Jos Jansen

90 Chapter 4 Secondary causes of NAFLD are important to recognize as their natural history, associated symptoms, and overall management differ from that of primary NAFLD. In this review, we describe a recently discovered group of genetic defects in assembly factors of the vacuolar H+ ATPase (V-ATPase), the intracellular proton pump. These defects result in abnormal protein glycosylation due to impaired Golgi trafficking and a complex phenotype, dominated by hepatic steatosis, which often is the primary manifestation of disease. We will discuss the process of protein glycosylation, the function of the V-ATPase complex and the mechanisms of hepatic lipid build-up in view of these novel disorders and propose that CCDC115-, TMEM199-, and ATP6AP1 deficiency are established as a cause of secondary NAFLD. Protein glycosylation Glycans are compounds of covalently linked monosaccharides and are one of four basic components of cells (in addition to nucleic acids, proteins, and lipids). (11) They serve multiple purposes including stabilization of folded proteins, intercellular communication, protein trafficking, and modulation of protein or lipid properties.(12) The attachment of a glycan to a protein or lipid is termed glycosylation and is a complex and highly regulated form of post translational modification.(13) Glycosylation starts in the endoplasmatic reticulum (ER) where the glycan build up and en bloc transfer to the nascent protein or lipid take place. If correctly folded, the newly formed glycoprotein travels to the Golgi apparatus (or simply ‘Golgi’). In the Golgi, modification of the glycan takes place which results in the finished glycoprotein ready to be transported to other cellular compartments or into the bloodstream.(12) Primary glycosylation defects Primary glycosylation defects are congenital defects of glycosylation (CDG). This group encompasses more than 100 monogenic defects and is rapidly expanding. (14) Overall prevalence rates are unknown, but exome sequencing data predict a carriership of 20% and a prevalence of 1-2/1.000 persons for all known CDG genes.(14) All defects are inherited in an (X-linked) autosomal recessive pattern and result in a complex heterogenic phenotype. CDG are classified based on an Endoplasmatic reticulum (ER)- or Golgi-located