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

被引：79

作者：

Jansen, Jos C. ^{[1
,2
]}

Cirak, Sebahattin ^{[3
,4
,5
]}

van Scherpenzeel, Monique ^{[2
,6
]}

Timal, Sharita ^{[2
,6
]}

Reunert, Janine ^{[7
]}

Rust, Stephan ^{[7
]}

Perez, Belen ^{[8
,9
,10
]}

Vicogne, Dorothee ^{[11
]}

Krawitz, Peter ^{[12
]}

Wada, Yoshinao ^{[13
,14
]}

Ashikov, Angel ^{[2
,6
]}

Perez-Cerda, Celia ^{[8
,9
,10
]}

Medrano, Celia ^{[8
,9
,10
]}

Arnoldy, Andrea ^{[15
]}

Hoischen, Alexander ^{[16
]}

Huijben, Karin ^{[2
]}

Steenbergen, Gerry ^{[2
]}

Quelhas, Dulce ^{[17
]}

Diogo, Luisa ^{[18
]}

Rymen, Daisy ^{[19
]}

Jaeken, Jaak ^{[19
]}

Guffon, Nathalie ^{[20
]}

Cheillan, David ^{[20
]}

van den Heuvel, Lambertus P. ^{[2
,21
]}

Maeda, Yusuke ^{[22
]}

Kaiser, Olaf ^{[23
]}

Schara, Ulrike ^{[23
]}

Gerner, Patrick ^{[24
]}

van den Boogert, Marjolein A. W. ^{[25
]}

Holleboom, Adriaan G. ^{[25
]}

Nassogne, Marie-Cecile ^{[26
]}

Sokal, Etienne ^{[26
]}

Salomon, Jody ^{[1
]}

van den Bogaart, Geert ^{[27
]}

Drenth, Joost P. H. ^{[1
]}

Huynen, Martijn A. ^{[28
]}

Veltman, Joris A. ^{[16
,29
]}

Wevers, Ron A. ^{[2
]}

Morava, Eva ^{[19
,30
]}

Matthijs, Gert ^{[19
]}

Foulquier, Francois ^{[11
]}

Marquardt, Thorsten ^{[7
]}

Lefeber, Dirk J. ^{[2
,6
]}

机构：

[1] Radboud Univ Nijmegen, Med Ctr, Dept Gastroenterol & Hepatol, NL-6525 GA Nijmegen, Netherlands

[2] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Mol Life Sci, Translat Metab Lab, NL-6525 GA Nijmegen, Netherlands

[3] Uniklin Koln, Inst Humangenet, D-50931 Cologne, Germany

[4] Uniklin Koln, Klin & Poliklin Kinder & Jugendmed, D-50937 Cologne, Germany

[5] Uniklin Koln, Zentrum Mol Med, D-50931 Cologne, Germany

[6] Radboud Univ Nijmegen, Med Ctr, Dept Neurol, Donders Inst Brain Cognit & Behav, NL-6525 GA Nijmegen, Netherlands

[7] Univ Munster, Dept Pediat, D-48149 Munster, Germany

[8] Univ Autonoma Madrid, Ctr Biol Mol Severo Ochoa UAM CSIC, Ctr Diagnost Enfermedades Mol, Campus Cantoblanco, E-28049 Madrid, Spain

[9] Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28049, Spain

[10] Inst Invest Sanitaria IdiPAZ, Madrid 28049, Spain

[11] Univ Lille, CNRS UMR 8576, Struct & Funct Glycobiol Unit, Federat Res Struct & Funct Biochem Biomol Assembl, F-59655 Villeneuve Dascq, France

[12] Inst Med Genet, D-13353 Berlin, Germany

[13] Osaka Med Ctr, Izumi, Osaka 5941101, Japan

[14] Res Inst Maternal & Child Hlth, Izumi, Osaka 5941101, Japan

[15] Univ Essen Gesamthsch, Dept Pediat, D-45122 Essen, Germany

[16] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 GA Nijmegen, Netherlands

[17] Ctr Hosp Porto, Biochem Genet Unit, Ctr Genet Med Jacinto de Magalhaes, P-4050466 Porto, Portugal

[18] Ctr Hosp Univ Coimbra, Hosp Pediat, Metab Dis Unit, Ctr Desenvolvimento Crianca, P-3000609 Coimbra, Portugal

[19] Univ Leuven, Dept Pediat, B-3000 Louvain, Belgium

[20] Hop Femme Mere Enfant, Ctr Reference Malad Hereditaires Metab, F-69677 Bron, France

[21] Radboud Univ Nijmegen, Med Ctr, Nijmegen Ctr Mitochondrial Disorders, Translat Metab Lab,Dept Pediat, NL-6525 GA Nijmegen, Netherlands

[22] Osaka Univ, Microbial Dis Res Inst, 2-2 Yamadaoka, Suita, Osaka 5650871, Japan

[23] Childrens Hosp Essen, Dept Pediat Neurol, D-45122 Essen, Germany

[24] Univ Hosp, Dept Pediat Gastroenterol Hepatol & Endoscopy, D-79110 Freiburg, Germany

[25] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands

[26] Catholic Univ Louvain, Clin Univ St Luc, B-1200 Woluwe St Lambert, Belgium

[27] Radboud Univ Nijmegen, Med Ctr, Dept Tumor Immunol, NL-6525 GA Nijmegen, Netherlands

[28] Radboud Univ Nijmegen, Med Ctr, Ctr Mol & Biomol Informat, NL-6525 GA Nijmegen, Netherlands

[29] Maastricht Univ, Med Ctr, Dept Clin Genet, NL-6229 HX Maastricht, Netherlands

[30] Tulane Univ, Sch Med, Dept Pediat, Hayward Genet Ctr, New Orleans, LA 70112 USA

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2016年 / 98卷 / 02期

关键词：

VACUOLAR PROTON PUMP; X-LINKED MYOPATHY; CONGENITAL DISORDERS; N-GLYCAN; ENDOPLASMIC-RETICULUM; MASS-SPECTROMETRY; MUTATIONS; ATPASE; YEAST; DIAGNOSIS;

D O I：

10.1016/j.ajhg.2015.12.010

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：310 / 321

页数：12

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