Jos Jansen

4 91 NAFLD Phenotype in Patients With V-ATPase Proton Pump Assembly Defects defect. One of the disease mechanisms of Golgi-located CDG is based on imbalance of Golgi homeostasis.(14) In these patients, abnormal glycosylation is a result of an improper electrolyte balance or defective trafficking of glycosyltransferases, part of the Golgi glycosylation machinery.(15-17) Diagnostics The field of glycosylation research (or ‘glycomics’) is challenging because of its complex and dynamic nature. Recent advances in techniques for glycoanalysis suchashigh-resolutionmass spectrometryhas led toan increasedunderstanding of function and regulation of glycans.(18) Ingastroenterologyandhepatology, glycomicswasmostly limitedto identification of biomarkers for liver cirrhosis, hepatocellular carcinoma, or colorectal cancer. (19-21) More recently, genetic studies implicated glycosylation genes in IBD and polycystic liver disease.(22) , (23) To what extent aberrant glycosylation plays a part in these pathomechanisms remains to be identified. Diagnostics for CDG are based on glycosylation properties of transferrin. Traditionally, iso-electric focusing was used for rapid determination of the two glycans attached to transferrin. Although this provided a quick and cheap entry test of the glycosylation state of transferrin, (and extrapolation to whole body glycosylation) more detailed insight in glycan build-up was required. Mass spectrometry of intact glycoprotein transferrin affords new insights into glycosylation patterns and has successfully been employed for discovery, diagnostics, and/or monitoring of other CDG subtypes.(24, 25) Next generation sequencing has greatly accelerated identification of newCDG.(26) Declining costs and increased availability will lead to an increased use of genomic sequencing in parallel with glycomics to identify CDG patients. TMEM199-, CCDC115-, and ATP6AP1 deficiency As the main site for protein synthesis, the liver is frequently affected in CDG patients and elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) serum levels are a common finding.(23) Recently, three CDG subtypes with a predominant liver phenotype have been discovered through advanced genetic studies.(27-29) Patients with pathogenic variants in the V-ATPase assembly factors TMEM199 (MIM: 616829), CCDC115 (MIM: 616828), or ATP6AP1 (MIM: 300972) have defective glycosylation based on abnormal Golgi