DOCSLIB.ORG

Not All Proteinuria Is Created Equal

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Not All Proteinuria Is Created Equal Not all proteinuria is created equal Andrew Beenken, … , Jonathan M. Barasch, Ali G. Gharavi J Clin Invest. 2020;130(1):74-76. https://doi.org/10.1172/JCI133250. Commentary Albuminuria acts as a marker of progressive chronic kidney disease and as an indicator for initiation of hypertension treatment via modulation of the renin-angiotensin-aldosterone system with angiotensin receptor blockers or angiotensin- converting enzyme inhibitors. However, the true significance of albuminuria has yet to be fully defined. Is it merely a marker of underlying pathophysiology, or does it play a causal role in the progression of kidney disease? The answer remains under debate. In this issue of the JCI, Bedin et al. used next-generation sequencing data to identify patients with chronic proteinuria who had biallelic variants in the cubilin gene (CUBN). Through investigation of these pathogenic mutations in CUBN, the authors have further illuminated the clinical implications of albuminuria. Find the latest version: https://jci.me/133250/pdf COMMENTARY The Journal of Clinical Investigation Not all proteinuria is created equal Andrew Beenken, Jonathan M. Barasch, and Ali G. Gharavi Division of Nephrology, Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA. recent low-resolution electron micros- copy data suggest that these C-terminal Albuminuria acts as a marker of progressive chronic kidney disease and as domains should cluster at the distal end of an indicator for initiation of hypertension treatment via modulation of the a 700-Å-long tree-like structure (7) where renin-angiotensin-aldosterone system with angiotensin receptor blockers or they are readily exposed to the urinary angiotensin-converting enzyme inhibitors. However, the true significance of filtrate and available to bind proteins. In albuminuria has yet to be fully defined. Is it merely a marker of underlying addition to albumin, it is possible that these pathophysiology, or does it play a causal role in the progression of kidney domains could bind other ligands of similar disease? The answer remains under debate. In this issue of the JCI, Bedin et size and isoelectric point (pI) such as vita- al. used next-generation sequencing data to identify patients with chronic min D–binding protein (DBP), which has a proteinuria who had biallelic variants in the cubilin gene (CUBN). Through close evolutionary relationship to albumin. investigation of these pathogenic mutations in CUBN, the authors have Varying proteinuric phenotypes have further illuminated the clinical implications of albuminuria. been reported in the literature, depending on which domains of cubilin are affected. Previously, a p.P1297L point mutation with- in the VitB12-IF binding site was observed Biallelic mutations related to (n = 2216 patients) of patients with chronic to lead to anemia without proteinuria. proteinuria proteinuria ranging from 0.5 to 2.5 g/d and Additionally, numerous variants causing The kidneys filter approximately 180 identified 39 patients who had biallelic global cubilin dysfunction have been docu- liters of plasma daily to balance the excre- variants in the CUBN gene. Interestingly, mented to cause IGS with both anemia and tion of water, acid, nitrogen, sodium, and the CUBN variants resulted in isolated pro- proteinuria that is inclusive of albumin as potassium with varying environmental teinuria without the megaloblastic anemia well as other cubilin ligands such as apoA-1, conditions. Larger proteins are retained typical of IGS, suggesting that there are transferrin, and DBP (8). Now, the study by in the plasma because of filtration bar- separate binding sites in cubilin for vita- Bedin et al. extends the known proteinuric riers in the glomeruli, but the kidney min B12–intrinsic factor (VitB12-IF) and phenotypes resulting from CUBN variants tubules must still capture up to 2.5 g/d of albumin. Cubilin is an enormous protein, to include isolated albumin-predominant low-molecular-weight (LMW) proteins a 460-kDa peripheral membrane glyco- proteinuria resulting from C-terminal that escape the glomerular barriers (1). protein with 27 putative ligand-binding mutations (4). Certainly, further analysis of Cubilin and megalin are located in the CUB domains (complement components urinary proteins from patients with CUBN apical membrane of the proximal tubule C1r/C1s, UEGF, and bone morphogenic variants is bound to delineate still more and are responsible for receptor-medi- protein-1) (5). Although biochemical and phenotypes of proteinuria. ated endocytosis of the filtered proteins structural methods have determined that The authors noted two interesting that leak through the glomerular barri- the binding site for VitB12-IF is CUB6–8 features of the patients in the studied ers. Biallelic mutations in megalin (LRP2) (6), the manner in which cubilin binds to cohorts: (a) despite experiencing chronic lead to Donnai-Barrow syndrome (DBS), other proteins including albumin is still proteinuria, these patients retained nor- characterized by LMW proteinuria and being investigated. mal estimated glomerular filtration rates abnormal neurological development (2), The patient cohorts in Bedin et al. (eGFRs), a standard assessment of renal whereas biallelic cubilin (CUBN) muta- offered an opportunity to genetically dis- function, which is consistent with prior tions can lead to another recessive disease, sect cubilin-albumin binding, and the studies reporting normal renal function in Imerslund-Gräsbeck syndrome (IGS), authors made the novel proposal that patients with IGS, and (b) the proteinuria which is characterized by LMW protein- CUB13 or CUB26 are potential albumin- they exhibited was albumin predominant, uria and megaloblastic anemia (3). binding domains due to their proximity with, on average, more than 60% of the In this issue of the JCI, Bedin et al. to Ca2+-coordinating motifs (4). CUB13 total proteinuria consisting of albumin (4). (4) analyzed next-generation sequenc- and CUB26 have not yet been structurally ing data from three different cohorts characterized at high resolution, although The impact of albuminuria on renal function Albuminuria is a predictor of negative clin- Related Article: p. 335 ical outcomes including the progression of renal disease, but the degree to which Conflict of interest: The authors have declared that no conflict of interest exists. Copyright: © 2020, American Society for Clinical Investigation. albuminuria can be used independently as Reference information: J Clin Invest. 2020;130(1):74–76. https://doi.org/10.1172/JCI133250. a surrogate therapeutic target is a matter of 74 jci.org Volume 130 Number 1 January 2020 The Journal of Clinical Investigation COMMENTARY ongoing discussion (9–12). Furthermore, er than 80 mL/min. Although the authors clinical practice that is essential for avoid- whether albuminuria causes progres- could not document an extended longi- ing unnecessary therapeutic or diagnostic sive chronic kidney disease (CKD) also tudinal follow-up of renal function mea- interventions. For instance, seven of the remains unknown. Causality has been sug- surements in their patients, their obser- patients in the Bedin et al. cohorts were gested by reductions in albuminuria asso- vation of normal or near-normal eGFRs in treated with ACEI/ARB therapy with- ciated with reduced CKD progression to patients with decades of exposure to albu- out benefit, and others underwent renal end-stage renal disease (ESRD) in several minuria is nonetheless intriguing. To fur- biopsies that were nondiagnostic (4). The different clinical trials that evaluated the ther investigate their findings, the authors importance of genetic screening to help treatment of CKD patients with angioten- conducted a meta-analysis of cohorts from exclude unnecessary therapy is even more sin-converting enzyme inhibitors (ACEIs) the CKDGen Consortium using CUBN pointed in situations in which steroid treat- or angiotensin receptor blockers (ARBs) variants previously associated with albu- ment is being considered, such as in cases (13–16). Notably, the Renoprotection of minuria in GWAS studies (24). Through of focal sclerosing glomerulosclerosis (or Optimal Antiproteinuric Doses (ROAD) this cross-sectional population-based in presumed cases of minimal change dis- trial showed a reduction in CKD progres- approach and using an additive model to ease in children. sion in nondiabetic proteinuric patients test for associations, the authors found an Ultimately, more longitudinal data will when renin-angiotensin-aldosterone sys- association of four different CUBN vari- be required to definitively establish that tem (RAAS) blockade was titrated to albu- ants with both albuminuria and a small but long-term, isolated albumin-predominant minuria targets (17), but the significance statistically significant increase in eGFR. proteinuria is truly benign. The diversity of those results has been disputed (10). Thus, in these patients with CUBN loss of proteinuria phenotypes that can occur So far, a reduction in albuminuria beyond of function and isolated chronic protein- in human disease and their subsequent, that achieved by ACEI/ARB monotherapy uria, the consequence of long-term albu- variable clinical consequences still remain has yet to show an effect on hard outcomes min exposure to the kidney tubules may to be fully appreciated. For instance, Bedin (18–22), raising the possibility that RAAS be benign. The authors reanalyzed their et al. draw a distinction between
Load more

Recommended publications
  • CLCN5 Gene Chloride Voltage-Gated Channel 5
    CLCN5 gene chloride voltage-gated channel 5 Normal Function The CLCN5 gene provides instructions for making a protein called ClC-5 that transports charged atoms (ions) across cell membranes. Specifically, ClC-5 exchanges negatively charged atoms of chlorine (chloride ions) for positively charged atoms of hydrogen ( protons or hydrogen ions). Based on this function, ClC-5 is known as a H+/Cl- exchanger. ClC-5 is found primarily in the kidneys, particularly in structures called proximal tubules. These structures help to reabsorb nutrients, water, and other materials that have been filtered from the bloodstream. The kidneys reabsorb needed materials into the blood and excrete everything else into the urine. Within proximal tubule cells, ClC-5 is embedded in specialized compartments called endosomes. Endosomes are formed at the cell surface to carry proteins and other molecules to their destinations within the cell. ClC-5 transports hydrogen ions into endosomes and chloride ions out, which helps these compartments maintain the proper acidity level (pH). Endosomal pH levels must be tightly regulated for proximal tubule cells to function properly. Health Conditions Related to Genetic Changes Dent disease About 150 mutations in the CLCN5 gene have been found to cause Dent disease 1, a chronic kidney disorder that can cause kidney failure. Most of the mutations lead to the production of an abnormally short, nonfunctional version of ClC-5 or prevent cells from producing any of this protein. A loss of ClC-5 alters the regulation of endosomal pH, which disrupts the overall function of proximal tubule cells and prevents them from reabsorbing proteins and other materials into the bloodstream.
    [Show full text]
  • Exome Sequencing Reveals Cubilin Mutation As a Single-Gene Cause of Proteinuria
    BRIEF COMMUNICATION www.jasn.org Exome Sequencing Reveals Cubilin Mutation as a Single-Gene Cause of Proteinuria Bugsu Ovunc,*† Edgar A. Otto,* Virginia Vega-Warner,* Pawaree Saisawat,* Shazia Ashraf,* Gokul Ramaswami,* Hanan M. Fathy,‡ Dominik Schoeb,* Gil Chernin,* Robert H. Lyons,§ ʈ Engin Yilmaz,† and Friedhelm Hildebrandt* ¶ ʈ Departments of *Pediatrics and Human Genetics, §Department of Biological Chemistry and DNA Sequencing Core, and ¶Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan; †Department of Medical Biology, Hacettepe University, Ankara, Turkey; and ‡The Pediatric Nephrology Unit, Alexandria University, Alexandria, Egypt ABSTRACT In two siblings of consanguineous parents with intermittent nephrotic-range pro- tion is still unknown.7 This forbids the use of teinuria, we identified a homozygous deleterious frameshift mutation in the gene cohort studies for gene identification and ne- CUBN, which encodes cubulin, using exome capture and massively parallel re- cessitates the ability to identify disease-caus- sequencing. The mutation segregated with affected members of this family and ing genes in single families. We therefore was absent from 92 healthy individuals, thereby identifying a recessive mutation in combined whole genome homozygosity CUBN as the single-gene cause of proteinuria in this sibship. Cubulin mutations mapping with consecutive whole human ex- cause a hereditary form of megaloblastic anemia secondary to vitamin B12 defi- ome capture (WHEC) and massively par- ciency, and proteinuria occurs in 50% of cases since cubilin is coreceptor for both allel re-sequencing to overcome this lim- 6 the intestinal vitamin B12-intrinsic factor complex and the tubular reabsorption of itation. In this way we here identify a protein in the proximal tubule.
    [Show full text]
  • Detailed Investigations of Proximal Tubular Function in Imerslund-Grasbeck Syndrome
    Detailed investigations of proximal tubular function in Imerslund-Grasbeck syndrome. Tina Storm, Christina Zeitz, Olivier Cases, Sabine Amsellem, Pierre Verroust, Mette Madsen, Jean-François Benoist, Sandrine Passemard, Sophie Lebon, Iben Jønsson, et al. To cite this version: Tina Storm, Christina Zeitz, Olivier Cases, Sabine Amsellem, Pierre Verroust, et al.. Detailed in- vestigations of proximal tubular function in Imerslund-Grasbeck syndrome.. BMC Medical Genetics, BioMed Central, 2013, 14 (1), pp.111. 10.1186/1471-2350-14-111. inserm-00904107 HAL Id: inserm-00904107 https://www.hal.inserm.fr/inserm-00904107 Submitted on 13 Nov 2013 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Storm et al. BMC Medical Genetics 2013, 14:111 http://www.biomedcentral.com/1471-2350/14/111 RESEARCHARTICLE Open Access Detailed investigations of proximal tubular function in Imerslund-Gräsbeck syndrome Tina Storm1, Christina Zeitz2,3,4, Olivier Cases2,3,4, Sabine Amsellem2,3,4, Pierre J Verroust1,2,3,4, Mette Madsen1, Jean-François Benoist6, Sandrine Passemard7,8, Sophie Lebon8, Iben Møller Jønsson9, Francesco Emma10, Heidi Koldsø11, Jens Michael Hertz12, Rikke Nielsen1, Erik I Christensen1* and Renata Kozyraki2,3,4,5* Abstract Background: Imerslund-Gräsbeck Syndrome (IGS) is a rare genetic disorder characterised by juvenile megaloblastic anaemia.
    [Show full text]
  • The Path to an Orally Administered Protein Therapeutic for the Treatment of Diabetes Mellitus
    Syracuse University SURFACE Chemistry - Dissertations College of Arts and Sciences 12-2012 The Path to an Orally Administered Protein Therapeutic for the Treatment of Diabetes Mellitus Susan Clardy James Syracuse University Follow this and additional works at: https://surface.syr.edu/che_etd Part of the Chemistry Commons Recommended Citation James, Susan Clardy, "The Path to an Orally Administered Protein Therapeutic for the Treatment of Diabetes Mellitus" (2012). Chemistry - Dissertations. 196. https://surface.syr.edu/che_etd/196 This Dissertation is brought to you for free and open access by the College of Arts and Sciences at SURFACE. It has been accepted for inclusion in Chemistry - Dissertations by an authorized administrator of SURFACE. For more information, please contact [email protected]. Abstract Protein therapeutics like insulin and glucagon-like peptide-1 analogues are currently used as injectable medications for the treatment of diabetes mellitus. An orally administered protein therapeutic is predicted to increase patient adherence to medication and bring a patient closer to metabolic norms through direct effects on hepatic glucose production. The major problem facing oral delivery of protein therapeutics is gastrointestinal tract hydrolysis/proteolysis and the inability to passage the enterocyte. Herein we report the potential use of vitamin B12 for the oral delivery of protein therapeutics. We first investigated the ability of insulin to accommodate the attachment of B12 at the B1 vs. B29 amino acid position. The insulinotropic profile of both conjugates was evaluated in streptozotocin induced diabetic rats. Oral administration of the conjugates produced significant drops in blood glucose levels, compared to an orally administered insulin control, but no significant difference was observed between conjugates.
    [Show full text]
  • Genetic Heterogeneity of Megaloblastic Anaemia Type 1 in Tunisian Patients
    J Hum Genet (2007) 52:262–270 DOI 10.1007/s10038-007-0110-0 ORIGINAL ARTICLE Genetic heterogeneity of megaloblastic anaemia type 1 in Tunisian patients Chiraz Bouchlaka Æ Chokri Maktouf Æ Bahri Mahjoub Æ Abdelkarim Ayadi Æ M. Tahar Sfar Æ Mahbouba Sioud Æ Neji Gueddich Æ Zouheir Belhadjali Æ Ahmed Rebaı¨ Æ Sonia Abdelhak Æ Koussay Dellagi Received: 2 August 2006 / Accepted: 21 December 2006 / Published online: 7 February 2007 Ó The Japan Society of Human Genetics and Springer 2007 Abstract Megaloblastic anaemia 1 (MGA1) is a rare geneous and can be caused by mutations in either the autosomal recessive condition characterized by selec- cubilin (CUBN) or the amnionless (AMN) gene. In tive intestinal vitamin B12 malabsorption and pro- the present study we investigated the molecular defect teinuria. More than 200 MGA1 patients have been underlying MGA1 in nine Tunisian patients belonging identified worldwide, but the disease is relatively to six unrelated consanguineous families. Haplotype prevalent in Finland, Norway and several Eastern and linkage analyses, using microsatellite markers Mediterranean regions. MGA1 is genetically hetero- surrounding both CUBN and AMN genes, indicated that four out of the six families were likely to be linked to the CUBN gene. Patients from these fami- C. Bouchlaka Á C. Maktouf Á S. Abdelhak (&) lies were screened for the Finnish, Mediterranean and Molecular Investigation of Genetic Orphan Diseases, Arabian mutations already published. None of the Institut Pasteur de Tunis, BP 74, 13 Place Pasteur 1002, screened mutations could be detected in our popula- Tunis Belve´de`re, Tunisia tion. One family showed a linkage to AMN gene.
    [Show full text]
  • Inherited LRP2 Dysfunction in Human Disease and Animal Models
    Kozyraki R and Cases O. J Rare Dis Res Treat. (2017) 2(5): 22-31 Journal of www.rarediseasesjournal.com Rare Diseases Research & Treatment Mini Review Open Access Inherited LRP2 dysfunction in human disease and animal models Renata Kozyraki1 and Olivier Cases1 1INSERM UMRS_1138, Centre de Recherche des Cordeliers, Paris-Diderot University, France Article Info ABSTRACT Article Notes Gp330/Megalin/Low-Density Lipoprotein Receptor-Related Protein 2 Received: June 29, 2017 (LRP2) is an endocytic receptor that plays multiple roles in embryonic and Accepted: September 25, 2017 adult tissues. It allows the cellular uptake of various bioactive molecules, *Correspondence: morphogens, vitamins and hormones. Lack or dysfunction of the receptor affects Dr. Renata Kozyraki, Ph.D. renal protein reabsorption, lung function, brain and eye development in both INSERM UMRS_1138, 15 rue de l’école de médecine, 75006 man and experimental models. Mutations inLRP2 cause the polymalformative Paris, France,Tel: + 33 144278007; Fax: + 33 144275590, Donnai-Barrow syndrome, a rare autosomal recessive condition, combining Email: [email protected] developmental delay, facial dysmorphology, hearing defects, high myopia and © 2017 Kozyraki R and Cases O. This article is distributed low-molecular weight proteinuria. under the terms of the Creative Commons Attribution 4.0 We here summarize current knowledge on the receptor action. We International License. particularly focus on the LRP2-associated face and eye anomalies and discuss Keywords how the receptor and its interacting proteins, including the multiligand Donnai-Barrow syndrome receptor Cubilin (CUBN) may promote health or cause disease. Endocytosis High Myopia LRP2: Low-density lipoprotein Receptor-related Protein 2 Megalin Introduction gp330 Myopia Endocytosis is an essential mechanism that allows selective RPE cellular uptake of numerous macromolecules.
    [Show full text]
  • Structural and Functional Characterisation of the Cobalamin Transport Protein Haptocorrin
    Research Collection Doctoral Thesis Structural and functional characterisation of the cobalamin transport protein haptocorrin Author(s): Furger, Evelyne Publication Date: 2012 Permanent Link: https://doi.org/10.3929/ethz-a-007608480 Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library DISS ETH 20838 Structural and Functional Characterisation of the Cobalamin Transport Protein Haptocorrin A dissertation submitted to ETH ZURICH for the degree of DOCTOR OF SCIENCES Presented by EVELYNE FURGER MSc ETH Pharm. Sci. Born 25.04.1981 Citizen of Silenen UR Accepted on the recommendation of Prof. Dr. Roger Schibli, examiner Prof. Dr. Ebba Nexø, co-examiner Prof. Dr. Simon M. Ametamey, co-examiner 2012 To my parents Acknowledgements I would like to express my gratitude to all those who supported me to complete this thesis. First and foremost, I owe my deepest gratitude to my supervisor Dr. Eliane Fischer whose help, encouragement and stimulating enthusiasm helped me through all the times of the dissertation. Furthermore, I want to thank all my colleagues from the Center of Radiopharmaceutical Sciences at the ETH Zurich and the Paul Scherrer Institute in Villigen for all their help, support and the nice time we spent together inside and outside the lab. I would like to thank Prof. Roger Schibli for giving me the opportunity to perform my doctorate in his group and Prof. Ebba Nexø and Prof. Simon M. Ametamey for being in the committee as co-referees. Finally, I want to express my heartfelt gratitude to my parents Eduard and Marianna, Carmen, Patricia, Thomas, Nicole and all my friends for their never-ending support and care.
    [Show full text]
  • Structural Assembly of the Megadalton-Sized Receptor for Intestinal Vitamin B12 Uptake and Kidney Protein Reabsorption
    University of Southern Denmark Structural assembly of the megadalton-sized receptor for intestinal vitamin B12 uptake and kidney protein reabsorption Larsen, Casper; Etzerodt, Anders; Madsen, Mette; Skjødt, Karsten; Moestrup, Søren Kragh; Andersen, Christian Brix Folsted Published in: Nature Communications DOI: 10.1038/s41467-018-07468-4 Publication date: 2018 Document version: Final published version Document license: CC BY Citation for pulished version (APA): Larsen, C., Etzerodt, A., Madsen, M., Skjødt, K., Moestrup, S. K., & Andersen, C. B. F. (2018). Structural assembly of the megadalton-sized receptor for intestinal vitamin B uptake and kidney protein reabsorption. Nature Communications, 9, [5204]. https://doi.org/10.1038/s41467-018-07468-412 Go to publication entry in University of Southern Denmark's Research Portal Terms of use This work is brought to you by the University of Southern Denmark. Unless otherwise specified it has been shared according to the terms for self-archiving. If no other license is stated, these terms apply: • You may download this work for personal use only. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying this open access version If you believe that this document breaches copyright please contact us providing details and we will investigate your claim. Please direct all enquiries to [email protected] Download date: 06. Oct. 2021 ARTICLE DOI: 10.1038/s41467-018-07468-4 OPEN Structural assembly of the megadalton-sized receptor for intestinal vitamin B12 uptake and kidney protein reabsorption Casper Larsen1, Anders Etzerodt 1, Mette Madsen1, Karsten Skjødt2, Søren Kragh Moestrup1,2,3 & Christian Brix Folsted Andersen1 1234567890():,; The endocytic receptor cubam formed by the 460-kDa protein cubilin and the 45-kDa transmembrane protein amnionless (AMN), is essential for intestinal vitamin B12 (B12) uptake and for protein (e.g.
    [Show full text]
  • CUBN Gene Cubilin
    CUBN gene cubilin Normal Function The CUBN gene provides instructions for making a protein called cubilin. This protein is involved in the uptake of vitamin B12 (also called cobalamin) from food into the body. Vitamin B12, which cannot be made in the body and can only be obtained from food, is essential for the formation of DNA and proteins, the production of cellular energy, and the breakdown of fats. This vitamin is involved in the formation of red blood cells and maintenance of the brain and spinal cord (central nervous system). The cubilin protein is primarily found associated with kidney cells and cells that line the small intestine. Cubilin is anchored to the outer membrane of these cells by its attachment to another protein called amnionless. Cubilin can interact with molecules and proteins passing through the small intestine and kidneys, including vitamin B12. During digestion, vitamin B12 is released from food. As the vitamin passes through the small intestine, cubilin attaches (binds) to it. Amnionless helps transfer the cubilin- vitamin B12 complex into the intestinal cell. From there, the vitamin is released into the blood and transported throughout the body. In the kidneys, cubilin and amnionless are involved in the reabsorption of certain proteins that would otherwise be released in urine. Health Conditions Related to Genetic Changes Imerslund-Gräsbeck syndrome At least 35 mutations in the CUBN gene have been found to cause a condition called Imerslund-Gräsbeck syndrome. This condition is characterized by low levels of vitamin B12 in the body, which leads to a blood disorder known as megaloblastic anemia.
    [Show full text]
  • A Study of Associations Between CUBN, HNF1A, and LIPC Gene
    www.nature.com/scientificreports OPEN A study of associations between CUBN, HNF1A, and LIPC gene polymorphisms and coronary artery disease Han Sung Park1,3, In Jai Kim2,3, Eun Gyo Kim1, Chang Soo Ryu1, Jeong Yong Lee1, Eun Ju Ko1, Hyeon Woo Park1, Jung Hoon Sung2* & Nam Keun Kim1* The aim of this study was to identify novel genetic markers related to coronary artery disease (CAD) using a whole-exome sequencing (WES) approach and determine any associations between the selected gene polymorphisms and CAD prevalence. CUBN, HNF1A and LIPC gene polymorphisms related to CAD susceptibility were identifed using WES screening. Possible associations between the fve gene polymorphisms and CAD susceptibility were examined in 452 CAD patients and 421 control subjects. Multivariate logistic regression analyses indicated that the CUBN rs2291521GA and HNF1A rs55783344CT genotypes were associated with CAD (GG vs. GA; adjusted odds ratio [AOR] = 1.530; 95% confdence interval [CI] 1.113–2.103; P = 0.002 and CC vs. CT; AOR = 1.512; 95% CI 1.119–2.045; P = 0.007, respectively). The CUBN rs2291521GA and HNF1A rs55783344CT genotype combinations exhibited a stronger association with CAD risk (AOR = 2.622; 95% CI 1.518–4.526; P = 0.001). Gene- environment combinatorial analyses indicated that the CUBN rs2291521GA, HNF1A rs55783344CT, and LIPC rs17269397AA genotype combination and several clinical factors (fasting blood sugar (FBS), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels) were associated with increased CAD risk. The CUBN rs2291521GA, HNF1A rs55783344CT, and LIPC rs17269397AA genotypes in conjunction with abnormally elevated cholesterol levels increase the risk of developing CAD.
    [Show full text]
  • Deficits in Receptor-Mediated Endocytosis and Recycling in Cells from Mice with Gpr107 Locus Disruption
    ß 2014. Published by The Company of Biologists Ltd | Journal of Cell Science (2014) 127, 3916–3927 doi:10.1242/jcs.135269 RESEARCH ARTICLE Deficits in receptor-mediated endocytosis and recycling in cells from mice with Gpr107 locus disruption Guo Ling Zhou*, Soon-Young Na, Rasma Niedra and Brian Seed* ABSTRACT factors, antibody complexes and essential factors for cellular proliferation. In this pathway, ligand-bound receptors on the cell GPR107 is a type III integral membrane protein that was initially surface are entrapped by deformation of plasma membrane predicted to be a member of the family of G-protein-coupled domains into coated pits that invaginate, detach from the plasma receptors. This report shows that deletion of Gpr107 leads to an membrane and undergo a complex, still poorly understood, embryonic lethal phenotype that is characterized by a reduction in sorting process (Pucadyil and Schmid, 2009). Clathrin, a key cubilin transcript abundance and a decrease in the representation of structural element of coated pits, is composed of 190-kDa heavy multiple genes implicated in the cubilin–megalin endocytic receptor chains (CHC) and 25-kDa light chains (CLC), which together complex (megalin is also known as LRP2). Gpr107-null fibroblast form three-legged trimmers (called triskelions). The triskelions cells exhibit reduced transferrin internalization, decreased uptake of are assembled into cage-like structures to coat vesicles (Harrison low-density lipoprotein (LDL) receptor-related protein-1 (LRP1) and Kirchhausen, 2010; Marsh and
    [Show full text]
  • LRP2 Gene LDL Receptor Related Protein 2
    LRP2 gene LDL receptor related protein 2 Normal Function The LRP2 gene provides instructions for making a protein called megalin, which functions as a receptor. Receptor proteins have specific sites into which certain other proteins, called ligands, fit like keys into locks. Together, ligands and their receptors trigger signals that affect cell development and function. Megalin has many ligands involved in various body processes, including the absorption of vitamins A and D, immune functioning, stress response, and the transport of fats in the bloodstream. Megalin is embedded in the membrane of cells that line the surfaces and cavities of the body (epithelial cells). The receptor helps move its ligands from the cell surface into the cell (endocytosis), and is also involved in transporting the ligands of a related receptor called cubulin. Megalin is active in the development and function of many parts of the body, including the brain and spinal cord (central nervous system), eyes, ears, lungs, intestine, reproductive system, and the small tubes in the kidneys where urine is formed (renal tubules). Health Conditions Related to Genetic Changes Donnai-Barrow syndrome At least twelve LRP2 gene mutations have been identified in people with Donnai-Barrow syndrome. These mutations are believed to result in the absence of functional megalin protein. The lack of functional megalin in the renal tubules causes megalin's various ligands to be excreted in the urine rather than being absorbed back into the bloodstream. The features of Donnai-Barrow syndrome are probably caused by the inability of megalin to help absorb these ligands, disruption of biochemical signaling pathways, or other effects of the nonfunctional megalin protein.
    [Show full text]