CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation

Jos C. Jansen, Sebahattin Cirak, Monique Van Scherpenzeel, Sharita Timal, Janine Reunert, Stephan Rust, Belén Pérez, Dorothée Vicogne, Peter Krawitz, Yoshinao Wada, Angel Ashikov, Celia Pérez-Cerdá, Celia Medrano, Andrea Arnoldy, Alexander Hoischen, Karin Huijben, Gerry Steenbergen, Dulce Quelhas, Luisa Diogo, Daisy RymenJaak Jaeken, Nathalie Guffon, David Cheillan, Lambertus P. Van Den Heuvel, Yusuke Maeda, Olaf Kaiser, Ulrike Schara, Patrick Gerner, Marjolein A.W. Van Den Boogert, Adriaan G. Holleboom, Marie Cécile Nassogne, Etienne Sokal, Jody Salomon, Geert Van Den Bogaart, Joost P.H. Drenth, Martijn A. Huynen, Joris A. Veltman, Ron A. Wevers, Eva Morava, Gert Matthijs, François Foulquier, Thorsten Marquardt, Dirk J. Lefeber

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


Disorders of Golgi homeostasis form an emerging group of genetic defects. The highly heterogeneous clinical spectrum is not explained by our current understanding of the underlying cell-biological processes in the Golgi. Therefore, uncovering genetic defects and annotating gene function are challenging. Exome sequencing in a family with three siblings affected by abnormal Golgi glycosylation revealed a homozygous missense mutation, c.92T>C (p.Leu31Ser), in coiled-coil domain containing 115 (CCDC115), the function of which is unknown. The same mutation was identified in three unrelated families, and in one family it was compound heterozygous in combination with a heterozygous deletion of CCDC115. An additional homozygous missense mutation, c.31G>T (p.Asp11Tyr), was found in a family with two affected siblings. All individuals displayed a storage-disease-like phenotype involving hepatosplenomegaly, which regressed with age, highly elevated bone-derived alkaline phosphatase, elevated aminotransferases, and elevated cholesterol, in combination with abnormal copper metabolism and neurological symptoms. Two individuals died of liver failure, and one individual was successfully treated by liver transplantation. Abnormal N- and mucin type O-glycosylation was found on serum proteins, and reduced metabolic labeling of sialic acids was found in fibroblasts, which was restored after complementation with wild-type CCDC115. PSI-BLAST homology detection revealed reciprocal homology with Vma22p, the yeast V-ATPase assembly factor located in the endoplasmic reticulum (ER). Human CCDC115 mainly localized to the ERGIC and to COPI vesicles, but not to the ER. These data, in combination with the phenotypic spectrum, which is distinct from that associated with defects in V-ATPase core subunits, suggest a more general role for CCDC115 in Golgi trafficking. Our study reveals CCDC115 deficiency as a disorder of Golgi homeostasis that can be readily identified via screening for abnormal glycosylation in plasma.

Original languageEnglish (US)
Pages (from-to)310-321
Number of pages12
JournalAmerican journal of human genetics
Issue number2
StatePublished - Feb 4 2016


  • Golgi homeostasis
  • V-ATPase assembly
  • Vma22p
  • alkaline phosphatase
  • glycosylation
  • hepatosplenomegaly

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


Dive into the research topics of 'CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation'. Together they form a unique fingerprint.

Cite this