DOCSLIB.ORG

Metachromatic Leukodystrophy Improved Diagnosis and Prognosis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Metachromatic Leukodystrophy Improved Diagnosis and Prognosis rJhlly /_ o I ME TACTIROMATIC LEUKODYS TR IMPROVED DIAGNOSIS ANI) PROGI{OSIS by Mohd Adi Firdaus TAN B.Biomedical Sc. (Hons) Department of Paediatrics The University of Adelaide Adelaide, South Australia This thesis is submitted for the degree of Doctor of Philosophy Date submitted: z8 March 2o,o,6 THESIS SUMMARY mole prevalent lysosomal storage Metachromatic leukodystrophy (MLD) is one of the births in Australia' The major cause of disorders with a reported incidence of I in 92,000 (ASA); this lysosomal enzyme, together this disease is the deficiency of arylsulphatase A of sulphatide' The with an activator protein, saposin B, is needed for the catabolism nervous system results in progressive subsequent accumulation of sulphatides in the central neurorogical function with a fatal outcome demyerination that reads to severe impairment of juvenile patients. for the more sevefely affected infantile and - l);. .1 MLD patients for more thanz' years' Bone marrow transprantation has been carried out in diffrcurt and remains a challenge However, successfur treatment of this disorder is often onset of neurological symptoms' At because patients are usually diagnosed after the in peripheral blood leucocltes present, MLD is diagnosed by measurement of ASA activity diagnosis is usually only obtained after and cultured skin fibroblasts. However, a definitive tests. The need for auxiliary tests is extensive testing with an arcay ofauxiliary laboratory (ASA-PD) mutation or ASA-PD/MLD' due to the presence of the ASA pseudo-deficiency low ASA enzyme activity' These which leads to clinically normal individuals who have conventional enzyme analysis; patients cannot be distinguished from MLD patients by MLD since saposin B deficiency is furthermore, normal enzyme activity cannot rule out also known to cause the disorder' and a simple skin fibroblast In this study, immune-based ASA activity and protein assays, a sulphatide quantification assay sulphatide-loading protocol, were developed. In addition, assays were shown to be using mass spectrometry was established. The immune-based was sensitive and clearly highly specific. The immune-quantification ASA protein assay in brood spots and skin fibroblast distinguished unaffected, ASA-PD and MLD individuars in either ASA-PD or MLD samples. However, ASA enzyme activity was not detected activity assay' a finding individuals in blood spots using the immune-capture ASA blood spots that had been stored at attributed to the instabitity of AsA activity in dried has enabled determination of room temperature. The combination of these two assays thereby providing information on the specific activity of the enzyme in different patients, as well as an additional parameter effect of the mutation on protein stability and activity with which to distinguish phenotypes' To further develop the capacity to predict phenotype, induced accumulation of sulphatide in skin fibroblast cultures \ryas performed; the resultant cells were quantified for accumulated sulphatide and other lipids using electrospray ionisation tandem mass spectrometry. A strong correlation was observed between residual enzyme activity and the amount of accumulated sulphatide: four out of five late-infantile MLD patients could be clearly distinguished from the juvenile and adult patients, although no difference was observed in the amount of accumulated sulphatide in the latter two groups. However, a clear difference was observed between attenuated adult-onset patients and ASA-PD/MLD compound heterozygotes. Analysis of urine for sulphatide and a range of other lipids from a cohort of unaffected controls, ASA-PD and MLD patients showed that, in addition to elevated sulphatide, MLD patients also showed alterations in some phosphatidylglycerol/ lysobisphosphatidic acid species, a finding that was also observed in the sulphatide-loaded skin fibroblasts. This observation enabled unequivocal discrimination of the late-infantile MLD phenotype. The immune-based ASA activity and protein assays will simplifl, the procedures for collection, handling and storage protocols for MLD testing. This will be particularly important for countries where sample collection and transport services are not well established or where transport overseas is required. The combination of residual ASA protein and activity, urinary sulphatide and other lipids, and sulphatide accumulation in cultured skin fibroblasts, provides a detailed picture of patient biochemistry and has the potential to provide predictive assessment of phenotype where patients are identified asymptomatically. tl ACI(NOWLEDGMENTS of this project and I would Numerous people have contributed to the successful completion like to thank them all most sincerely Prof' John Hopwood, for Firstly, I would like to thank my supervisors, Dr Peter Meikle and most grateful to them for their encouragement and guidance throughout this project. I am me constantly on my toes' the precious time they spent in the weekly meetings that kept valuable throughout the Their superb guidance and interest in the project proved to be most (Field supervisor) for his tenure of this project. I would also like to thank Ptof. Zabidi scholarships necessary for support, and the Universiti Sains Malaysia for granting me the me to come to Adelaide to undertake this study' clements, Dr' Maria Fuller, I am most grateful to Assoc. Prof. Douglas Brooks, Dr. Peter Dr Dr Michael Bawden, Dr Emma Parkinson, Dr Caroline Dean, Dr David Johnson' Elaine Ravenscroft' Melissa Chang, Peter Sharp, Christine Boulter, Dr Litsa Karageorgos, over the years' Tina Rozaklis and Minh Trinh for their expertise and contributions Nielsen, I would also like to thank Melanie Lovejoy, Michelle Bockmann, Timothy Lazenkas for their help christopher Tumer, Debbie Zimmerman, Kerryn Mason and sophie my life' I also wish to and wonderful friendship that I will continue to cherish throughout studies in Adelaide in the thank Dr. Rowani Mohd Rawi, who is also undertaking her PhD up the laboratory back in area of lysosomal storage disorders; together, we hope to build Malaysia. always remember Special thanks to David Blacklock for his great companionship' I will and the grand 40th birthday we those wonderful fishing and crabbing trips in his 'Tinnie', celebrated together. 'Women's at the and Many thanks to all the staff in the Department of Genetic Medicine to me during my children's Hospital in North Adelaide, for their kind assistance rendered work in the DePartment. this work to my lovely From the bottom of my heart, I would like to thank and dedicate and sadrina, for their wife, sabariah, and my children, Alif, Asyraf, Sabrina, syazana their love and understanding and the sacrif,rces they made during my absence. without iv encouragement, I doubt I would have made it. I love you all; no words can describe the extent of my love for all of You. Finally, a special dedication to my beloved mother. I know she is beaming with pride at my achievement; sadly, her untimely demise during my study has changed the celebration we had planned. May God bless her soul. "May God bless us all. Together, we cân make this world a better place" LIST OF ABBREVIATIONS 4-MUS 4-metþlumbelliferYl sulPhate acid) ABTS 2, 2' -azino-bis (3 -ethylbenzo -thiazo line-6- sulphonic diammonium salt AEC anion exchange chromatograPhY ASA arylsulphatase A ASA-PD arylsulphatase pseudo-deficiency BBB blood-brain barrier BCA bicinchoninic acid BME Basal Eagle media BMT bone marrow transPlantation BSA bovine semm albumin CAD collisionally activated dissociation acid CAPS 3 -[cyclohexylamino]- 1 -propanesulphonic cDNA complementary DNA CE collision energy Cer ceramide - 1 - CHAPS 3 - {(3 -cholamidopropyl)-dimetþlammonio} propanesulfonate CHO-K1 Chinese hamster ovary DHFR cell line millimetre(s); micrometre(s); nanometre(s) cm; mm; Lrm; nm centimetre(s); CNS central nervous sYstem CR creatinine CSF cerebrospinal fluir CTH ceramide trihexoside CUR curtain gas setting CV co effr cient of variance CXP collision cell exit Potential DELFIA dissociation-enhanced lanthanide fluorescence immunoassay dhSulp dihexosyl sulPhatide DMEM dodecyl modified Eagles medium DMSO dimetþlsulPhoxide DNA deoxyribonucleic acid DP declustering Potential EDTA ethylenediaminetetraacetic acid v1 ELISA enzyme-linked immunosorbent assay EP exit potential ER endoplasmic reticulum ERT eîzy me replacement theraPY ESI-MS/MS electrospray ionisation tandem mass spectrometry -3+tru europium FA-amide fatty acid amide FCS foetal calf serum FP focusing potential FPLC fast protein liquid chromatography nanogram(s) g; mgj, pg; ng gram(s); milligram(s); microgram(s); c418 gentamycin GC glucosylceramide GSD glycophingoliPidoses GSL glycosphingoliPids HAT hypoxanthine, aminopterin and tþmidine - (2- ethanesulfonic acid) HEPES N-(2-hydroxyethyl) piperazine-N' hFA o-hydroxy fattY acid HIFCS heat-inactivated foetal calf serum HPLC high pressure liquid chromatography hr(s); min(s) hour(s); minute(s) HRP horse radish peroxidase hSulp hydroxyl sulphatide HT hypoxanthine and thYmidine IS ion spray voltage ISTD internal standards kDa kilo-daltons microlitre(s) L; mL;' ¡tL litre(s); millilitre(s); LAMP lyso some-associated membrane protein LB Luria broth LC lactosylceramide LIMPS lysosomal integral membrane proteins LPBA lysobisphosphatidic acid LSD lysosomal storage disorder(s) mlz mass-to-charge ratio vll M6PR mannose-6-phosphate receptor MAL myelin and lymphocyte protein MEM minimum essential medium MLD metachromatic leukodystrophy mM; nM millimoles per litre; nanomoles per litre
Load more

Recommended publications
  • Soonerstart Automatic Qualifying Syndromes and Conditions 001
    SoonerStart Automatic Qualifying Syndromes and Conditions 001 Abetalipoproteinemia 272.5 002 Acanthocytosis (see Abetalipoproteinemia) 272.5 003 Accutane, Fetal Effects of (see Fetal Retinoid Syndrome) 760.79 004 Acidemia, 2-Oxoglutaric 276.2 005 Acidemia, Glutaric I 277.8 006 Acidemia, Isovaleric 277.8 007 Acidemia, Methylmalonic 277.8 008 Acidemia, Propionic 277.8 009 Aciduria, 3-Methylglutaconic Type II 277.8 010 Aciduria, Argininosuccinic 270.6 011 Acoustic-Cervico-Oculo Syndrome (see Cervico-Oculo-Acoustic Syndrome) 759.89 012 Acrocephalopolysyndactyly Type II 759.89 013 Acrocephalosyndactyly Type I 755.55 014 Acrodysostosis 759.89 015 Acrofacial Dysostosis, Nager Type 756.0 016 Adams-Oliver Syndrome (see Limb and Scalp Defects, Adams-Oliver Type) 759.89 017 Adrenoleukodystrophy, Neonatal (see Cerebro-Hepato-Renal Syndrome) 759.89 018 Aglossia Congenita (see Hypoglossia-Hypodactylia) 759.89 019 Albinism, Ocular (includes Autosomal Recessive Type) 759.89 020 Albinism, Oculocutaneous, Brown Type (Type IV) 759.89 021 Albinism, Oculocutaneous, Tyrosinase Negative (Type IA) 759.89 022 Albinism, Oculocutaneous, Tyrosinase Positive (Type II) 759.89 023 Albinism, Oculocutaneous, Yellow Mutant (Type IB) 759.89 024 Albinism-Black Locks-Deafness 759.89 025 Albright Hereditary Osteodystrophy (see Parathyroid Hormone Resistance) 759.89 026 Alexander Disease 759.89 027 Alopecia - Mental Retardation 759.89 028 Alpers Disease 759.89 029 Alpha 1,4 - Glucosidase Deficiency (see Glycogenosis, Type IIA) 271.0 030 Alpha-L-Fucosidase Deficiency (see Fucosidosis)
    [Show full text]
  • Sphingolipid Metabolism Diseases ⁎ Thomas Kolter, Konrad Sandhoff
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1758 (2006) 2057–2079 www.elsevier.com/locate/bbamem Review Sphingolipid metabolism diseases ⁎ Thomas Kolter, Konrad Sandhoff Kekulé-Institut für Organische Chemie und Biochemie der Universität, Gerhard-Domagk-Str. 1, D-53121 Bonn, Germany Received 23 December 2005; received in revised form 26 April 2006; accepted 23 May 2006 Available online 14 June 2006 Abstract Human diseases caused by alterations in the metabolism of sphingolipids or glycosphingolipids are mainly disorders of the degradation of these compounds. The sphingolipidoses are a group of monogenic inherited diseases caused by defects in the system of lysosomal sphingolipid degradation, with subsequent accumulation of non-degradable storage material in one or more organs. Most sphingolipidoses are associated with high mortality. Both, the ratio of substrate influx into the lysosomes and the reduced degradative capacity can be addressed by therapeutic approaches. In addition to symptomatic treatments, the current strategies for restoration of the reduced substrate degradation within the lysosome are enzyme replacement therapy (ERT), cell-mediated therapy (CMT) including bone marrow transplantation (BMT) and cell-mediated “cross correction”, gene therapy, and enzyme-enhancement therapy with chemical chaperones. The reduction of substrate influx into the lysosomes can be achieved by substrate reduction therapy. Patients suffering from the attenuated form (type 1) of Gaucher disease and from Fabry disease have been successfully treated with ERT. © 2006 Elsevier B.V. All rights reserved. Keywords: Ceramide; Lysosomal storage disease; Saposin; Sphingolipidose Contents 1. Sphingolipid structure, function and biosynthesis ..........................................2058 1.1.
    [Show full text]
  • Characterization of a Mutation in a Family with Saposin B Deficiency
    Proc. Nadl. Acad. Sci. USA Vol. 87, pp. 2541-2544, April 1990 Genetics Characterization of a mutation in a family with saposin B deficiency: A glycosylation site defect (sphingolipid activator protein/SAP-1/metachromatic leukodystrophy/arylsulfatase A) KEITH A. KRETZ*, GEOFFREY S. CARSON*, SATOSHI MORIMOTO*t, YASUO KISHIMOTO*, ARVAN L. FLUHARTYt, AND JOHN S. O'BPUEN*§ *Department of Neurosciences and Center for Molecular Genetics, University of California, San Diego, School of Medicine, M-034J, La Jolla, CA 92093; and tUniversity of California, Los Angeles, Mental Retardation Research Center Group at Lanterman Developmental Center, Pomona, CA 91766 Communicated by Dan L. Lindsley, January 19, 1990 ABSTRACT Saposins are small, heat-stable glycoproteins these four saposin proteins has now been isolated and their required for the hydrolysis of sphingolipids by specific lyso- activating properties have been determined (3-14). somal hydrolases. Saposins A, B, C, and D are derived by Saposins A and C specifically activate hydrolysis of glu- proteolytic processing from a single precursor protein named cocerebroside byB-glucosylceramidase (D-glucosyl-N-acyl- prosaposin. Saposin B, previously known as SAP-1 and sul- sphingosine glucohydrolase; EC 3.2.1.45) and ofgalactocere- fatide activator, stimulates the hydrolysis of a wide variety of broside by galactosylceramidase (D-galactosyl-N-acyl- substrates including cerebroside sulfate, GM1 ganglioside, and sphingosine galactohydrolase; EC 3.2.1.46) (3, 4). Saposin D globotriaosylceramide by arylsulfatase A, acid 8-galacto- specifically activates the hydrolysis of sphingomyelin by sidase, and a-galactosidase, respectively. Human saposin B sphingomyelin phosphodiesterase (sphingomyelin choline- deficiency, transmitted as an autosomal recessive trait, results phosphohydrolase; EC 3.1.4.12) (5).
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • HHS Public Access Author Manuscript
    HHS Public Access Author manuscript Author Manuscript Author ManuscriptJ Registry Author Manuscript Manag. Author Author Manuscript manuscript; available in PMC 2015 May 11. Published in final edited form as: J Registry Manag. 2014 ; 41(4): 182–189. Exclusion of Progressive Brain Disorders of Childhood for a Cerebral Palsy Monitoring System: A Public Health Perspective Richard S. Olney, MD, MPHa, Nancy S. Doernberga, and Marshalyn Yeargin-Allsopp, MDa aNational Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention (CDC) Abstract Background—Cerebral palsy (CP) is defined by its nonprogressive features. Therefore, a standard definition and list of progressive disorders to exclude would be useful for CP monitoring and epidemiologic studies. Methods—We reviewed the literature on this topic to 1) develop selection criteria for progressive brain disorders of childhood for public health surveillance purposes, 2) identify categories of disorders likely to include individual conditions that are progressive, and 3) ascertain information about the relative frequency and natural history of candidate disorders. Results—Based on 19 criteria that we developed, we ascertained a total of 104 progressive brain disorders of childhood, almost all of which were Mendelian disorders. Discussion—Our list is meant for CP surveillance programs and does not represent a complete catalog of progressive genetic conditions, nor is the list meant to comprehensively characterize disorders that might be mistaken for cerebral
    [Show full text]
  • 2016 Mock Exam General Pathology Answer Sheet
    Name___________________________ 2016 Mock Exam General Pathology 1. You have 1 HOUR to complete this 50-question multiple choice exam. 2. Write your name on all pages of the exam packet. 3. Use capital letters on the answer sheet. 4. For each question, select the ONE best answer and mark it on the answer sheet. 5. Credit will be given only for correct answers recorded on the answer sheet. 6. All questions for which more than one answer is marked will be recorded as incorrect. 7. No credit will be awarded or deducted for incorrect answers. 8. Turn in the entire exam packet when you are done. 2016 Mock Exam General Pathology Answer sheet 1. ______ 26. ______ 2. ______ 27. ______ 3. ______ 28. ______ 4. ______ 29. ______ 5. ______ 30. ______ 6. ______ 31. ______ 7. ______ 32. ______ 8. ______ 33. ______ 9. ______ 34. ______ 10. ______ 35. ______ 11. ______ 36. ______ 12. ______ 37. ______ 13. ______ 38. ______ 14. ______ 39. ______ 15. ______ 40. ______ 16. ______ 41. ______ 17. ______ 42. ______ 18. ______ 43. ______ 19. ______ 44. ______ 20. ______ 45. ______ 21. ______ 46. ______ 22. ______ 47. ______ 23. ______ 48. ______ 24. ______ 49. ______ 25. ______ 50. ______ ii 2016 Mock Exam Name___________________________ General Pathology 1. Which of the following toxins reaches its target cell using retrograde axonal transport? a. tetanospasmin b. botulinum toxin c. syntaxin d. SNAP-25 2. All of the following EXCEPT which are true regarding high mobility group box protein 1 (HMGB-1)? a.
    [Show full text]
  • Structural Study of the Acid Sphingomyelinase Protein Family
    Structural Study of the Acid Sphingomyelinase Protein Family Alexei Gorelik Department of Biochemistry McGill University, Montreal August 2017 A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of Doctor of Philosophy © Alexei Gorelik, 2017 Abstract The acid sphingomyelinase (ASMase) converts the lipid sphingomyelin (SM) to ceramide. This protein participates in lysosomal lipid metabolism and plays an additional role in signal transduction at the cell surface by cleaving the abundant SM to ceramide, thus modulating membrane properties. These functions are enabled by the enzyme’s lipid- and membrane- interacting saposin domain. ASMase is part of a small family along with the poorly characterized ASMase-like phosphodiesterases 3A and 3B (SMPDL3A,B). SMPDL3A does not hydrolyze SM but degrades extracellular nucleotides, and is potentially involved in purinergic signaling. SMPDL3B is a regulator of the innate immune response and podocyte function, and displays a partially defined lipid- and membrane-modifying activity. I carried out structural studies to gain insight into substrate recognition and molecular functions of the ASMase family of proteins. Crystal structures of SMPDL3A uncovered the helical fold of a novel C-terminal subdomain, a slightly distinct catalytic mechanism, and a nucleotide-binding mode without specific contacts to their nucleoside moiety. The ASMase investigation revealed a conformational flexibility of its saposin domain: this module can switch from a detached, closed conformation to an open form which establishes a hydrophobic interface to the catalytic domain. This open configuration represents the active form of the enzyme, likely allowing lipid access to the active site. The SMPDL3B structure showed a narrow, boot-shaped substrate binding site that accommodates the head group of SM.
    [Show full text]
  • A Possible Role for Arylsulfatase G in Dermatan Sulfate Metabolism
    International Journal of Molecular Sciences Article A Possible Role for Arylsulfatase G in Dermatan Sulfate Metabolism Aleksandra Poterala-Hejmo 1,*, Adam Golda 2 , Marcin Pacholczyk 1 , Sebastian Student 1, Anna Tylki-Szyma´nska 3 and Anna Lalik 1,* 1 Department of Systems Biology and Engineering, Silesian University of Technology, 44-100 Gliwice, Poland; [email protected] (M.P.); [email protected] (S.S.) 2 Department of Cardiology, 4th Municipal Hospital, 44-100 Gliwice, Poland; [email protected] 3 Department of Pediatrics, Nutrition and Metabolic Diseases, The Children’s Memorial Health Institute, 04-730 Warsaw, Poland; [email protected] * Correspondence: [email protected] (A.P.-H.); [email protected] (A.L.); Tel.: +48-32-2371168 (A.P.-H.); +48-32-2372769 (A.L.) Received: 2 June 2020; Accepted: 6 July 2020; Published: 12 July 2020 Abstract: Perturbations of glycosaminoglycan metabolism lead to mucopolysaccharidoses (MPS)—lysosomal storage diseases. One type of MPS (type VI) is associated with a deficiency of arylsulfatase B (ARSB), for which we previously established a cellular model using pulmonary artery endothelial cells with a silenced ARSB gene. Here, we explored the effects of silencing the ARSB gene on the growth of human pulmonary artery smooth muscle cells in the presence of different concentrations of dermatan sulfate (DS). The viability of pulmonary artery smooth muscle cells with a silenced ARSB gene was stimulated by the dermatan sulfate. In contrast, the growth of pulmonary artery endothelial cells was not affected. As shown by microarray analysis, the expression of the arylsulfatase G (ARSG) in pulmonary artery smooth muscle cells increased after silencing the arylsulfatase B gene, but the expression of genes encoding other enzymes involved in the degradation of dermatan sulfate did not.
    [Show full text]
  • Soonerstart Automatic Qualifying Syndromes and Conditions
    SoonerStart Automatic Qualifying Syndromes and Conditions - Appendix O Abetalipoproteinemia Acanthocytosis (see Abetalipoproteinemia) Accutane, Fetal Effects of (see Fetal Retinoid Syndrome) Acidemia, 2-Oxoglutaric Acidemia, Glutaric I Acidemia, Isovaleric Acidemia, Methylmalonic Acidemia, Propionic Aciduria, 3-Methylglutaconic Type II Aciduria, Argininosuccinic Acoustic-Cervico-Oculo Syndrome (see Cervico-Oculo-Acoustic Syndrome) Acrocephalopolysyndactyly Type II Acrocephalosyndactyly Type I Acrodysostosis Acrofacial Dysostosis, Nager Type Adams-Oliver Syndrome (see Limb and Scalp Defects, Adams-Oliver Type) Adrenoleukodystrophy, Neonatal (see Cerebro-Hepato-Renal Syndrome) Aglossia Congenita (see Hypoglossia-Hypodactylia) Aicardi Syndrome AIDS Infection (see Fetal Acquired Immune Deficiency Syndrome) Alaninuria (see Pyruvate Dehydrogenase Deficiency) Albers-Schonberg Disease (see Osteopetrosis, Malignant Recessive) Albinism, Ocular (includes Autosomal Recessive Type) Albinism, Oculocutaneous, Brown Type (Type IV) Albinism, Oculocutaneous, Tyrosinase Negative (Type IA) Albinism, Oculocutaneous, Tyrosinase Positive (Type II) Albinism, Oculocutaneous, Yellow Mutant (Type IB) Albinism-Black Locks-Deafness Albright Hereditary Osteodystrophy (see Parathyroid Hormone Resistance) Alexander Disease Alopecia - Mental Retardation Alpers Disease Alpha 1,4 - Glucosidase Deficiency (see Glycogenosis, Type IIA) Alpha-L-Fucosidase Deficiency (see Fucosidosis) Alport Syndrome (see Nephritis-Deafness, Hereditary Type) Amaurosis (see Blindness) Amaurosis
    [Show full text]
  • Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
    BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in
    [Show full text]
  • Lab Dept: Chemistry Test Name: ARYLSULFATASE A, LEUKOCYTES
    Lab Dept: Chemistry Test Name: ARYLSULFATASE A, LEUKOCYTES General Information Lab Order Codes: ARYL Synonyms: Metachromic Leukodystrophy; Mucolipidoses, Types II and III; ARS-A (Arylsulfatase A); WBC Aryl Sulfatase A CPT Codes: 82657 – Enzyme activity in blood cells, cultured cells, or tissue, not elsewhere specified; nonradioactive substrate Test Includes: Arylsulfatase A, Leukocyte level reported in nmol/h/mg. Logistics Test Indications: Leukocyte assay is the preferred test to order first to rule out metachromatic leukodystrophy. Not reliable in identifying carriers due both to analytical variation and unusual genetic variants. The urine assay should be used in confirming leukocyte results. Lab Testing Sections: Chemistry - Sendouts Referred to: Mayo Medical Laboratories (MML Test: ARSAW) Phone Numbers: MIN Lab: 612-813-6280 STP Lab: 651-220-6550 Test Availability: Daily, 24 hours (Specimen must be received by reference lab within 96 hours of collection and must be received 1 day prior to assay day for processing) Turnaround Time: 8 – 15 days; test set up Tuesday Special Instructions: Specimen must arrive within 48 hours of draw. Obtain special collection tube from the laboratory. Specimen Specimen Type: Whole blood Container: Yellow top (ACD Solution B) tube available from laboratory Alternate: Yellow top (ACD Solution A) Draw Volume: 6 mL (Minimum: 5 mL) ACD Whole blood Processed Volume: Same as Draw Volume Collection: Routine blood collection Special Processing: Lab Staff: Do Not process specimen, leave in original draw container.
    [Show full text]
  • Dysregulation of Autophagy As a Common Mechanism in Lysosomal
    University of Birmingham Dysregulation of autophagy as a common mechanism in lysosomal storage diseases Seranova, Elena; Connolly, Kyle J; Zatyka, Malgorzata; Rosenstock, Tatiana R; Barrett, Timothy; Tuxworth, Richard I; Sarkar, Sovan DOI: 10.1042/EBC20170055 10.1042/EBC20170055 License: Creative Commons: Attribution (CC BY) Document Version Publisher's PDF, also known as Version of record Citation for published version (Harvard): Seranova, E, Connolly, KJ, Zatyka, M, Rosenstock, TR, Barrett, T, Tuxworth, RI & Sarkar, S 2017, 'Dysregulation of autophagy as a common mechanism in lysosomal storage diseases', Essays in Biochemistry, vol. 61, no. 6, pp. 733-749. https://doi.org/10.1042/EBC20170055, https://doi.org/10.1042/EBC20170055 Link to publication on Research at Birmingham portal Publisher Rights Statement: Checked for eligibility: 08/01/2018 General rights Unless a licence is specified above, all rights (including copyright and moral rights) in this document are retained by the authors and/or the copyright holders. The express permission of the copyright holder must be obtained for any use of this material other than for purposes permitted by law. •Users may freely distribute the URL that is used to identify this publication. •Users may download and/or print one copy of the publication from the University of Birmingham research portal for the purpose of private study or non-commercial research. •User may use extracts from the document in line with the concept of ‘fair dealing’ under the Copyright, Designs and Patents Act 1988 (?) •Users may not further distribute the material nor use it for the purposes of commercial gain. Where a licence is displayed above, please note the terms and conditions of the licence govern your use of this document.
    [Show full text]