Jos Jansen

80 Chapter 3 We have shown that prioritization of exome data based on functional knowledge of abnormal protein glycosylation can successfully elucidate previously unknown Golgi homeostasis defects. Protein interaction maps can be a useful tool for further identification of novel candidate proteins. During our studies, a protein interaction map of Drosophila melanogaster identified interactions between CG7071 (the fruit fly TMEM199) and multiple V-ATPase subunits.(31) Recently, an ongoing effort to map the human interactome reported similar protein- protein interactions in humans (accessed via BioGRID, see Web Resources). Such interactomes will be of great benefit for disease-gene prioritization in cohorts of families with genetically unsolved cases of type 2 CDG. In conclusion, we used comparative genomics to uncover TMEM199 as a protein involved in Golgi homeostasis, most likely with at least a partial role in V-ATPase functioning. TMEM199 deficiency should be considered in individuals with unexplained mildly elevated serum ATs, elevated ALP, hepatic steatosis, hypercholesterolemia, and low serum ceruloplasmin. We suggest screening for abnormal glycosylation in individuals with these symptoms. Accession Numbers The accession numbers for the pathogenic variants c.92G > C, c.20C > A, and c.40G > C; 376-1G > A reported in this paper are ClinVar: SCV000257475, SCV000257473, and SCV000257476, respectively. Acknowledgments We would like to thank the CDG-affected families for their participation in this study. We would also like to thank the group of Dr. Y. Guerardel and Prof. C. Biot for their generous donation of ManNAl. This work was financially supported by grants from the Institute of Genetic and Metabolic Disease (to D.J.L., R.J.R., and J.A.V.), the Dutch Organization for Scientific Research (ZONMW Medium Investment Grant 40-00506-98-9001 and VIDI Grant 91713359 to D.J.L. and VENI grant to A.G.H.), the Metakids foundation (J.C.J., M.v.S., J.P.H.D., and D.J.L.), the AMC graduate school Ph.D scholarship (M.A.W.v.d.B.), the Dr. Karel-Lodewijk Verleysen Award (J.C.J. and J.P.H.D.), the French National Agency (ANR SOLV-CDG to F.F.), and by grant ERARE11-135 of the ERANet for Research Programs on Rare Diseases Joint Transnational Call 2011 (EURO-CDG).