Jos Jansen

6 133 Discussion and conclusion Chapter Main findings Implications Limitations 2 and 3 • 12 patients from 8 fami- lies were clustered based on comparable hepatic phenotype and glycosyla- tion defects • Comparative genomics identified TMEM199 and CCDC115 as the human orthologs of yeast V-AT- Pase assembly factors Vph2p and Vma22p • NGS revealed pathogenic variants in CCDC115 and TMEM199 • CCDC115 and TMEM199 localize to the ER-to-Golgi region • (TMEM199 only) Ultra- structural hepatocyte analysis shows dilated Golgi and steatosis • Defects in CCDC115 and TMEM199 are recognized as a new type 2 CDG • Clinicians should be aware of CCDC115- and TMEM199 deficiency in patients with abnormal glycosylation, elevated liver enzymes and hepa- tosplenomegaly • Additional indirect evidence for the link between V-ATPase and abnormal glycosylation • All observations are in skin fibroblasts and HeLa cells, not in hepatocytes or hepatocyte-derived cell cultures 4 • This narrative review summarizes the findings of chapter 2 and 3 and puts them into perspec- tive • Increased awareness among hepatologists • Few patients • Large gaps in knowledge regarding function and pathogenicity 5 • No CDG were found • Hyperfucosylation is as- sociated with end-stage liver disease • CDG screening can be hampered by synchro- nous liver disease • Fair amount of drop- out due to low-quality samples • Sample size not large enough for CDG detec- tion HC=healthy controls, CLD=chronic liver disease, LTx=liver transplantation, K-W=Kruskal Wallis test, SD=standard deviation