2. Academic Validation
  3. CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation

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

  • Am J Hum Genet. 2016 Feb 4;98(2):310-21. doi: 10.1016/j.ajhg.2015.12.010.
Jos C Jansen 1,  Sebahattin Cirak 2,  Monique van Scherpenzeel 3,  Sharita Timal 3,  Janine Reunert 4,  Stephan Rust 4,  Belén Pérez 5,  Dorothée Vicogne 6,  Peter Krawitz 7,  Yoshinao Wada 8,  Angel Ashikov 3,  Celia Pérez-Cerdá 5,  Celia Medrano 5,  Andrea Arnoldy 9,  Alexander Hoischen 10,  Karin Huijben 11,  Gerry Steenbergen 11,  Dulce Quelhas 12,  Luisa Diogo 13,  Daisy Rymen 14,  Jaak Jaeken 14,  Nathalie Guffon 15,  David Cheillan 15,  Lambertus P van den Heuvel 16,  Yusuke Maeda 17,  Olaf Kaiser 18,  Ulrike Schara 18,  Patrick Gerner 19,  Marjolein A W van den Boogert 20,  Adriaan G Holleboom 20,  Marie-Cécile Nassogne 21,  Etienne Sokal 21,  Jody Salomon 22,  Geert van den Bogaart 23,  Joost P H Drenth 22,  Martijn A Huynen 24,  Joris A Veltman 25,  Ron A Wevers 11,  Eva Morava 26,  Gert Matthijs 14,  François Foulquier 6,  Thorsten Marquardt 4,  Dirk J Lefeber 27
Affiliations

Affiliations

  • 1 Department of Gastroenterology and Hepatology, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
  • 2 Institut für Humangenetik, Uniklinik Köln, 50931 Köln, Germany; Klinik und Poliklinik für Kinder- und Jugendmedizin, Uniklinik Köln, 50937 Köln, Germany; Zentrum für Molekulare Medizin, Uniklinik Köln, 50931 Köln, Germany.
  • 3 Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
  • 4 Department of Pediatrics, Westfälische Wilhelms-Universität Münster, 48149 Münster, Germany.
  • 5 Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular Severo Ochoa UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) and Instituto de Investigación Sanitaria (IdiPAZ), 28049 Madrid, Spain.
  • 6 CNRS-UMR 8576, Structural and Functional Glycobiology Unit, Federation of Research Structural & Functional Biochemistry of Biomolecular Assemblies (FRABio), University of Lille, 59655 Villeneuve d'Ascq, France.
  • 7 Institute for Medical Genetics, 13353 Berlin, Germany.
  • 8 Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka 594-1101, Japan.
  • 9 Department of Pediatrics, University of Essen, 45122 Essen, Germany.
  • 10 Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
  • 11 Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
  • 12 Biochemical Genetics Unit, Centro de Genética Médica Jacinto de Magalhães, Centro Hospitalar do Porto, 4050-466 Porto, Portugal.
  • 13 Metabolic Diseases Unit, Centro de Desenvolvimento da Criança, Hospital Pediátrico, Centro Hospitalar Universitário de Coimbra, 3000-609 Coimbra, Portugal.
  • 14 Department of Pediatrics, University of Leuven, 3000 Leuven, Belgium.
  • 15 Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Femme Mère Enfant, 69677 Bron Cedex, France.
  • 16 Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Nijmegen Center for Mitochondrial Disorders, Translational Metabolic Laboratory, Department of Pediatrics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
  • 17 Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
  • 18 Department of Pediatric Neurology, Children's Hospital Essen, 45122 Essen, Germany.
  • 19 Department of Pediatric Gastroenterology, Hepatology and Endoscopy, University Hospital, 79110 Freiburg, Germany.
  • 20 Department of Vascular Medicine, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
  • 21 Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, 1200 Woluwe-Saint-Lambert, Belgium.
  • 22 Department of Gastroenterology and Hepatology, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
  • 23 Department of Tumor Immunology, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
  • 24 Center for Molecular and Biomolecular Informatics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
  • 25 Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Clinical Genetics, Maastricht University Medical Centre, 6229 HX Maastricht, the Netherlands.
  • 26 Department of Pediatrics, University of Leuven, 3000 Leuven, Belgium; Hayward Genetics Center, Department of Pediatrics, Tulane University Medical School, New Orleans, LA 70112, USA.
  • 27 Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands. Electronic address: [email protected].
PMID: 26833332 DOI: 10.1016/j.ajhg.2015.12.010
Abstract

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.

Keywords

Golgi homeostasis; V-ATPase assembly; Vma22p; alkaline phosphatase; glycosylation; hepatosplenomegaly.

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