TMEM199 Deficiency Is a Disorder of Golgi Homeostasis Characterized by Elevated Aminotransferases, Alkaline Phosphatase, and Cholesterol and Abnormal Glycosylation
| Autor: | Sharita Timal, Richard J. Rodenburg, Helen Michelakakis, Mersyni Mavrikou, Marina Moraitou, Karin Huijben, Angel Ashikov, Dirk Lefeber, Jos C. Jansen, Ron A. Wevers, Jody Salomon, Monique van Scherpenzeel, Giovanna Cenacchi, Marjolein A.W. van den Boogert, Martijn A. Huynen, Pier Luigi Calvo, Joris A. Veltman, Francesco Porta, François Foulquier, Adriaan G. Holleboom, Dorothée Vicogne, Alexander Hoischen, Eva Morava, Joost P.H. Drenth, Gerry Steenbergen, Geert van den Bogaart |
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| Přispěvatelé: | 01 Internal and external specialisms, Graduate School, Vascular Medicine, DIPARTIMENTO DI SCIENZE BIOMEDICHE E NEUROMOTORIE, Genetica & Celbiologie, Klinische Genetica, RS: GROW - School for Oncology and Reproduction, RS: GROW - R4 - Reproductive and Perinatal Medicine |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Glycosylation Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] Golgi Apparatus Golgi homeostasis Endoplasmic Reticulum chemistry.chemical_compound 0302 clinical medicine Congenital Disorders of Glycosylation Homeostasis Exome Genetics(clinical) Genetics (clinical) hypercholesterolemia TMEM199 deficiency Ceruloplasmin Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] COPI Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] Cholesterol Phenotype Biochemistry COPI vesicular transport V-ATPase assembly symbols Alkaline phosphatase Vph2p Adult Genotype alkaline phosphatase elevated aminotransferases Molecular Sequence Data Biology Abnormal glycosylation 03 medical and health sciences symbols.namesake Young Adult Alkaline Phosphatase Amino Acid Sequence Fibroblasts Humans Membrane Proteins Mutation Transaminases Genetics Report Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] Endoplasmic reticulum Golgi apparatus Sialic acid Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] 030104 developmental biology chemistry Membrane protein 030217 neurology & neurosurgery |
| Zdroj: | American Journal of Human Genetics, 98, 322-30 American journal of human genetics, 98(2), 322-330. Cell Press American Journal of Human Genetics, 98(2), 322-330. Cell Press American Journal of Human Genetics, 98, 2, pp. 322-30 |
| ISSN: | 0002-9297 |
| Popis: | none 26 si This work was financially supported by grants from the Institute of Genetic and Metabolic Disease (to D.J.L., R.J.R., and J.A.V.), the Dutch Organization for Scientific Research (ZONMW Medium Investment Grant 40-00506-98-9001 and VIDI Grant 91713359 to D.J.L. and VENI grant to A.G.H.), the Metakids foundation (J.C.J., M.v.S., J.P.H.D., and D.J.L.), the AMC graduate school Ph.D scholarship (M.A.W.v.d.B.), the Dr. Karel-Lodewijk Verleysen Award (J.C.J. and J.P.H.D.), the French National Agency (ANR SOLV-CDG to F.F.), and by grant ERARE11-135 of the ERA-Net for Research Programs on Rare Diseases Joint Transnational Call 2011 (EURO-CDG). Congenital disorders of glycosylation (CDGs) form a genetically and clinically heterogeneous group of diseases with aberrant protein glycosylation as a hallmark. A subgroup of CDGs can be attributed to disturbed Golgi homeostasis. However, identification of pathogenic variants is seriously complicated by the large number of proteins involved. As part of a strategy to identify human homologs of yeast proteins that are known to be involved in Golgi homeostasis, we identified uncharacterized transmembrane protein 199 (TMEM199, previously called C17orf32) as a human homolog of yeast V-ATPase assembly factor Vph2p (also known as Vma12p). Subsequently, we analyzed raw exome-sequencing data from families affected by genetically unsolved CDGs and identified four individuals with different mutations in TMEM199. The adolescent individuals presented with a mild phenotype of hepatic steatosis, elevated aminotransferases and alkaline phosphatase, and hypercholesterolemia, as well as low serum ceruloplasmin. Affected individuals showed abnormal N- and mucin-type O-glycosylation, and mass spectrometry indicated reduced incorporation of galactose and sialic acid, as seen in other Golgi homeostasis defects. Metabolic labeling of sialic acids in fibroblasts confirmed deficient Golgi glycosylation, which was restored by lentiviral transduction with wild-type TMEM199. V5-tagged TMEM199 localized with ERGIC and COPI markers in HeLa cells, and electron microscopy of a liver biopsy showed dilated organelles suggestive of the endoplasmic reticulum and Golgi apparatus. In conclusion, we have identified TMEM199 as a protein involved in Golgi homeostasis and show that TMEM199 deficiency results in a hepatic phenotype with abnormal glycosylation. mixed Jansen, Jc; Timal, S; van Scherpenzeel, M; Michelakakis, H; Vicogne, D; Ashikov, A; Moraitou, M; Hoischen, A; Huijben, K; Steenbergen, G; van den Boogert, Ma; Porta, F; Calvo, Pl; Mavrikou, M; Cenacchi, Giovanna; van den Bogaart, G; Salomon, J; Holleboom, Ag; Rodenburg, Rj; Drenth, Jp; Huynen, Ma; Wevers, Ra; Morava, E; Foulquier, F; Veltman, Ja; Lefeber, D. j. Jansen, Jc; Timal, S; van Scherpenzeel, M; Michelakakis, H; Vicogne, D; Ashikov, A; Moraitou, M; Hoischen, A; Huijben, K; Steenbergen, G; van den Boogert, Ma; Porta, F; Calvo, Pl; Mavrikou, M; Cenacchi, Giovanna; van den Bogaart, G; Salomon, J; Holleboom, Ag; Rodenburg, Rj; Drenth, Jp; Huynen, Ma; Wevers, Ra; Morava, E; Foulquier, F; Veltman, Ja; Lefeber, D. j. |
| Databáze: | OpenAIRE |
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