TMEM199 is a novel Golgi factor involved in protein glycosylation

Jansen, Jos.jpg

Jos Jansen, Dept. of Gastroenterology and Hepatology, under supervision of Dirk Lefeber identified uncharacterized Transmembrane protein 199 as a novel factor in ER-Golgi trafficking, as reported in the American Journal of Human Genetics.

In a strategy to identify human homologs of yeast proteins that are known to be involved in Golgi homeostasis, TMEM199 was predicted as human homolog of yeast V-ATPase assembly factor Vma12p. Subsequent analysis of raw exome sequencing data of unsolved families with abnormal glycosylation revealed pathogenic mutations in TMEM199. The adolescent individuals presented with a mild liver phenotype, hypercholesterolemia, and muscle hypotonia. 

Unraveling the role of the Golgi apparatus in protein glycosylation

Protein glycosylation is one of the major functions of the Golgi apparatus.  More than 1000 proteins are involved in Golgi homeostasis in diverse processes such as vesicle transport. Little is known about the molecular mechanisms of Golgi transport in relation to protein glycosylation. Congenital Disorders of Glycosylation(CDG) form a group of autosomal recessive diseases with abnormal glycosylation and an emerging subgroup is caused by defects in Golgi vesicular trafficking.

In several families with abnormal protein glycosylation, no gene defect could be identified despite extensive genetic testing. A bio-informatics strategy was employed to search for human homologs of yeast genes that are known to be involved in Golgi homeostasis. TMEM199 (C17orf32) was identified as human homolog of yeast V-ATPase assembly factor Vph2p (also known as Vma12p). Subsequently, TMEM199 mutations were identified by inspection of the raw exome sequencing data.

Patients presented with abnormal protein N-glycosylation and O-glycosylation as shown by glycomics analysis of serum proteins. In addition, metabolic labeling of glycans in patient cells showed reduced incorporation and a dilated Golgi, which could be restored by lentiviral mediated complementation. TMEM199 in human cells localizes in ERGIC and COPI vesicles, in contrast to the ER localization of Vma12p in yeast. These data indicate TMEM199 as a novel Golgi factor that is important for various glycosylation pathways.

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