Title :

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

Author(s) :

Jansen, Jos C. [Auteur]
Timal, Sharita [Auteur]
van Scherpenzeel, Monique [Auteur]
Michelakakis, Helen [Auteur]
Vicogne, Dorothee [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF]
Ashikov, Angel [Auteur]
Moraitou, Marina [Auteur]
Hoischen, Alexander [Auteur]
Huijben, Karin [Auteur]
Steenbergen, Gerry [Auteur]
van den Boogert, Marjolein A. W. [Auteur]
Porta, Francesco [Auteur]
Calvo, Pier Luigi [Auteur]
Mavrikou, Mersyni [Auteur]
Cenacchi, Giovanna [Auteur]
van den Bogaart, Geert [Auteur]
Salomon, Jody [Auteur]
Holleboom, Adriaan G. [Auteur]
Rodenburg, Richard [Auteur]
Drenth, Joost P. H. [Auteur]
Huynen, Martijn A. [Auteur]
Wevers, Ron A. [Auteur]
Morava, Eva [Auteur]
Foulquier, Francois [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF]
Veltman, Joris A. [Auteur]
Lefeber, Dirk J. [Auteur]

Journal title :

American journal of human genetics

Abbreviated title :

Am. J. Hum. Genet.

Volume number :

98

Pages :

322-330

Publication date :

2016-02-04

ISSN :

1537-6605

English keyword(s) :

Ceruloplasmin
Humans
Molecular Sequence Data
Homeostasis
Male
Endoplasmic Reticulum
Alkaline Phosphatase
V-ATPase assembly
hypercholesterolemia
Young Adult
Exome
Fibroblasts
Adult
elevated aminotransferases
TMEM199 deficiency
Amino Acid Sequence
Golgi homeostasis
Genotype
Glycosylation
Cholesterol
Golgi Apparatus
Phenotype
Congenital Disorders of Glycosylation
Transaminases
Membrane Protein
Mutation
Vph2p
COPI vesicular transport

HAL domain(s) :

Chimie/Chimie théorique et/ou physique

English abstract : [en]

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 ...
Show more >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.Show less >

Language :

Anglais

Administrative institution(s) :

CNRS
Université de Lille

Collections :

• Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576

Research team(s) :

Mécanismes moléculaires de la N-glycosylation et pathologies associées

Submission date :

2020-02-12T15:12:01Z