Jos Jansen

138 Chapter 6 ER-to-Golgi trafficking and non-NAFLD hepatic disorders Chapter 4 provides in-depth analysis of possible mechanisms for the NAFLD phenotype. NAFLD is not the only disease resembling CCDC115 and TMEM199 deficiency. Clinicians also considered Wilson disease and Niemann-Pick C. Additionally, LAL deficiency patients also show a similar phenotype. Knowledge on ER-to-Golgi trafficking in these diseases could provide clues for the pathogenesis in CCC115 and TMEM199 deficiency and vice versa. Wilson disease Unexplained elevated aminotransferases and low ceruloplasmin triggered several physicians of patients with CCDC115 and TMEM199 mutations to consider Wilson disease (WD, MIM: 227900). This autosomal recessively inherited disease is characterized by intracellular copper accumulation leading to hepatic, neurologic and psychiatric symptoms. Here, I will focus on the pathologic effects of WD on the liver. For a comprehensive review on neurological symptoms I refer elsewhere. (17) Patients with WD typically present with liver symptoms between the first and second decade of life, two to five years before neurological symptoms occur.(18) Around 5% of patients with WD are indicated to receive a liver transplantation. (19) WD is caused by mutations in ATP7B , localized in the trans -Golgi network (TGN) were it provides copper to enzymes such as ceruloplasmin, which can then be secreted into the bloodstream (20). Furthermore, excessive Cu 2+ in hepatocytes is removed from the cells by translocation of ATP7B to the bile canaliculi.(21) ATP7B is primarily expressed in hepatocytes in contrast to its paralog ATP7A which is located in all non-hepatic tissues. (22) Insights on TGN-to-endosome trafficking show that ATP7A/B endocytosis is dependent on regulatory transporter proteins such as clathrin, AP-1, AP-2 and Rab22.(23) Interestingly, exocytosis of ATP7B in case of excessive copper follows a lysosomal exocytotic pathway, known to be disturbed in Ac45 knockdown mice.(24, 25) In contrast to post-Golgi trafficking not much is known on ER-to- Golgi and intra Golgi regulation of copper. Golgi-homeostasis defects in CCDC115- and TMEM199 deficient patients may lead to copper homeostasis defects through different mechanisms. Although not