Jos Jansen

2 47 CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation Discussion We identified CCDC115 mutations in eight individuals fromfive unrelated families, and we provide evidence that these mutations affect protein N- and mucin-type O-glycosylation via their effect on Golgi homeostasis. Also, we showed that CCDC115 is localized to the ER-to-Golgi region. However, the question remains— what is the function of CCDC115 and how does its deficiency result in abnormal protein glycosylation and clinical symptoms? Previous studies in mice suggest localization of CCDC115 to the lysosomal- endosomal system and upregulation of Ccdc115 in mouse cortical neurons after fibroblast growth factor 2 (FGF2) stimulation.(29) Overexpression of Ccdc115 in mouse embryonic fibroblasts has been shown to have a positive effect on cell proliferation.(30) Our data suggest a physiological role for CCDC115 in Golgi homeostasis, and loss-of-function mutations lead to the inability of the Golgi to perform its core functions: post-translational modification and protein secretion and sorting. A disturbance in Golgi homeostasis is indicated by the combined defect ofN- andO-glycosylation. Detailedstructural studiesonN-glycans revealed an accumulation of incomplete glycans lacking both sialic acid and galactose. These data indicate a general disturbance in Golgi homeostasis with an effect on multiple glycosylation pathways, for example, via incorrect targeting and/or recycling of glycosyltransferases and nucleotide-sugar transporters. Previously, deficient vesicular transport has been proposed as explanation for abnormal Golgi glycosylation in COG and ATP6V0A2 defects.(5,10) Localization of CCDC115 to, among others, COPI vesicles that are involved in ER-to-Golgi transport and sorting of cargo proteins, could indicate a similar mechanism. Based on comparative genomics, it is likely that CCDC115 and the yeast protein Vma22p are orthologs and have, at least partially, overlapping functions. Vma22p is involved in assembly of the V-ATPase proton pump by stabilizing the V0 domain during early assembly in the ER. Vma22 knockout yeast showed diminished V-ATPase activity and destabilization of the V0 domain.(31) Possibly, mutations in CCDC115 could exert part of the effect via alteration of V-ATPase assembly or function. Vma22p exerts its function as a V-ATPase assembly factor by interacting with Vph2p (also called Vma12p [GenBank: NP_012803]) and Vma21p (GenBank: NP_011619.3).(27) In another study in this issue, we have identified TMEM199 (also known as C17orf32 [GenBank: NP_689677.1]) as the human homolog of Vph2p, and recently VMA21 (GenBank: NP_001017980.1)