title: CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation.
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.
authors.affiliation: 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.
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authors.lastname: Marquardt
authors.affiliation: 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: dirk.lefeber@radboudumc.nl.
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mesh_terms: D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D003001:Cloning, Molecular; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059472:Exome; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D006031:Glycosylation; D006056:Golgi Apparatus / Q000235:genetics* / Q000378:metabolism; D006367:HeLa Cells; D006579:Heterozygote; D006706:Homeostasis; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D009419:Nerve Tissue Proteins
keywords: Golgi homeostasis; V-ATPase assembly; Vma22p; alkaline phosphatase; glycosylation; hepatosplenomegaly
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