Title :

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

Author(s) :

Jansen, Jos C. [Auteur]
Cirak, Sebahattin [Auteur]
van Scherpenzeel, Monique [Auteur]
Timal, Sharita [Auteur]
Reunert, Janine [Auteur]
Rust, Stephan [Auteur]
Pérez, Belén [Auteur]
Vicogne, Dorothee [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Krawitz, Peter [Auteur]
Wada, Yoshinao [Auteur]
Ashikov, Angel [Auteur]
Pérez-Cerdá, Celia [Auteur]
Medrano, Celia [Auteur]
Arnoldy, Andrea [Auteur]
Hoischen, Alexander [Auteur]
Huijben, Karin [Auteur]
Steenbergen, Gerry [Auteur]
Quelhas, Dulce [Auteur]
Diogo, Luisa [Auteur]
Rymen, Daisy [Auteur]
Jaeken, Jaak [Auteur]
Guffon, Nathalie [Auteur]
Cheillan, David [Auteur]
van den Heuvel, Lambertus P. [Auteur]
Maeda, Yusuke [Auteur]
Kaiser, Olaf [Auteur]
Schara, Ulrike [Auteur]
Gerner, Patrick [Auteur]
van den Boogert, Marjolein A. W. [Auteur]
Holleboom, Adriaan G. [Auteur]
Nassogne, Marie-Cécile [Auteur]
Sokal, Etienne [Auteur]
Salomon, Jody [Auteur]
van den Bogaart, Geert [Auteur]
Drenth, Joost P. H. [Auteur]
Huynen, Martijn A. [Auteur]
Veltman, Joris A. [Auteur]
Wevers, Ron A. [Auteur]
Morava, Eva [Auteur]
Matthijs, Gert [Auteur]
Foulquier, Francois [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Marquardt, Thorsten [Auteur]
Lefeber, Dirk J. [Auteur]

Journal title :

American journal of human genetics

Abbreviated title :

Am. J. Hum. Genet.

Volume number :

98

Pages :

310-321

Publication date :

2016-02-04

ISSN :

1537-6605

English keyword(s) :

Humans
Child, Preschool
Molecular Sequence Data
Homeostasis
hepatosplenomegaly
Male
Infant
Endoplasmic Reticulum
Alkaline Phosphatase
V-ATPase assembly
Exome
Cloning, Molecular
Fibroblasts
Female
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Child
Amino Acid Sequence
Golgi homeostasis
Glycosylation
Nerve Tissue Proteins
Vma22p
Golgi Apparatus
Phenotype
Pedigree
Heterozygote
HeLa Cells

HAL domain(s) :

Chimie/Chimie théorique et/ou physique

English abstract : [en]

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. ...
Show more >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.Show less >

Language :

Anglais

Administrative institution(s) :

CNRS
Université de Lille

Collections :

• Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576

Research team(s) :

Mécanismes moléculaires de la N-glycosylation et pathologies associées

Submission date :

2020-02-12T16:20:23Z