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

Jos C. Jansen, Sebahattin Cirak, Monique Van Scherpenzeel, Sharita Timal, Janine Reunert, Stephan Rust, Belén Pérez, Dorothée Vicogne, Peter Krawitz, Yoshinao Wada, Angel Ashikov, Celia Pérez-Cerdá, Celia Medrano, Andrea Arnoldy, Alexander Hoischen, Karin Huijben, Gerry Steenbergen, Dulce Quelhas, Luisa Diogo, Daisy RymenJaak Jaeken, Nathalie Guffon, David Cheillan, Lambertus P. Van Den Heuvel, Yusuke Maeda, Olaf Kaiser, Ulrike Schara, Patrick Gerner, Marjolein A.W. Van Den Boogert, Adriaan G. Holleboom, Marie Cécile Nassogne, Etienne Sokal, Jody Salomon, Geert Van Den Bogaart, Joost P.H. Drenth, Martijn A. Huynen, Joris A. Veltman, Ron A. Wevers, Eva Morava-Kozicz, Gert Matthijs, François Foulquier, Thorsten Marquardt, Dirk J. Lefeber

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)310-321
Number of pages12
JournalAmerican Journal of Human Genetics
Volume98
Issue number2
DOIs
StatePublished - Feb 4 2016
Externally publishedYes

Fingerprint

Glycosylation
Homeostasis
Missense Mutation
Endoplasmic Reticulum
Adenosine Triphosphatases
Coat Protein Complex I
Sialic Acids
Exome
Biological Phenomena
Liver Failure
Mucins
Transaminases
Hypercholesterolemia
Liver Transplantation
Alkaline Phosphatase
Blood Proteins
Copper
Fibroblasts
Yeasts
Phenotype

Keywords

  • alkaline phosphatase
  • glycosylation
  • Golgi homeostasis
  • hepatosplenomegaly
  • V-ATPase assembly
  • Vma22p

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Jansen, J. C., Cirak, S., Van Scherpenzeel, M., Timal, S., Reunert, J., Rust, S., ... Lefeber, D. J. (2016). CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation. American Journal of Human Genetics, 98(2), 310-321. https://doi.org/10.1016/j.ajhg.2015.12.010

CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation. / Jansen, Jos C.; Cirak, Sebahattin; Van Scherpenzeel, Monique; Timal, Sharita; Reunert, Janine; Rust, Stephan; Pérez, Belén; Vicogne, Dorothée; Krawitz, Peter; Wada, Yoshinao; Ashikov, Angel; Pérez-Cerdá, Celia; Medrano, Celia; Arnoldy, Andrea; Hoischen, Alexander; Huijben, Karin; Steenbergen, Gerry; Quelhas, Dulce; 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 Cécile; Sokal, Etienne; Salomon, Jody; Van Den Bogaart, Geert; Drenth, Joost P.H.; Huynen, Martijn A.; Veltman, Joris A.; Wevers, Ron A.; Morava-Kozicz, Eva; Matthijs, Gert; Foulquier, François; Marquardt, Thorsten; Lefeber, Dirk J.

In: American Journal of Human Genetics, Vol. 98, No. 2, 04.02.2016, p. 310-321.

Research output: Contribution to journalArticle

Jansen, JC, Cirak, S, Van Scherpenzeel, M, Timal, S, Reunert, J, Rust, S, Pérez, B, Vicogne, D, Krawitz, P, Wada, Y, Ashikov, A, Pérez-Cerdá, C, Medrano, C, Arnoldy, A, Hoischen, A, Huijben, K, Steenbergen, G, Quelhas, D, Diogo, L, Rymen, D, Jaeken, J, Guffon, N, Cheillan, D, Van Den Heuvel, LP, Maeda, Y, Kaiser, O, Schara, U, Gerner, P, Van Den Boogert, MAW, Holleboom, AG, Nassogne, MC, Sokal, E, Salomon, J, Van Den Bogaart, G, Drenth, JPH, Huynen, MA, Veltman, JA, Wevers, RA, Morava-Kozicz, E, Matthijs, G, Foulquier, F, Marquardt, T & Lefeber, DJ 2016, 'CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation', American Journal of Human Genetics, vol. 98, no. 2, pp. 310-321. https://doi.org/10.1016/j.ajhg.2015.12.010
Jansen, Jos C. ; Cirak, Sebahattin ; Van Scherpenzeel, Monique ; Timal, Sharita ; Reunert, Janine ; Rust, Stephan ; Pérez, Belén ; Vicogne, Dorothée ; Krawitz, Peter ; Wada, Yoshinao ; Ashikov, Angel ; Pérez-Cerdá, Celia ; Medrano, Celia ; Arnoldy, Andrea ; Hoischen, Alexander ; Huijben, Karin ; Steenbergen, Gerry ; Quelhas, Dulce ; 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 Cécile ; Sokal, Etienne ; Salomon, Jody ; Van Den Bogaart, Geert ; Drenth, Joost P.H. ; Huynen, Martijn A. ; Veltman, Joris A. ; Wevers, Ron A. ; Morava-Kozicz, Eva ; Matthijs, Gert ; Foulquier, François ; Marquardt, Thorsten ; Lefeber, Dirk J. / CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation. In: American Journal of Human Genetics. 2016 ; Vol. 98, No. 2. pp. 310-321.
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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 - Pérez, Belén

AU - Vicogne, Dorothée

AU - Krawitz, Peter

AU - Wada, Yoshinao

AU - Ashikov, Angel

AU - Pérez-Cerdá, 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 Cécile

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-Kozicz, Eva

AU - Matthijs, Gert

AU - Foulquier, François

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.

KW - alkaline phosphatase

KW - glycosylation

KW - Golgi homeostasis

KW - hepatosplenomegaly

KW - V-ATPase assembly

KW - Vma22p

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