Associations of SLC6A20 Genetic Polymorphisms with Hirschsprung's

Total Page:16

File Type:pdf, Size:1020Kb

Associations of SLC6A20 Genetic Polymorphisms with Hirschsprung's Bioscience Reports (2019) 39 BSR20182290 https://doi.org/10.1042/BSR20182290 Research Article Associations of SLC6A20 genetic polymorphisms with Hirschsprung’s disease in a Southern Chinese population * * Xiaoli Xie , Qiuming He , Lihua Huang, Le Li, Yuxiao Yao, Huimin Xia, Jinglu Zhao, Wei Zhong and Downloaded from http://portlandpress.com/bioscirep/article-pdf/39/8/BSR20182290/863686/bsr-2018-2290.pdf by guest on 29 September 2021 Yan Zhang Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China Correspondence: Wei Zhong ([email protected]) or Yan Zhang ([email protected]) Hirschsprung’s disease (HSCR) is a neurodevelopmental disorder characterized by the ab- sence of nerves in intestine with strong genetic components. SLC6A20 was found to be associated with HSCR in Korean population waiting for replication in an independent co- hort. In the present study, ten single nucleotide polymorphisms (SNPs) in the SLC6A20 were selected from Southern Chinese with 1470 HSCR cases and 1473 ethnically matched healthy controls. Our results indicated that SNP rs7640009 was associated with HSCR and SLC6A20 has a gene–dose effect in the extent of the aganglionic segment during enteric nervous system (ENS) development. It is the first time to reveal the relationship between SNP rs2191026 and HSCR-associated enterocolitis (HAEC) susceptibility. Introduction Hirschsprung’s disease (HSCR) is a congenital disease characterized by the absence of intrinsic ganglion cells in the submucosal and myenteric plexuses of the intestinal tract involving a variable portion. It is common that HSCR leads to the mechanical intestinal obstruction in infants and children. At present, surgery is a unique way to cure HSCR in spite of its fraught complications such as constipation, diarrhea, incontinenceandsoon.Ifleftuntreated,HSCRcanleadtodeath.SimilartoWesternEurope[1]andNorth America [2], the incidence in Asians is approximately 1 in 5000 neonates [3,4]. HSCR was classified by the length of intestine lacking nerve cells, known as short-segment HSCR (SHSCR) when the aganglionic segment does not extend beyond the upper sigmoid, long-segment HSCR (LHSCR) when the agangliono- sis extends proximally to the sigmoid, or total colonic aganglionosis (TCA) when the aganglionosis ex- tends throughout the entire colon [5]. To the most extreme, total intestinal aganglionosis (TIA), whose aganglionosis extends to almost total intestines in sporadic rare cases, can be deadly [6]. While all cases present a functional intestinal obstruction, but the mode of presentations often differs. The diagnosis of HSCR is mostly made in the newborn period, only a few patients’ diagnoses are delayed into infancy *These authors contributed stage or adulthood. The typical clinical features are as follows: delayed passage of meconium (24 h after equally to this work. birth), constipation in the neonatal period, abdominal distension and vomiting during the first few days Received: 07 December 2018 of life and neonatal enterocolitis. Persistent constipation, chronic abdominal distension, loss of appetite Revised: 06 May 2019 and failure to thrive are common symptoms in older children [5]. Timely surgical treatment to remove Accepted: 24 July 2019 the affected bowel segment can save most patients’ lives, but obvious postoperative complications, such as fecal incontinence, constipation, repeated enterocolitis, nutrition disorder and so on [7], could bring Accepted Manuscript Online: 29 July 2019 the patients and their families severe economic burden and great psychological pressure [8], which might Version of Record published: affect their quality of life in adulthood [9,10]. Even more, severe complications like HSCR-related short 13 August 2019 bowel syndrome could also kill the patients after surgery [11]. © 2019 The Author(s). This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution 1 License 4.0 (CC BY). Bioscience Reports (2019) 39 BSR20182290 https://doi.org/10.1042/BSR20182290 It is widely believed that genetic factors playing an important role though the etiology of HSCR is still unknown. In the past decades, several genes have been identified to be associated with HSCR, including RET [12], EDNRB [13], GDNF [14] and SOX10 [15], which however failed to explain the disease cause of large sporadic cases. In 2014, SLC6A20 on chromosome 3p21.3 was suggested as associated with HSCR using 124 patients and 450 controls [16]. These single nucleotide polymorphisms (SNPs) were subsequently replicated, and 13 SNPs were significantly asso- ciated with HSCR using 187 patients and 283 unaffected controls [17]. The haplotype analysis also indicated their significant associations with HSCR susceptibility. Limited by the sample size and incomplete clinical records in pre- vious studies, the functional mechanisms of the variants related to the identified HSCR were not clarified. In addition, it is still necessary to further validate the associations between these SNPs derived from one single causal variant or the congregation of multiple variants that is still awaited for further validation in independent cohorts. In order to further investigate the association between SLC6A20 and HSCR susceptibility, a case–control study was conducted to verify the effects of selected SNPs from an independent South Chinese population with 1470 cases and Downloaded from http://portlandpress.com/bioscirep/article-pdf/39/8/BSR20182290/863686/bsr-2018-2290.pdf by guest on 29 September 2021 1473 controls. We failed to further verify the association between nine previously confirmed SNPs and HSCR except SNP rs7640009. However, six of the other SNPs were found to contribute to the risk of severe subtypes of HSCR in the following detailed analysis stratified by clinical subphenotypes. Furthermore, the relationships between selected SNPs and HSCR-associated enterocolitis (HAEC) susceptibility were also examined. Materials and methods Study population From 2005 to 2015, 1470 HSCR patients from Guangzhou Women and Children’ Medical Center were selected in our study, including 1034 SHSCR, 295 LHSCR, 82 TCA and 3 TIA patients. Inclusion: (1.) sporadic HSCR with histological examination of biopsy specimens with the absence of the enteric ganglia; (2.) age <18 years; (3.) claimed as south Chinese. Exclusion: diagnosis of familial HSCR or syndromic HSCR. The blood samples of 1473 individuals matched geographically and ethnically with no history of HSCR or neurologically associated disorders were collected as controls. Written informed consent was obtained from all the subjects and the legal guardians of every child. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Ethics Committee on Human Research of the Faculty of Guangzhou Women and Children’ Medical Center. SNP genotyping and quality control Nine SNPs (rs2191027, rs6770261, rs2191026, rs10461016, rs4299518, rs764177, rs2108917, rs17279465 and rs78962450 ) of SLC6A20 involved in the present study were selected from to the replication study with 187 Ko- rean HSCR cases [17]. Rs4299518 in SLC6A20 was chosen from the GWAS of HSCR by Kim et al. [16]. Ten SNPs in SLC6A20 weregenotypedbyMassARRAYiPLEXGoldsystem(Sequenom)onallthesamples.Theassociatedstudies searched by NCBI based on the criteria as follows: (1.) SNP with high probability to be regulatory variants were kept for further pursuing (Regulome DB score higher than 2. http://regulomedb.org/). (2.) Removed one of the two SNPs with Linkage disequilibrium (LD) (r2) larger than 0.8 were kept one. (3.) SNP with minor allele frequency larger than 5% in the Chinese population (Han Chinese in Beijing (CHB)) was kept (https://www.ncbi.nlm.nih.gov/snp/?term=). We carried out quality control of the ten SNPs using the following two criteria: (1.) SNPs with >10% missing data were removed (one SNP). (2.)Three SNPs were removed according to the genotyping allele intensity plots for clus- tering quality and violation of Hardy–Weinberg equilibrium (HWE). SNPs were removed if HWE, P<1.0E-04, was calculated by control subjects. After quality control, all ten SNPs were kept for further analysis consisted of 1470 cases and 1473 controls). Association analysis and subphenotype analysis TheSNPswereanalyzedforassociationswiththediseaseusingacomparisonoftheminorallelefrequencyinpatients and controls (basic allelic test) as well as other tests using PLINK1.9 (genotype test of 3 × 2contingencytables, Cochran–Armitage trend test, a test of dominant and recessive models). Association of the SNPs with disease risk was also corrected by logistic regression using age and sex as covariates and the associations found in the present study remain significant. Association with subphenotype was analyzed by comparing cases with a certain subphenotype with controls, cases without the subphenotype with controls. Independence testing LD patterns and values were obtained using HaploView. SNPTEST v2.5b was used to perform the logistic regression tests in the present study. Tests of independent contributions toward disease associations for SNPs in a single locus 2 © 2019 The Author(s). This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY). Bioscience Reports (2019)
Recommended publications
  • 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]
  • Frontiersin.Org 1 April 2015 | Volume 9 | Article 123 Saunders Et Al
    ORIGINAL RESEARCH published: 28 April 2015 doi: 10.3389/fnins.2015.00123 Influx mechanisms in the embryonic and adult rat choroid plexus: a transcriptome study Norman R. Saunders 1*, Katarzyna M. Dziegielewska 1, Kjeld Møllgård 2, Mark D. Habgood 1, Matthew J. Wakefield 3, Helen Lindsay 4, Nathalie Stratzielle 5, Jean-Francois Ghersi-Egea 5 and Shane A. Liddelow 1, 6 1 Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, VIC, Australia, 2 Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark, 3 Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia, 4 Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland, 5 Lyon Neuroscience Research Center, INSERM U1028, Centre National de la Recherche Scientifique UMR5292, Université Lyon 1, Lyon, France, 6 Department of Neurobiology, Stanford University, Stanford, CA, USA The transcriptome of embryonic and adult rat lateral ventricular choroid plexus, using a combination of RNA-Sequencing and microarray data, was analyzed by functional groups of influx transporters, particularly solute carrier (SLC) transporters. RNA-Seq Edited by: Joana A. Palha, was performed at embryonic day (E) 15 and adult with additional data obtained at University of Minho, Portugal intermediate ages from microarray analysis. The largest represented functional group Reviewed by: in the embryo was amino acid transporters (twelve) with expression levels 2–98 times Fernanda Marques, University of Minho, Portugal greater than in the adult. In contrast, in the adult only six amino acid transporters Hanspeter Herzel, were up-regulated compared to the embryo and at more modest enrichment levels Humboldt University, Germany (<5-fold enrichment above E15).
    [Show full text]
  • Epigenetic Mechanisms Are Involved in the Oncogenic Properties of ZNF518B in Colorectal Cancer
    Epigenetic mechanisms are involved in the oncogenic properties of ZNF518B in colorectal cancer Francisco Gimeno-Valiente, Ángela L. Riffo-Campos, Luis Torres, Noelia Tarazona, Valentina Gambardella, Andrés Cervantes, Gerardo López-Rodas, Luis Franco and Josefa Castillo SUPPLEMENTARY METHODS 1. Selection of genomic sequences for ChIP analysis To select the sequences for ChIP analysis in the five putative target genes, namely, PADI3, ZDHHC2, RGS4, EFNA5 and KAT2B, the genomic region corresponding to the gene was downloaded from Ensembl. Then, zoom was applied to see in detail the promoter, enhancers and regulatory sequences. The details for HCT116 cells were then recovered and the target sequences for factor binding examined. Obviously, there are not data for ZNF518B, but special attention was paid to the target sequences of other zinc-finger containing factors. Finally, the regions that may putatively bind ZNF518B were selected and primers defining amplicons spanning such sequences were searched out. Supplementary Figure S3 gives the location of the amplicons used in each gene. 2. Obtaining the raw data and generating the BAM files for in silico analysis of the effects of EHMT2 and EZH2 silencing The data of siEZH2 (SRR6384524), siG9a (SRR6384526) and siNon-target (SRR6384521) in HCT116 cell line, were downloaded from SRA (Bioproject PRJNA422822, https://www.ncbi. nlm.nih.gov/bioproject/), using SRA-tolkit (https://ncbi.github.io/sra-tools/). All data correspond to RNAseq single end. doBasics = TRUE doAll = FALSE $ fastq-dump -I --split-files SRR6384524 Data quality was checked using the software fastqc (https://www.bioinformatics.babraham. ac.uk /projects/fastqc/). The first low quality removing nucleotides were removed using FASTX- Toolkit (http://hannonlab.cshl.edu/fastxtoolkit/).
    [Show full text]
  • Role and Characteristics of Selected Amino Acid and Peptide Transporters in Epithelial Cells
    TECHNISCHE UNIVERSITÄT MÜNCHEN Lehrstuhl für Ernährungsphysiologie Role and characteristics of selected amino acid and peptide transporters in epithelial cells Alexander Georg Nickel Vollständiger Abdruck der von der Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigten Dissertation. Vorsitzender: Univ.-Prof. Dr. M. Schemann Prüfer der Dissertation: 1. Univ.-Prof. Dr. H. Daniel 2. Univ.-Prof. Dr. Th. F. Hofmann Die Dissertation wurde am 12.05.2009 bei der Technischen Universität München eingereicht und durch die Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt am 01.09.2009 angenommen. A 2 Zum Erfolg braucht der Forscher die vier großen "G": Geist, Geduld, Geld und Glück. Paul Ehrlich 3 Table of contents 1 Characteristics of L-proline transport in OK cells................................................................ 10 1.1 Introduction ............................................................................................................. 10 1.1.1 Physiological importance of amino acids..................................................... 10 1.1.2 Basic principles of amino acid transport...................................................... 10 1.1.3 Amino acid transport in kidney .................................................................... 11 1.1.3.1 Apical amino acid transporters of the kidney proximal tubule ..................... 12 1.1.3.2
    [Show full text]
  • RNA-Seq Reveals Altered Gene Expression Levels in Proximal
    www.nature.com/scientificreports OPEN RNA‑seq reveals altered gene expression levels in proximal tubular cell cultures compared to renal cortex but not during early glucotoxicity Linnéa M. Nilsson1, Miguel Castresana‑Aguirre 2, Lena Scott3 & Hjalmar Brismar 1,3* Cell cultures are often used to study physiological processes in health and disease. It is well‑known that cells change their gene expression in vitro compared to in vivo, but it is rarely experimentally addressed. High glucose is a known trigger of apoptosis in proximal tubular cells (PTC). Here we used RNA-seq to detect diferentially expressed genes in cultures of primary rat PTC, 3 days old, compared to cells retrieved directly from rat outer renal cortex and between PTC exposed to 15 mM glucose and control for 8 h. The expression of 6,174 genes was signifcantly up- or downregulated in the cultures of PTC compared to the cells in the outer renal cortex. Most altered were mitochondrial and metabolism related genes. Gene expression of proapoptotic proteins were upregulated and gene expression of antiapoptotic proteins were downregulated in PTC. Expression of transporter related genes were generally downregulated. After 8 h, high glucose had not altered the gene expression in PTC. The current study provides evidence that cells alter their gene expression in vitro compared to in vivo and suggests that short‑term high glucose exposure can trigger apoptosis in PTC without changing the gene expression levels of apoptotic proteins. Cell cultures, both primary and immortalized, are ofen used as models in biological research to investigate physi- ological processes in health and disease.
    [Show full text]
  • Downregulation of Carnitine Acyl-Carnitine Translocase by Mirnas
    Page 1 of 288 Diabetes 1 Downregulation of Carnitine acyl-carnitine translocase by miRNAs 132 and 212 amplifies glucose-stimulated insulin secretion Mufaddal S. Soni1, Mary E. Rabaglia1, Sushant Bhatnagar1, Jin Shang2, Olga Ilkayeva3, Randall Mynatt4, Yun-Ping Zhou2, Eric E. Schadt6, Nancy A.Thornberry2, Deborah M. Muoio5, Mark P. Keller1 and Alan D. Attie1 From the 1Department of Biochemistry, University of Wisconsin, Madison, Wisconsin; 2Department of Metabolic Disorders-Diabetes, Merck Research Laboratories, Rahway, New Jersey; 3Sarah W. Stedman Nutrition and Metabolism Center, Duke Institute of Molecular Physiology, 5Departments of Medicine and Pharmacology and Cancer Biology, Durham, North Carolina. 4Pennington Biomedical Research Center, Louisiana State University system, Baton Rouge, Louisiana; 6Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York. Corresponding author Alan D. Attie, 543A Biochemistry Addition, 433 Babcock Drive, Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, (608) 262-1372 (Ph), (608) 263-9608 (fax), [email protected]. Running Title: Fatty acyl-carnitines enhance insulin secretion Abstract word count: 163 Main text Word count: 3960 Number of tables: 0 Number of figures: 5 Diabetes Publish Ahead of Print, published online June 26, 2014 Diabetes Page 2 of 288 2 ABSTRACT We previously demonstrated that micro-RNAs 132 and 212 are differentially upregulated in response to obesity in two mouse strains that differ in their susceptibility to obesity-induced diabetes. Here we show the overexpression of micro-RNAs 132 and 212 enhances insulin secretion (IS) in response to glucose and other secretagogues including non-fuel stimuli. We determined that carnitine acyl-carnitine translocase (CACT, Slc25a20) is a direct target of these miRNAs.
    [Show full text]
  • Integrative Approach Identifies SLC6A20 and CXCR6 As Putative Causal Genes for the COVID-19 GWAS Signal in the 3P21.31 Locus
    medRxiv preprint doi: https://doi.org/10.1101/2021.04.09.21255184; this version posted April 13, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Integrative approach identifies SLC6A20 and CXCR6 as putative causal genes for the COVID-19 GWAS signal in the 3p21.31 locus Silva Kasela1,2,*, Zharko Daniloski1,3, Tristan X. Jordan4, Benjamin R. tenOever4, Neville E. Sanjana1,3, Tuuli Lappalainen1,3,* 1 - New York Genome Center, New York, NY, USA 2 - Department of Systems Biology, Columbia University, New York, NY, USA 3 - Department of Biology, New York University, New York, NY, USA 4 - Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA *Correspondence to: [email protected] (S.K.), [email protected] (T.L.) ABstract To date the locus with the most robust human genetic association to COVID-19 susceptibility is 3p21.31. Here, we integrate genome-scale CRISPR loss-of-function screens and eQTLs in diverse cell types and tissues to pinpoint genes underlying COVID-19 risk. Our findings identify SLC6A20 and CXCR6 as putative causal genes that mediate COVID-19 risk and highlight the usefulness of this integrative approach to bridge the divide between correlational and causal studies of human biology. Keywords: COVID-19, SARS-CoV-2, GWAS, eQTL, CRISPR 1 NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
    [Show full text]
  • Comprehensive in Vitro Characterization of the Mechanism of Action of EPI-7386, an Androgen Receptor N-Terminal Domain Inhibitor
    #1209 Comprehensive in vitro characterization of the mechanism of action of EPI-7386, an androgen receptor N-terminal domain inhibitor Nan Hyung Hong1, Shihua Sun2, Peter Virsik1, Alessandra Cesano1, Han-Jie Zhou1, Elahe A. Mostaghel3,4,5, Stephen R. Plymate2,4, Ronan Le Moigne1 1 ESSA Pharma Corp, South San Francisco , CA 2 University of Washington, Division of Gerontology and Geriatric Medicine, Seattle, WA 3 Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA 4 VA Puget Sound Health Care System, Seattle, WA 5 University of Washington, Medical Oncology Division, Seattle, WA Contact: [email protected] Presented at AACR Annual Meeting 2021 Background v As a key driver of prostate cancer, androgen receptor (AR) signaling has been a major target of prostate cancer therapy v All current anti-androgens function through the ligand-binding aniten domain (LBD) of the AR v Anti-androgen resistance mechanisms generally develop at the LBD, due to mutations in the LBD itself and the expression of constitutively active splice variants of AR that lack the LBD v Anitens are small molecules capable of targeting the AR N- terminal domain that can inhibit transcriptional activity of the AR even in the presence of LBD-driven anti-androgen resistance Figure 1. Anitens are first-in-class NTD inhibitors of the androgen receptor. Structure of the androgen receptor (AR) and mechanism of inhibition. The AR comprises three main functional domains: the LBD, involved v EPI-7386 is a new generation of aniten which exhibits high in binding with androgens, the DBD, and the NTD, which orchestrate the potency, low metabolism, on-target specificity transactivation of the receptor.
    [Show full text]
  • Pflügers Archiv : European Journal of Physiology, 466(1):25-42
    Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2014 The SLC6 transporters: perspectives on structure, functions, regulation, and models for transporter dysfunction Rudnick, Gary ; Krämer, Reinhard ; Blakely, Randy D ; Murphy, Dennis L ; Verrey, Francois Abstract: The human SLC6 family is composed of approximately 20 structurally related symporters (co- transporters) that use the transmembrane electrochemical gradient to actively import their substrates into cells. Approximately half of the substrates of these transporters are amino acids, with others transporting biogenic amines and/or closely related compounds, such as nutrients and compatible osmolytes. In this short review, five leaders in the field discuss a number of currently important research themesthat involve SLC6 transporters, highlighting the integrative role they play across a wide spectrum of different functions. The first essay, by Gary Rudnick, describes the molecular mechanism of their coupled transport which is being progressively better understood based on new crystal structures, functional studies, and modeling. Next, the question of multiple levels of transporter regulation is discussed by Reinhard Krämer, in the context of osmoregulation and stress response by the related bacterial betaine transporter BetP. The role of selected members of the human SLC6 family that function as nutrient amino acid transporters is then reviewed by François Verrey. He discusses how some of these transporters mediate the active uptake of (essential) amino acids into epithelial cells of the gut and the kidney tubule to support systemic amino acid requirements, whereas others are expressed in specific cells to support their specialized metabolism and/or growth.
    [Show full text]
  • Wo 2008/156655 A9
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) CORRECTED VERSION (19) World Intellectual Property Organization International Bureau (43) International Publication Date (10) International Publication Number 24 December 2008 (24.12.2008) PCT WO 2008/156655 A9 (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07K 14/00 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, (21) International Application Number: CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, PCT/US2008/007377 EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, (22) International Filing Date: 13 June 2008 (13.06.2008) LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, (25) Filing Language: English PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, (26) Publication Language: English ZA, ZM, ZW (30) Priority Data: (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, 60/934,768 15 June 2007 (15.06.2007) US GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), (71) Applicants (for all designated States except US): European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, GENELUX CORPORATION [US/US]; 3030 Bunker FR, GB, GR, HR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, Hill Street, Suite 310, San Diego, CA 92109 (US).
    [Show full text]
  • Comparative Gene Expression Analysis Reveals a Characteristic Molecular Profile of the Superior Olivary Complex
    tapraid5/z3x-anrec/z3x-anrec/z3x00406/z3x1168d06g royerl Sϭ7 3/1/06 4:24 Art: 05-0227 THE ANATOMICAL RECORD PART A 00A:000–000 (2006) Comparative Gene Expression Analysis Reveals a Characteristic Molecular Profile of the Superior Olivary Complex HANS GERD NOTHWANG,* ALEXANDER KOEHL, AND ECKHARD FRIAUF Abteilung Tierphysiologie, Technische Universita¨t Kaiserslautern, Kaiserslautern, Germany ABSTRACT The superior olivary complex (SOC) is a very conspicuous structure in the mammalian auditory brainstem. It represents the first binaural processing center and is important for sound localization in the azimuth and in feedback regulation of cochlear function. In order to define molecular determinants of the SOC, which are of potential functional relevance, we have performed a comprehensive analysis of its transcriptome by serial analysis of gene expression in adult rats. Here, we performed a detailed analysis of the SOC’s gene expression profile compared to that of two other neural tissues, the striatum and the hippocampus, and with extraocular muscle tissue. This tested the hypothesis that SOC-specific or significantly upregulated transcripts provide candidates for the specific function of auditory neurons. Thirty-three genes were significantly upregulated in the SOC when compared to the two other neural tissues. Thirteen encoded proteins involved in neurotransmission, including action potential propagation, exocytosis, and myelination; five genes are important for the energy metabolism; and five transcripts are unknown or poorly characterized and have yet to be described in the nervous system. The comparison of functional gene classes indicates that the SOC has the highest energy demand of the three neural tissues, yet protein turnover is apparently not increased.
    [Show full text]
  • Iminoglycinuria and Hyperglycinuria Are Discrete Human Phenotypes Resulting from Complex Mutations in Proline and Glycine Transporters
    Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters Stefan Bröer, … , Angelika Bröer, John E.J. Rasko J Clin Invest. 2008;118(12):3881-3892. https://doi.org/10.1172/JCI36625. Research Article Genetics Iminoglycinuria (IG) is an autosomal recessive abnormality of renal transport of glycine and the imino acids proline and hydroxyproline, but the specific genetic defect(s) have not been determined. Similarly, although the related disorder hyperglycinuria (HG) without iminoaciduria has been attributed to heterozygosity of a putative defective glycine, proline, and hydroxyproline transporter, confirming the underlying genetic defect(s) has been difficult. Here we applied a candidate gene sequencing approach in 7 families first identified through newborn IG screening programs. Both inheritance and functional studies identified the gene encoding the proton amino acid transporter SLC36A2 (PAT2) as the major gene responsible for IG in these families, and its inheritance was consistent with a classical semidominant pattern in which 2 inherited nonfunctional alleles conferred the IG phenotype, while 1 nonfunctional allele was sufficient to confer the HG phenotype. Mutations in SLC36A2 that retained residual transport activity resulted in the IG phenotype when combined with mutations in the gene encoding the imino acid transporter SLC6A20 (IMINO). Additional mutations were identified in the genes encoding the putative glycine transporter SLC6A18 (XT2) and the neutral amino acid transporter SLC6A19 (B0AT1) in families with either IG or HG, suggesting that mutations in the genes encoding these transporters may also contribute to these phenotypes. In summary, although recognized as apparently simple Mendelian disorders, IG and HG exhibit complex molecular […] Find the latest version: https://jci.me/36625/pdf Research article Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters Stefan Bröer,1 Charles G.
    [Show full text]