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Am J Hum Genet. 2016 Feb 4;98(2):322-30. doi: 10.1016/j.ajhg.2015.12.011. Epub 2016 Jan 28.

TMEM199 Deficiency Is a Disorder of Golgi Homeostasis Characterized by Elevated Aminotransferases, Alkaline Phosphatase, and Cholesterol and Abnormal Glycosylation.

Author information

1
Department of Gastroenterology and Hepatology, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
2
Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
3
Department of Enzymology and Cellular Function, Institute of Child Health, Athens 11526, Greece.
4
CNRS-UMR 8576, Structural and Functional Glycobiology Unit, Federation of Research Structural & Functional Biochemistry of Biomolecular Assemblies (FRABio), University of Lille, 59655 Villeneuve d'Ascq, France.
5
Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
6
Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
7
Department of Vascular Medicine, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
8
Department of Pediatrics, Azienda Ospedaliera Città della Salute e della Scienza, University of Torino, 10126 Torino, Italy.
9
1(st) Department of Pediatrics, P. & A. Kyriakou Children's Hospital, Athens 11527, Greece.
10
Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum-University of Bologna, 40138 Bologna, Italy.
11
Department of Tumor Immunology, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
12
Department of Gastroenterology and Hepatology, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
13
Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Nijmegen Centre for Mitochondrial Disorders, Department of Pediatrics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
14
Centre for Molecular and Biomolecular Informatics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
15
Department of Human Genetics, University of Leuven, 3000 Leuven, Belgium; Hayward Genetics Center, Department of Pediatrics, Tulane University Medical School, New Orleans, LA 70112, USA.
16
Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Clinical Genetics, Maastricht University Medical Centre, 6229 HX Maastricht, the Netherlands.
17
Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands. Electronic address: dirk.lefeber@radboudumc.nl.

Abstract

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.

KEYWORDS:

COPI vesicular transport; Congenital Disorders of Glycosylation; Golgi homeostasis; TMEM199 deficiency; V-ATPase assembly; Vph2p; alkaline phosphatase; elevated aminotransferases; hypercholesterolemia

PMID:
26833330
PMCID:
PMC4746368
DOI:
10.1016/j.ajhg.2015.12.011
[Indexed for MEDLINE]
Free PMC Article

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