Jansen, Jos C., Cirak, Sebahattin, van Scherpenzeel, Monique ORCID: 0000-0002-9696-4562, Timal, Sharita, Reunert, Janine, Rust, Stephan, Perez, Belen, Vicogne, Dorothee, Krawitz, Peter, Wada, Yoshinao, Ashikov, Angel ORCID: 0000-0001-9679-7955, Perez-Cerda, Celia, Medrano, Celia ORCID: 0000-0001-9634-7874, Arnoldy, Andrea, Hoischen, Alexander ORCID: 0000-0002-8072-4476, Huijben, Karin, Steenbergen, Gerry, Quelhas, Dulce ORCID: 0000-0001-9989-9236, Diogo, Luisa, Rymen, Daisy, Jaeken, Jaak, Guffon, Nathalie, Cheillan, David, van den Heuvel, Lambertus P., Maeda, Yusuke, Kaiser, Olaf, Schara, Ulrike, Gerner, Patrick, van den Boogert, Marjolein A. W., Holleboom, Adriaan G., Nassogne, Marie-Cecile ORCID: 0000-0001-6936-1611, Sokal, Etienne ORCID: 0000-0001-5597-4708, Salomon, Jody, van den Bogaart, Geert ORCID: 0000-0003-2180-6735, Drenth, Joost P. H., Huynen, Martijn A., Veltman, Joris A., Wevers, Ron A., Morava, Eva, Matthijs, Gert ORCID: 0000-0001-6710-1912, Foulquier, Francois, Marquardt, Thorsten and Lefeber, Dirk J. (2016). CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation. Am. J. Hum. Genet., 98 (2). S. 310 - 322. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Jansen, Jos C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cirak, SebahattinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Scherpenzeel, MoniqueUNSPECIFIEDorcid.org/0000-0002-9696-4562UNSPECIFIED
Timal, SharitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reunert, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rust, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perez, BelenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vicogne, DorotheeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krawitz, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wada, YoshinaoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ashikov, AngelUNSPECIFIEDorcid.org/0000-0001-9679-7955UNSPECIFIED
Perez-Cerda, CeliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Medrano, CeliaUNSPECIFIEDorcid.org/0000-0001-9634-7874UNSPECIFIED
Arnoldy, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoischen, AlexanderUNSPECIFIEDorcid.org/0000-0002-8072-4476UNSPECIFIED
Huijben, KarinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steenbergen, GerryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Quelhas, DulceUNSPECIFIEDorcid.org/0000-0001-9989-9236UNSPECIFIED
Diogo, LuisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rymen, DaisyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jaeken, JaakUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guffon, NathalieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cheillan, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van den Heuvel, Lambertus P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maeda, YusukeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kaiser, OlafUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schara, UlrikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gerner, PatrickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van den Boogert, Marjolein A. W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holleboom, Adriaan G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nassogne, Marie-CecileUNSPECIFIEDorcid.org/0000-0001-6936-1611UNSPECIFIED
Sokal, EtienneUNSPECIFIEDorcid.org/0000-0001-5597-4708UNSPECIFIED
Salomon, JodyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van den Bogaart, GeertUNSPECIFIEDorcid.org/0000-0003-2180-6735UNSPECIFIED
Drenth, Joost P. H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huynen, Martijn A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Veltman, Joris A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wevers, Ron A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morava, EvaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Matthijs, GertUNSPECIFIEDorcid.org/0000-0001-6710-1912UNSPECIFIED
Foulquier, FrancoisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marquardt, ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lefeber, Dirk J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-284774
DOI: 10.1016/j.ajhg.2015.12.010
Journal or Publication Title: Am. J. Hum. Genet.
Volume: 98
Number: 2
Page Range: S. 310 - 322
Date: 2016
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1537-6605
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
VACUOLAR PROTON PUMP; X-LINKED MYOPATHY; CONGENITAL DISORDERS; N-GLYCAN; ENDOPLASMIC-RETICULUM; MASS-SPECTROMETRY; MUTATIONS; ATPASE; YEAST; DIAGNOSISMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/28477

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