Hexosaminidase a in Tay–Sachs Disease
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
Carrier Screening for Genetic Diseases Policy Number: PG0442 ADVANTAGE | ELITE | HMO Last Review: 07/25/2019
Carrier Screening for Genetic Diseases Policy Number: PG0442 ADVANTAGE | ELITE | HMO Last Review: 07/25/2019 INDIVIDUAL MARKETPLACE | PROMEDICA MEDICARE PLAN | PPO GUIDELINES This policy does not certify benefits or authorization of benefits, which is designated by each individual policyholder contract. Paramount applies coding edits to all medical claims through coding logic software to evaluate the accuracy and adherence to accepted national standards. This guideline is solely for explaining correct procedure reporting and does not imply coverage and reimbursement. SCOPE X Professional X Facility DESCRIPTION Carrier screening is testing asymptomatic individuals to identify those who are heterozygous for serious or lethal single-gene disorders with the purpose of informing the risk of conceiving an affected child. Risk-based carrier screening is performed in individuals having an increased risk based on population carrier prevalence, and personal or family history. Conditions selected for screening can be based on ethnicities at high risk (e.g., Tay- Sachs disease in individuals of Ashkenazi Jewish descent) or may be pan-ethnic (e.g., screening for cystic fibrosis carriers). Ethnicity-based screening for some conditions has been offered for decades and, in some cases, has reduced the prevalence of diseases. While methods for carrier screening of conditions individually may have been onerous in the past, contemporary molecular techniques including next-generation sequencing allow simultaneously identifying carriers of a wide range of disorders efficiently and inexpensively. Expanded carrier screening (ECS) involves screening individuals or couples for disorders in many genes (up to 100s). The disorders included may also span a range of disease severity or phenotype. Arguments for ECS include potential issues in assessing ethnicity, ability to identify more potential conditions, efficiency, and cost. -
Binding of Undamaged Double Stranded DNA to Vaccinia Virus
Schormann et al. BMC Structural Biology (2015) 15:10 DOI 10.1186/s12900-015-0037-1 RESEARCH ARTICLE Open Access Binding of undamaged double stranded DNA to vaccinia virus uracil-DNA Glycosylase Norbert Schormann1, Surajit Banerjee2, Robert Ricciardi3 and Debasish Chattopadhyay1* Abstract Background: Uracil-DNA glycosylases are evolutionarily conserved DNA repair enzymes. However, vaccinia virus uracil-DNA glycosylase (known as D4), also serves as an intrinsic and essential component of the processive DNA polymerase complex during DNA replication. In this complex D4 binds to a unique poxvirus specific protein A20 which tethers it to the DNA polymerase. At the replication fork the DNA scanning and repair function of D4 is coupled with DNA replication. So far, DNA-binding to D4 has not been structurally characterized. Results: This manuscript describes the first structure of a DNA-complex of a uracil-DNA glycosylase from the poxvirus family. This also represents the first structure of a uracil DNA glycosylase in complex with an undamaged DNA. In the asymmetric unit two D4 subunits bind simultaneously to complementary strands of the DNA double helix. Each D4 subunit interacts mainly with the central region of one strand. DNA binds to the opposite side of the A20-binding surface on D4. Comparison of the present structure with the structure of uracil-containing DNA-bound human uracil-DNA glycosylase suggests that for DNA binding and uracil removal D4 employs a unique set of residues and motifs that are highly conserved within the poxvirus family but different in other organisms. Conclusion: The first structure of D4 bound to a truly non-specific undamaged double-stranded DNA suggests that initial binding of DNA may involve multiple non-specific interactions between the protein and the phosphate backbone. -
Low Levels of 18 Hexosaminidase a in Healthy Individuals with Apparent Deficiency of This Enzyme
Am J Hum Genet 28:339-349, 1976 Low Levels of 18 Hexosaminidase A in Healthy Individuals with Apparent Deficiency of This Enzyme R. NAVON,1 B. GEIGER,2 Y. BEN YOSEPH,2 AND M. C. RATTAZZI3 INTRODUCTION The association between Tay-Sachs disease (TSD; GM,2 gangliosidosis type I) and generalized deficiency of /8 hexosaminidase A (hex A) activity with artificial sub- strates, first reported by Okada and O'Brien [1], is now well established. Using natural substrates, it has also been shown that tissues from patients with TSD cannot degrade GM2 ganglioside in vitro [2, 3] and that purified hex A, but ap- parently not purified /f hexosaminidase B (hex B), can hydrolyze GM2 ganglioside to a measurable extent [3, 4]. Thus, hex A deficiency is commonly believed to be the cause of the accumulation of GM2 ganglioside in patients with TSD. However, it has recently been reported that purified hex B can cleave GM2 ganglioside in vitro [5], raising the question of its participation in the catabolism of this glyco- lipid in vivo. In a recent publication [6], Navon et al. described a Jewish family in which four healthy adult individuals showed a severe deficiency of hex A activity. Using a heat inactivation method based on the differential thermal lability of hex A and hex B [7, 8], it was shown that, in these subjects, hex A activity with artificial substrates was comparable to that of patients with TSD [6]. Further studies em- ploying radioactive natural substrates, however, showed that leukocytes from these "variant" individuals were capable of hydrolysis of GA12 ganglioside in vitro [9]. -
Broad and Thematic Remodeling of the Surface Glycoproteome on Isogenic
bioRxiv preprint doi: https://doi.org/10.1101/808139; this version posted October 17, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Broad and thematic remodeling of the surface glycoproteome on isogenic cells transformed with driving proliferative oncogenes Kevin K. Leung1,5, Gary M. Wilson2,5, Lisa L. Kirkemo1, Nicholas M. Riley2,4, Joshua J. Coon2,3, James A. Wells1* 1Department of Pharmaceutical Chemistry, UCSF, San Francisco, CA, USA Departments of Chemistry2 and Biomolecular Chemistry3, University of Wisconsin- Madison, Madison, WI, 53706, USA 4Present address Department of Chemistry, Stanford University, Stanford, CA, 94305, USA 5These authors contributed equally *To whom correspondence should be addressed bioRxiv preprint doi: https://doi.org/10.1101/808139; this version posted October 17, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Abstract: The cell surface proteome, the surfaceome, is the interface for engaging the extracellular space in normal and cancer cells. Here We apply quantitative proteomics of N-linked glycoproteins to reveal how a collection of some 700 surface proteins is dramatically remodeled in an isogenic breast epithelial cell line stably expressing any of six of the most prominent proliferative oncogenes, including the receptor tyrosine kinases, EGFR and HER2, and downstream signaling partners such as KRAS, BRAF, MEK and AKT. -
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. -
GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies
International Journal of Molecular Sciences Review GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies Andrés Felipe Leal 1 , Eliana Benincore-Flórez 1, Daniela Solano-Galarza 1, Rafael Guillermo Garzón Jaramillo 1 , Olga Yaneth Echeverri-Peña 1, Diego A. Suarez 1,2, Carlos Javier Alméciga-Díaz 1,* and Angela Johana Espejo-Mojica 1,* 1 Institute for the Study of Inborn Errors of Metabolism, Faculty of Science, Pontificia Universidad Javeriana, Bogotá 110231, Colombia; [email protected] (A.F.L.); [email protected] (E.B.-F.); [email protected] (D.S.-G.); [email protected] (R.G.G.J.); [email protected] (O.Y.E.-P.); [email protected] (D.A.S.) 2 Faculty of Medicine, Universidad Nacional de Colombia, Bogotá 110231, Colombia * Correspondence: [email protected] (C.J.A.-D.); [email protected] (A.J.E.-M.); Tel.: +57-1-3208320 (ext. 4140) (C.J.A.-D.); +57-1-3208320 (ext. 4099) (A.J.E.-M.) Received: 6 July 2020; Accepted: 7 August 2020; Published: 27 August 2020 Abstract: GM2 gangliosidoses are a group of pathologies characterized by GM2 ganglioside accumulation into the lysosome due to mutations on the genes encoding for the β-hexosaminidases subunits or the GM2 activator protein. Three GM2 gangliosidoses have been described: Tay–Sachs disease, Sandhoff disease, and the AB variant. Central nervous system dysfunction is the main characteristic of GM2 gangliosidoses patients that include neurodevelopment alterations, neuroinflammation, and neuronal apoptosis. Currently, there is not approved therapy for GM2 gangliosidoses, but different therapeutic strategies have been studied including hematopoietic stem cell transplantation, enzyme replacement therapy, substrate reduction therapy, pharmacological chaperones, and gene therapy. -
Enhancer Variants Reveal a Conserved Transcription Factor Network Governed by PU.1 During Osteoclast Differentiation
Enhancer variants reveal a conserved transcription factor network governed by PU.1 during osteoclast differentiation The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Carey, H. A., B. E. Hildreth, J. A. Geisler, M. C. Nickel, J. Cabrera, S. Ghosh, Y. Jiang, et al. 2018. “Enhancer variants reveal a conserved transcription factor network governed by PU.1 during osteoclast differentiation.” Bone Research 6 (1): 8. doi:10.1038/ s41413-018-0011-1. http://dx.doi.org/10.1038/s41413-018-0011-1. Published Version doi:10.1038/s41413-018-0011-1 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:37067793 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Bone Research www.nature.com/boneres ARTICLE OPEN Enhancer variants reveal a conserved transcription factor network governed by PU.1 during osteoclast differentiation Heather A. Carey1, Blake E. Hildreth III 1,2,3, Jennifer A. Geisler1,2, Mara C. Nickel1, Jennifer Cabrera1, Sankha Ghosh1, Yue Jiang1, Jing Yan4, James Lee1, Sandeep Makam1, Nicholas A. Young5, Giancarlo R. Valiente5, Wael N. Jarjour5, Kun Huang6, Thomas J. Rosol2, Ramiro E. Toribio2, Julia F. Charles4, Michael C. Ostrowski1,3 and Sudarshana M. Sharma 1,3 Genome-wide association studies (GWASs) have been instrumental in understanding complex phenotypic traits. However, they have rarely been used to understand lineage-specific pathways and functions that contribute to the trait. -
O-Glcnacase Fragment Discovery with Fluorescence Polarimetry
Articles Cite This: ACS Chem. Biol. 2018, 13, 1353−1360 O‑GlcNAcase Fragment Discovery with Fluorescence Polarimetry Vladimir S. Borodkin,*,†,∥ Karim Rafie,†,∥ Nithya Selvan,†,§,∥ Tonia Aristotelous,‡ Iva Navratilova,‡ Andrew T. Ferenbach,† and Daan M. F. van Aalten*,† † ‡ Centre for Gene Regulation and Expression and Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, United Kingdom *S Supporting Information ABSTRACT: The attachment of the sugar N-acetyl-D-glucosamine (GlcNAc) to specific serine and threonine residues on proteins is referred to as protein O-GlcNAcylation. O-GlcNAc transferase (OGT) is the enzyme responsible for carrying out the modification, while O-GlcNAcase (OGA) reverses it. Protein O-GlcNAcylation has been implicated in a wide range of cellular processes including transcription, proteostasis, and stress response. Dysregulation of O-GlcNAc has been linked to diabetes, cancer, and neurodegenerative and cardiovascular disease. OGA has been proposed to be a drug target for the treatment of Alzheimer’s and cardiovascular disease given that increased O-GlcNAc levels appear to exert a protective effect. The search for specific, potent, and drug-like OGA inhibitors with bioavailability in the brain is therefore a field of active research, requiring orthogonal high-throughput assay platforms. Here, we describe the synthesis of a novel probe for use in a fluorescence polarization based assay for the discovery of inhibitors of OGA. We show that the probe is suitable for use with both human OGA, as well as the orthologous bacterial counterpart from Clostridium perfringens, CpOGA, and the lysosomal hexosaminidases HexA/B. We structurally characterize CpOGA in complex with a ligand identified from a fragment library screen using this assay. -
In-Silico Chaperone Model for ATSD and Case Study
CASE REPORT OF CHAPERONE THERAPY FOR ADULT TAY-SACHS DISEASE AND COMPARISON TO AN IN-SILICO PHARMACOKINETIC AND CELLULAR SIMULATION John G. (Jack) Keimel and Lawrence Charnas MD PhD, University of Minnesota, Minneapolis, Minnesota ABSTRACT CELLULAR MODELS CELLULAR SIMULATION RESULTS CASE STUDY OF PYRIMETHAMINE IN AN ATSD PATIENT Background: Individuals with Adult Tay-Sachs Disease (ATSD) Model 2: Model 3: Model Calibration: Patient History: Drug Regimen: develop ataxia and dysarthria by early teenage years and later lose Endoplasmic Reticulum Lysosome A single constant calibration factor, “cal”, sets the translation rate of α, A male confirmed with ATSD (alpha mutations: +1IVS12 (G>C) and At the request of the patient and parents, pyrimethamine ability to walk. No therapy has yet been shown clinically effective. α , and β HexA monomers. The factor was chosen such that, for Dimer Formation GM2 GM2 Degradation m G269S ) had been taking a substrate reduction therapy, miglustat, (PYR) 25mg QD was begun for two weeks followed by 75mg ATSD is caused by inadequate β-hexosaminidase-A (HexA) activity normal individuals with no PYR present, the steady state lysosomal for greater than four years, but at age 25 showed accelerated QD for eight weeks. Folic acid (5mg QD) was initiated with the and GM2 ganglioside accumulation in neuronal lysosomes. The concentration of HexA is equal to the above calculated value of 25μM. decline in coordination and leg muscle strength, verified by EMG first dose of PYR to offset partial dihydrofolate reductase most prevalent ATSD mutation, αG269S, is not believed to impact [PYR] [PYR] αβ evaluations. The patient lost the ability to climb stairs and required inhibition caused by PYR. -
Oxidative Demethylation of DNA Damage by Escherichia Coli Alkb
Oxidative déméthylation of DNA damage by Escherichia coli AlkB and its human homologs ABH2 and ABH3 A thesis submitted for the degree of Ph D. by Sarah Catherine Trewick Clare Hall Laboratories Cancer Research UK London Research Institute South Mimms, Potters Bar Hertfordshire, EN6 3LD and Department of Biochemistry University College London Gower Street, London, WCIE 6BT ProQuest Number: U642489 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest U642489 Published by ProQuest LLC(2015). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 ABSTRACT The E. coli AlkB protein was implicated in the repair or tolerance of DNA méthylation damage. However, despite the early isolation of an E. coli alkB mutant, the function of the AlkB protein had not been resolved (Kataoka et al, 1983). The E. coli alkB mutant is defective in processing methylated single stranded DNA, therefore, it was suggested that the AlkB protein either repairs or tolerates lesions generated in single stranded DNA, such as 1-methyladenine (1-meA) or 3-methylcytosine (3-meC), or that AlkB only acts on single stranded DNA (Dinglay et al, 2000). -
Impaired Β-Glucocerebrosidase Activity and Processing in Frontotemporal Dementia Due to Progranulin Mutations Andrew E
Arrant et al. Acta Neuropathologica Communications (2019) 7:218 https://doi.org/10.1186/s40478-019-0872-6 RESEARCH Open Access Impaired β-glucocerebrosidase activity and processing in frontotemporal dementia due to progranulin mutations Andrew E. Arrant1,2*, Jonathan R. Roth1, Nicholas R. Boyle1, Shreya N. Kashyap1, Madelyn Q. Hoffmann1, Charles F. Murchison1,3, Eliana Marisa Ramos4, Alissa L. Nana5, Salvatore Spina5, Lea T. Grinberg5,6, Bruce L. Miller5, William W. Seeley5,6 and Erik D. Roberson1,7* Abstract Loss-of-function mutations in progranulin (GRN) are a major autosomal dominant cause of frontotemporal dementia. Most pathogenic GRN mutations result in progranulin haploinsufficiency, which is thought to cause frontotemporal dementia in GRN mutation carriers. Progranulin haploinsufficiency may drive frontotemporal dementia pathogenesis by disrupting lysosomal function, as patients with GRN mutations on both alleles develop the lysosomal storage disorder neuronal ceroid lipofuscinosis, and frontotemporal dementia patients with GRN mutations (FTD-GRN) also accumulate lipofuscin. The specific lysosomal deficits caused by progranulin insufficiency remain unclear, but emerging data indicate that progranulin insufficiency may impair lysosomal sphingolipid- metabolizing enzymes. We investigated the effects of progranulin insufficiency on sphingolipid-metabolizing enzymes in the inferior frontal gyrus of FTD-GRN patients using fluorogenic activity assays, biochemical profiling of enzyme levels and posttranslational modifications, and quantitative neuropathology. Of the enzymes studied, only β-glucocerebrosidase exhibited impairment in FTD-GRN patients. Brains from FTD-GRN patients had lower activity than controls, which was associated with lower levels of mature β-glucocerebrosidase protein and accumulation of insoluble, incompletely glycosylated β-glucocerebrosidase. Immunostaining revealed loss of neuronal β- glucocerebrosidase in FTD-GRN patients. -
In Silico Prediction and Experimental Validation of Natural Antisense Transcripts in Two Cancer-Associated Regions of Human Chromosome 6
1099-1108 27/2/2009 01:48 ÌÌ ™ÂÏ›‰·1099 INTERNATIONAL JOURNAL OF ONCOLOGY 34: 1099-1108, 2009 In silico prediction and experimental validation of natural antisense transcripts in two cancer-associated regions of human chromosome 6 LAURA MONTI1*, RAFFAELLA CINQUETTI1*, ALESSANDRO GUFFANTI2*, FRANCESCO NICASSIO3, MATTIA CREMONA4, GIOVANNI LAVORGNA5, FABRIZIO BIANCHI3, FRANCESCA VIGNATI1, DAVIDE CITTARO6, ROBERTO TARAMELLI1 and FRANCESCO ACQUATI1 1Department of Biotechnology and Molecular Sciences, University of Insubria, Via JH Dunant 3, I-21100 Varese; 2Nanotechnologies Group, Institute of Biomedical Technologies, CNR, Via Fantoli 16/15, I-20138 Milano; 3IFOM - FIRC Institute of Molecular Oncology, Via Adamello 16, I-20139 Milano; 4Proteomic Unit, Department of Experimental Oncology, National Institute of Cancer, Via Venezian 21, I-20133 Milano; 5DIBIT, San Raffaele Hospital, Via Olgettina 58, I-20132 Milano; 6HPC and Bioinformatics Systems @ Informatics Core, FIRC Insitute of Molecular Oncology (IFOM), Via Adamello 16, I-20139 Milano, Italy Received August 28, 2008; Accepted October 27, 2008 DOI: 10.3892/ijo_00000237 Abstract. Antisense transcription has long been recognized human malignancies, such as non-Hodgkin's lymphomas, as a mechanism involved in the regulation of gene expression. melanoma and carcinomas of the mammary gland, ovary, Therefore, several human diseases associated with abnormal uterus, stomach, kidney and salivary gland (1-3). The involve- patterns of gene expression might display antisense RNA- ment of this chromosome in the pathogenesis of the above- mediated pathogenetic mechanisms. Such issue could be mentioned cancer types has been demonstrated by LOH particularly relevant for cancer pathogenesis, since deregulated studies and chromosome-transfer assays, which led to the gene expression has long been established as a hallmark of identification of several regions of minimal deletion spanning cancer cells.