Jos Jansen

6 141 Discussion and conclusion One possible explanation could be that patients that develop severe liver disease warranting liver transplantation have more progressive disease and are likely to be diagnosed at young age. Indeed, of all TMEM199-, CCDC115-, and ATP6AP1 deficient patients only 3 (all 3 CCDC115 deficient) required liver transplantation. The oldest was 8 years old. Another explanation could be that patients with a mild phenotype (especially TMEM199-deficient patients) never require a liver transplantation. These patients would more likely be diagnosed at the outward patient clinic. However, few patients have been described thus far and the clinical spectrum will very likely expand over time. Off course, when we started the screening project, CCDC115-CDG and TMEM199- CDG had yet to be discovered and the rationale was based on other potential CDG that can be accompanied by liver disease such as steatosis or fibrosis.(38) Reflections This dissertation focuses on the association between glycosylation and liver disease. We believe that with our findings we contributed in unravelling the fascinating science of glycosylation. Strengths of our study result from our excellent collaborations with experts in the field. This allowed us to identify the number of patients we did for the CCDC115 and TMEM199 papers in the EUROGLYCAN network. Also, establishing a cohort of > 1000 patient samples for screening could only be possible because of collaborations with all national liver transplantation centers. Additionally, a particular strength of all studies is the QTOF-MS, which provides in depth glycan analysis that earlier methods cannot. Limitations andgaps are statedhereand in the researchagenda. For theCCDC115 and TMEM199 articles, one limitation was that we did not use hepatocyte derived cell cultures as glycosylation is known to be tissue specific. These papers were the first to identify the cause ( CCDC115 and TMEM199 pathogenic variants) and effect (abnormal glycosylation and a hepatic phenotype). Everything in between still needs to be explored. We started with localization of both proteins. Another group provided evidence for protein interaction and an effect on acidification. Next groups should focus on finding direct evidence that TMEM199 and CCDC115 are V-ATPase assembly factors. After that, it will be very interesting to see if both proteins are involved in canonical or non-canonical V-ATPase pathways. The narrative review was intended to increase awareness among hepatologists and pediatricians. We first wrote an extensive review on the function of the V-ATP