TMEM199 Deficiency is a Disorder of Golgi Homeostasis Characterized by Elevated Aminotransferases, Alkaline Phosphatase, and Cholesterol and Abnormal Glycosylation

Jos C. Jansen, Sharita Timal, Monique Van Scherpenzeel, Helen Michelakakis, Dorothée Vicogne, Angel Ashikov, Marina Moraitou, Alexander Hoischen, Karin Huijben, Gerry Steenbergen, Marjolein A.W. Van Den Boogert, Francesco Porta, Pier Luigi Calvo, Mersyni Mavrikou, Giovanna Cenacchi, Geert Van Den Bogaart, Jody Salomon, Adriaan G. Holleboom, Richard J. Rodenburg, Joost P.H. DrenthMartijn A. Huynen, Ron A. Wevers, Eva Morava-Kozicz, François Foulquier, Joris A. Veltman, Dirk J. Lefeber

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Congenital disorders of glycosylation (CDGs) form a genetically and clinically heterogeneous group of diseases with aberrant protein glycosylation as a hallmark. A subgroup of CDGs can be attributed to disturbed Golgi homeostasis. However, identification of pathogenic variants is seriously complicated by the large number of proteins involved. As part of a strategy to identify human homologs of yeast proteins that are known to be involved in Golgi homeostasis, we identified uncharacterized transmembrane protein 199 (TMEM199, previously called C17orf32) as a human homolog of yeast V-ATPase assembly factor Vph2p (also known as Vma12p). Subsequently, we analyzed raw exome-sequencing data from families affected by genetically unsolved CDGs and identified four individuals with different mutations in TMEM199. The adolescent individuals presented with a mild phenotype of hepatic steatosis, elevated aminotransferases and alkaline phosphatase, and hypercholesterolemia, as well as low serum ceruloplasmin. Affected individuals showed abnormal N- and mucin-type O-glycosylation, and mass spectrometry indicated reduced incorporation of galactose and sialic acid, as seen in other Golgi homeostasis defects. Metabolic labeling of sialic acids in fibroblasts confirmed deficient Golgi glycosylation, which was restored by lentiviral transduction with wild-type TMEM199. V5-tagged TMEM199 localized with ERGIC and COPI markers in HeLa cells, and electron microscopy of a liver biopsy showed dilated organelles suggestive of the endoplasmic reticulum and Golgi apparatus. In conclusion, we have identified TMEM199 as a protein involved in Golgi homeostasis and show that TMEM199 deficiency results in a hepatic phenotype with abnormal glycosylation.

Original languageEnglish (US)
Pages (from-to)322-330
Number of pages9
JournalAmerican Journal of Human Genetics
Volume98
Issue number2
DOIs
StatePublished - Feb 4 2016
Externally publishedYes

Fingerprint

Congenital Disorders of Glycosylation
Transaminases
Glycosylation
Alkaline Phosphatase
Homeostasis
Cholesterol
Liver
Coat Protein Complex I
Sialic Acids
Exome
Phenotype
Proteins
Ceruloplasmin
Fungal Proteins
Golgi Apparatus
N-Acetylneuraminic Acid
Mucins
Hypercholesterolemia
Galactose
HeLa Cells

Keywords

  • alkaline phosphatase
  • Congenital Disorders of Glycosylation
  • COPI vesicular transport
  • elevated aminotransferases
  • Golgi homeostasis
  • hypercholesterolemia
  • TMEM199 deficiency
  • V-ATPase assembly
  • Vph2p

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

TMEM199 Deficiency is a Disorder of Golgi Homeostasis Characterized by Elevated Aminotransferases, Alkaline Phosphatase, and Cholesterol and Abnormal Glycosylation. / Jansen, Jos C.; Timal, Sharita; Van Scherpenzeel, Monique; Michelakakis, Helen; Vicogne, Dorothée; Ashikov, Angel; Moraitou, Marina; Hoischen, Alexander; Huijben, Karin; Steenbergen, Gerry; Van Den Boogert, Marjolein A.W.; Porta, Francesco; Calvo, Pier Luigi; Mavrikou, Mersyni; Cenacchi, Giovanna; Van Den Bogaart, Geert; Salomon, Jody; Holleboom, Adriaan G.; Rodenburg, Richard J.; Drenth, Joost P.H.; Huynen, Martijn A.; Wevers, Ron A.; Morava-Kozicz, Eva; Foulquier, François; Veltman, Joris A.; Lefeber, Dirk J.

In: American Journal of Human Genetics, Vol. 98, No. 2, 04.02.2016, p. 322-330.

Research output: Contribution to journalArticle

Jansen, JC, Timal, S, Van Scherpenzeel, M, Michelakakis, H, Vicogne, D, Ashikov, A, Moraitou, M, Hoischen, A, Huijben, K, Steenbergen, G, Van Den Boogert, MAW, Porta, F, Calvo, PL, Mavrikou, M, Cenacchi, G, Van Den Bogaart, G, Salomon, J, Holleboom, AG, Rodenburg, RJ, Drenth, JPH, Huynen, MA, Wevers, RA, Morava-Kozicz, E, Foulquier, F, Veltman, JA & Lefeber, DJ 2016, 'TMEM199 Deficiency is a Disorder of Golgi Homeostasis Characterized by Elevated Aminotransferases, Alkaline Phosphatase, and Cholesterol and Abnormal Glycosylation', American Journal of Human Genetics, vol. 98, no. 2, pp. 322-330. https://doi.org/10.1016/j.ajhg.2015.12.011
Jansen, Jos C. ; Timal, Sharita ; Van Scherpenzeel, Monique ; Michelakakis, Helen ; Vicogne, Dorothée ; Ashikov, Angel ; Moraitou, Marina ; Hoischen, Alexander ; Huijben, Karin ; Steenbergen, Gerry ; Van Den Boogert, Marjolein A.W. ; Porta, Francesco ; Calvo, Pier Luigi ; Mavrikou, Mersyni ; Cenacchi, Giovanna ; Van Den Bogaart, Geert ; Salomon, Jody ; Holleboom, Adriaan G. ; Rodenburg, Richard J. ; Drenth, Joost P.H. ; Huynen, Martijn A. ; Wevers, Ron A. ; Morava-Kozicz, Eva ; Foulquier, François ; Veltman, Joris A. ; Lefeber, Dirk J. / TMEM199 Deficiency is a Disorder of Golgi Homeostasis Characterized by Elevated Aminotransferases, Alkaline Phosphatase, and Cholesterol and Abnormal Glycosylation. In: American Journal of Human Genetics. 2016 ; Vol. 98, No. 2. pp. 322-330.
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abstract = "Congenital disorders of glycosylation (CDGs) form a genetically and clinically heterogeneous group of diseases with aberrant protein glycosylation as a hallmark. A subgroup of CDGs can be attributed to disturbed Golgi homeostasis. However, identification of pathogenic variants is seriously complicated by the large number of proteins involved. As part of a strategy to identify human homologs of yeast proteins that are known to be involved in Golgi homeostasis, we identified uncharacterized transmembrane protein 199 (TMEM199, previously called C17orf32) as a human homolog of yeast V-ATPase assembly factor Vph2p (also known as Vma12p). Subsequently, we analyzed raw exome-sequencing data from families affected by genetically unsolved CDGs and identified four individuals with different mutations in TMEM199. The adolescent individuals presented with a mild phenotype of hepatic steatosis, elevated aminotransferases and alkaline phosphatase, and hypercholesterolemia, as well as low serum ceruloplasmin. Affected individuals showed abnormal N- and mucin-type O-glycosylation, and mass spectrometry indicated reduced incorporation of galactose and sialic acid, as seen in other Golgi homeostasis defects. Metabolic labeling of sialic acids in fibroblasts confirmed deficient Golgi glycosylation, which was restored by lentiviral transduction with wild-type TMEM199. V5-tagged TMEM199 localized with ERGIC and COPI markers in HeLa cells, and electron microscopy of a liver biopsy showed dilated organelles suggestive of the endoplasmic reticulum and Golgi apparatus. In conclusion, we have identified TMEM199 as a protein involved in Golgi homeostasis and show that TMEM199 deficiency results in a hepatic phenotype with abnormal glycosylation.",
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AU - Jansen, Jos C.

AU - Timal, Sharita

AU - Van Scherpenzeel, Monique

AU - Michelakakis, Helen

AU - Vicogne, Dorothée

AU - Ashikov, Angel

AU - Moraitou, Marina

AU - Hoischen, Alexander

AU - Huijben, Karin

AU - Steenbergen, Gerry

AU - Van Den Boogert, Marjolein A.W.

AU - Porta, Francesco

AU - Calvo, Pier Luigi

AU - Mavrikou, Mersyni

AU - Cenacchi, Giovanna

AU - Van Den Bogaart, Geert

AU - Salomon, Jody

AU - Holleboom, Adriaan G.

AU - Rodenburg, Richard J.

AU - Drenth, Joost P.H.

AU - Huynen, Martijn A.

AU - Wevers, Ron A.

AU - Morava-Kozicz, Eva

AU - Foulquier, François

AU - Veltman, Joris A.

AU - Lefeber, Dirk J.

PY - 2016/2/4

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N2 - Congenital disorders of glycosylation (CDGs) form a genetically and clinically heterogeneous group of diseases with aberrant protein glycosylation as a hallmark. A subgroup of CDGs can be attributed to disturbed Golgi homeostasis. However, identification of pathogenic variants is seriously complicated by the large number of proteins involved. As part of a strategy to identify human homologs of yeast proteins that are known to be involved in Golgi homeostasis, we identified uncharacterized transmembrane protein 199 (TMEM199, previously called C17orf32) as a human homolog of yeast V-ATPase assembly factor Vph2p (also known as Vma12p). Subsequently, we analyzed raw exome-sequencing data from families affected by genetically unsolved CDGs and identified four individuals with different mutations in TMEM199. The adolescent individuals presented with a mild phenotype of hepatic steatosis, elevated aminotransferases and alkaline phosphatase, and hypercholesterolemia, as well as low serum ceruloplasmin. Affected individuals showed abnormal N- and mucin-type O-glycosylation, and mass spectrometry indicated reduced incorporation of galactose and sialic acid, as seen in other Golgi homeostasis defects. Metabolic labeling of sialic acids in fibroblasts confirmed deficient Golgi glycosylation, which was restored by lentiviral transduction with wild-type TMEM199. V5-tagged TMEM199 localized with ERGIC and COPI markers in HeLa cells, and electron microscopy of a liver biopsy showed dilated organelles suggestive of the endoplasmic reticulum and Golgi apparatus. In conclusion, we have identified TMEM199 as a protein involved in Golgi homeostasis and show that TMEM199 deficiency results in a hepatic phenotype with abnormal glycosylation.

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