Jos Jansen

2 49 CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation high bone-derived ALP can be observed in individuals with defects of GPI anchor biosynthesis.(44,45) However, this is not supported for CCDC115 deficiency. Trafficking of GPI-anchored proteins, which might include ALP, is suggested to occur through a COPII-dependent process from ER exit sites.(46) In Vma22p mutant yeast, trafficking of ALP to the yeast vacuole is not majorly altered. (31) However, yeast ALP is membrane bound and not a GPI-anchored protein. Treatment of yeast with bafilomycin A1, a potent V-ATPase inhibitor known to block vacuole acidification, did not show any effect on trafficking and maturation of membrane-bound yeast ALP.(47) This suggests that transport of vacuolar membrane proteins, including ALP, in yeast is independent from acidification. A study in mouse pituitary corticotrope tumor cells showed decreased trafficking of cargo proteins, independent of pH, after incubationwith Concamycin A (ConA), another V-ATPase inhibitor. Although knockdown of the V-ATPase showed an overlapping phenotype with ConA treatment, this was not investigated for protein secretion. Additionally, processing of the investigated protein, PC1, begins in the trans-Golgi network and could therefore not be representative for Golgi trafficking.(48) Based on the localization of CCDC115 in the ER-to-Golgi region, it could be speculated that CCDC115 has a role in protein cargo sorting or trafficking of alkaline phosphatase in addition to a possible role in V-ATPase assembly. In conclusion, we describe eight individuals with a type 2 CDG fromfive unrelated families affected by mutations in CCDC115 . The phenotype consists of elevated aminotransferases and alkaline phosphatase and hepatosplenomegaly in combination with psychomotor disability, hypercholesterolemia, and hypotonia. Based on homology detection, glycosylation studies, and cellular co-localization, we propose a role for CCDC115 in Golgi homeostasis.