Jos Jansen

2 29 CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation Introduction Congenital Disorders of glycosylation (CDG) are a heterogeneous group of monogenic diseases affecting the glycosylation of proteins and lipids. Approximately 100 CDG have been described so far, and they affect multiple glycosylation pathways.(1) CDG with abnormal protein N-linked glycosylation can be divided into type 1 CDG, affecting glycan assembly in the endoplasmatic reticulum (ER), and type 2 CDG, affecting glycan modification in the Golgi apparatus. Identification of disease-associated genes in the latter group is complicated by the complexity of the Golgi apparatus and the heterogeneous phenotype of individuals with CDG, making phenotypic clustering difficult. Type 2 CDG can be further grouped on the basis of disease mechanism. Mutations in genes encoding for proteins directly involved in Golgi glycosylation (e.g., SLC35A1 [MIM: 605634], B4GALT1 [MIM: 137060], and MGAT2 [MIM: 602616]) were the first to be discovered.(2–4) Another group of type 2 CDG are caused by disturbances in Golgi homeostasis. This group encompasses several conserved oligomeric Golgi (COG)-CDG, TMEM165-CDG (MIM: 14726) and ATP6V0A2-CDG (MIM:611716). The COG complex is involved in retrograde Golgi transport, and mutations lead to abnormal distribution of proteins involved in the glycosylation machinery, such as glycosyltransferases.(5) TMEM165 mutations were recently described in individuals with skeletal symptoms and linked with deficient Ca2 + and pH homeostasis.(6,7) ATP6V0A2 mutations were described in autosomal- recessive cutis laxa type 2 (ARCL2 [MIM: 219200]).(8) ATP6V0A2 encodes a subunit of the vacuolar H + ATPase (V-ATPase), which is primarily responsible for acidification of organelles within the secretory pathway and endolysosomal system.(9) Fibroblasts from ARCL2-affected individuals show delayed retrograde Golgi transport, in accordance with the versatile role of the V-ATPase and its involvement in multiple cellular processes.(10,11) Traditionally, diagnostics for protein N-glycosylation defects is performed with isoelectric focusing (IEF) of serum transferrin (Tf). This method is used to distinguish between type 1 and type 2 CDG.(12) Additionally, IEF of serum apolipoprotein C-III (ApoC-III) can detect abnormal mucin-type O-glycosylation. (13) Recently, we described the use of a high resolution nanochip-C8 QTOF mass spectrometry method for annotation of glycan structures on intact serum Tf.(14)