CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation
| Autor: | Marjolein A.W. van den Boogert, Joost P.H. Drenth, Gerry Steenbergen, Adriaan G. Holleboom, Marie-Cécile Nassogne, Dirk Lefeber, Gert Matthijs, Ulrike Schara, Luísa Diogo, Ron A. Wevers, Sharita Timal, Belén Pérez, Yoshinao Wada, Etienne Sokal, Jaak Jaeken, Peter Krawitz, Martijn A. Huynen, Monique van Scherpenzeel, Lambertus P. van den Heuvel, Patrick Gerner, Celia Medrano, Dorothée Vicogne, Sebahattin Cirak, Eva Morava, Joris A. Veltman, Alexander Hoischen, Daisy Rymen, Geert van den Bogaart, Janine Reunert, Andrea Arnoldy, Thorsten Marquardt, François Foulquier, O. Kaiser, Angel Ashikov, Stephan Rust, Dulce Quelhas, David Cheillan, Celia Pérez-Cerdá, Karin Huijben, Yusuke Maeda, Nathalie Guffon, Jody Salomon, Jos C. Jansen |
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| Přispěvatelé: | Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Genetica & Celbiologie, Klinische Genetica, RS: GROW - School for Oncology and Reproduction, RS: GROW - R4 - Reproductive and Perinatal Medicine, 01 Internal and external specialisms, Graduate School, Vascular Medicine, Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA) |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Glycosylation Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] [SDV]Life Sciences [q-bio] Medizin Golgi Apparatus Compound heterozygosity Golgi homeostasis Endoplasmic Reticulum chemistry.chemical_compound 0302 clinical medicine Missense mutation Homeostasis Genetics(clinical) Exome Cloning Molecular Child Genetics (clinical) Genetics Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] COPI Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] 3. Good health Pedigree Phenotype V-ATPase assembly Child Preschool symbols Female alkaline phosphatase Heterozygote Molecular Sequence Data Nerve Tissue Proteins Biology Vma22p Article Abnormal protein glycosylation Abnormal glycosylation 03 medical and health sciences symbols.namesake Humans Amino Acid Sequence Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] Endoplasmic reticulum Infant Golgi apparatus Fibroblasts Molecular biology 030104 developmental biology Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] chemistry Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization hepatosplenomegaly 030217 neurology & neurosurgery HeLa Cells |
| Zdroj: | Repositorio Institucional de la Consejería de Sanidad de la Comunidad de Madrid Consejería de Sanidad de la Comunidad de Madrid American Journal of Human Genetics American Journal of Human Genetics, Elsevier (Cell Press), 2016, 98 (2), pp.310-21. ⟨10.1016/j.ajhg.2015.12.010⟩ American Journal of Human Genetics, 98, 2, pp. 310-21 American Journal of Human Genetics, 98(2), 310-321. Cell Press American journal of human genetics, 98(2), 310-321. Cell Press American Journal of Human Genetics, 98, 310-21 |
| ISSN: | 1537-6605 0002-9297 |
| DOI: | 10.1016/j.ajhg.2015.12.010⟩ |
| Popis: | Contains fulltext : 167630.pdf (Publisher’s version ) (Closed access) 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. |
| Databáze: | OpenAIRE |
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