TY - JOUR
T1 - CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation
AU - Jansen, Jos C.
AU - Cirak, Sebahattin
AU - van Scherpenzeel, Monique
AU - Timal, Sharita
AU - Reunert, Janine
AU - Rust, Stephan
AU - Perez, Belen
AU - Vicogne, Dorothee
AU - Krawitz, Peter
AU - Wada, Yoshinao
AU - Ashikov, Angel
AU - Perez-Cerda, Celia
AU - Medrano, Celia
AU - Arnoldy, Andrea
AU - Hoischen, Alexander
AU - Huijben, Karin
AU - Steenbergen, Gerry
AU - Quelhas, Dulce
AU - Diogo, Luisa
AU - Rymen, Daisy
AU - Jaeken, Jaak
AU - Guffon, Nathalie
AU - Cheillan, David
AU - van den Heuvel, Lambertus P.
AU - Maeda, Yusuke
AU - Kaiser, Olaf
AU - Schara, Ulrike
AU - Gerner, Patrick
AU - van den Boogert, Marjolein A. W.
AU - Holleboom, Adriaan G.
AU - Nassogne, Marie-Cecile
AU - Sokal, Etienne
AU - Salomon, Jody
AU - van den Bogaart, Geert
AU - Drenth, Joost P. H.
AU - Huynen, Martijn A.
AU - Veltman, Joris A.
AU - Wevers, Ron A.
AU - Morava, Eva
AU - Matthijs, Gert
AU - Foulquier, Francois
AU - Marquardt, Thorsten
AU - Lefeber, Dirk J.
PY - 2016/2/4
Y1 - 2016/2/4
N2 - 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.
AB - 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.
U2 - 10.1016/j.ajhg.2015.12.010
DO - 10.1016/j.ajhg.2015.12.010
M3 - Article
C2 - 26833332
SN - 0002-9297
VL - 98
SP - 310
EP - 321
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 2
ER -