti Singh1,2,5, Maryam Ghiassi-Nejad1,2, Ron A. Adelman2 & Lawrence J. Rizzolo 1,2 1234567890():,; Mutations of claudin-19 cause Familial Hypomagnesaemia and Hypercalciuria, Nephrocalci- nosis with Ocular Involvement. To study the ocular disease without the complications of the kidney disease, naturally occurring point mutations of human CLDN19 were recreated in human induced pluripotent cells or overexpressed in the retinae of newborn mice. In human induced pluripotent cells, we show that the mutation affects retinal neurogenesis and maturation of retinal pigment epithelium (RPE). In mice, the mutations diminish the P1 wave of the electroretinogram, activate apoptosis in the outer nuclear layer, and alter the mor- phology of bipolar cells. If mice are given 9-cis-retinal to counter the loss of retinal isomerase, the P1 wave is partially restored. The ARPE19 cell line fails to express claudin-19. Exogenous expression of wild type, but not mutant claudin-19, increases the expression of RPE signature genes. Mutated claudin-19 affects multiple stages of RPE and retinal differentiation through its effects on multiple functions of the RPE. 1 Department of Surgery, Yale University, PO Box 208062, New Haven, CT, USA. 2 Department of Ophthalmology, Yale University, 40 Temple Street, New Haven, CT, USA. 3 Aier School of Ophthalmology, Central South University, 198 Furong Middle Ave Section 2, Tianxin District, Changsha, China. 4Present address: Center for Advanced Vision Science, Department of Ophthalmology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
    [Show full text]
  • Primepcr™Assay Validation Report
    PrimePCR™Assay Validation Report Gene Information Gene Name claudin 19 Gene Symbol Cldn19 Organism Mouse Gene Summary This gene encodes a member of the claudin family. Claudins are integral membrane proteins and components of tight junction strands. Tight junction strands serve as a physical barrier to prevent solutes and water from passing freely through the paracellular space between epithelial or endothelial cell sheets and also play critical roles in maintaining cell polarity and signal transductions. siRNA knockdown of this gene in mice develops the FHHNC (familial hypomagnesemia with hypercalciuria and nephrocalcinosis) symptoms of chronic renal wasting of magnesium and calcium together with defective renal salt handling. The protein encoded by this gene interacts with another family member Claudin 16 and their interaction is required for their assembly into tight junctions and for renal reabsorption of magnesium. This protein is a constituent of tight junctions in the Schwann cells of peripheral myelinated nerves and the gene deficiency affects the nerve conduction of peripheral myelinated fibers. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. Gene Aliases Not Available RefSeq Accession No. NC_000070.6, NT_039264.7 UniGene ID Mm.130701 Ensembl Gene ID ENSMUSG00000066058 Entrez Gene ID 242653 Assay Information Unique Assay ID qMmuCIP0035726 Assay Type Probe - Validation information is for the primer pair using SYBR® Green detection Detected Coding Transcript(s) ENSMUST00000084309,
    [Show full text]
  • Mouse Models of Human Claudin-Associated Disorders: Benefits and Limitations
    International Journal of Molecular Sciences Review Mouse Models of Human Claudin-Associated Disorders: Benefits and Limitations Murat Seker 1 , Cármen Fernández-Rodríguez 2, Luis Alfonso Martínez-Cruz 2 and Dominik Müller 1,* 1 Department of Pediatric Gastroenterology, Nephrology and Metabolism, Charité—Universitätsmedizin Berlin, Charité, 13353 Berlin, Germany; [email protected] 2 ClC BioGUNE, Bizkaia Science and Technology Park, 801A, 48160 Derio, Spain; [email protected] (C.F.-R.); [email protected] (L.A.M.-C.) * Correspondence: [email protected] Received: 15 October 2019; Accepted: 2 November 2019; Published: 5 November 2019 Abstract: In higher organisms, epithelia separate compartments in order to guarantee their proper function. Such structures are able to seal but also to allow substances to pass. Within the paracellular pathway, a supramolecular structure, the tight junction transport is largely controlled by the temporospatial regulation of its major protein family called claudins. Besides the fact that the expression of claudins has been identified in different forms of human diseases like cancer, clearly defined mutations in the corresponding claudin genes have been shown to cause distinct human disorders. Such disorders comprise the skin and its adjacent structures, liver, kidney, the inner ear, and the eye. From the phenotype analysis, it has also become clear that different claudins can cause a complex phenotype when expressed in different organs. To gain deeper insights into the physiology and pathophysiology of claudin-associated disorders, several mouse models have been generated. In order to model human disorders in detail, they have been designed either as full knockouts, knock-downs or knock-ins by a variety of techniques.
    [Show full text]