Jos Jansen

142 Chapter 6 assembly factors (published in this dissertation) but soon realized that this was not for a broad public. Therefore, a concise letter was drafted accompanied by an informative figure. We believe it is essential that awareness is increased as this will shed light on prevalence and the clinical spectrum. Our screening study did not identify a CDG. A limitation of this study was that a large number of samples had to be excluded because of low quality. As sample agepotentiallynegatively affects quality, webelieve it is best tobuildaprospective database with the drawing of fresh samples and immediate glycoanalysis. Careful patient selection will increase the likelihood for CDG identification. Cut-off values based on liver enzymes, cholesterol and ceruloplasmin seem an obvious choice. Also, there should be a maximum age of 30-40 years as all V-ATPase deficient patients are diagnosed at a relatively young age. Concerning the methods used, we would suggest to abandon tIEF and directly screen with QTOF-MS. Improvements in QTOF-MS workflow makes this possible nowadays. Future perspectives and conclusions Identification of TMEM199-CDG and CCDC115-CDG is important for two reasons. The first is that patients with a resembling phenotype get a correct diagnosis. This prevents excessive treatment, such as Zinc, which can potentially be harmful. We are still far away from a treatment for these patients, however, identifying the affected genes is a first step. Treatment options can be pathway specific, for example, modulators of protein trafficking or V-ATPase functioning. This all depends on the function of both proteins. Another exciting option is knock-in of the wildtype gene with CRISPR/Cas9 technology in patient-derived organoids and subsequent retransplantation.(39) This technique is still a distinct prospect but could cure metabolic liver disease. More readily available treatments rely on unraveling the function of TMEM199 and CCDC115. Therefore, I believe that future research should focus on establishing the function of both proteins in human by answering questions such as: what is the protein interaction network of both proteins and what are the effects on glycosylation, protein trafficking and the V-ATPase? (See also Box 1). As a secondary important topic, the role of these two proteins, and V-ATPase assembly factors more general, should be studied in more common hepatic diseases, such as NAFLD and WD. This will further our understandings of these diseases and hopefully aid in finding a cure for these patients.