title: Vitamin D-binding protein as a biomarker of active disease in acute intermittent porphyria.
abstract: Acute intermittent porphyria (AIP) is an autosomal dominant metabolic disorder caused by a deficiency of hepatic porphobilinogen deaminase (PBGD). The disease is characterized by life threatening acute neurovisceral attacks. The aim of this study was to identify metabolites secreted by the hepatocytes that reflect differential metabolic status in the liver and that may predict response to the acute attack treatment. Plasma vitamin D binding protein (VDBP) from a mouse model of AIP displayed an abnormal migration in 2D-electrophoresis that is efficiently recovered upon gene therapy leading to liver specific over-expression of the PBGD protein. The change in VDBP mobility results from a differential isoelectric point suggesting a post-translational modification that takes place preferably in the liver. Liquid chromatography-mass spectrometry (LC-MS) analysis of human samples before and after glycosidase treatment revealed glycosylated plasma VDBP specifically in patients with recurrent attacks of AIP. Glycosylated VDBP recovered normal values in three severely afflicted AIP patients submitted to therapeutic liver transplantation. Our findings suggest that post-translational modification of VDBP might be considered as a promising biomarker to study and monitor the liver metabolic status in patients with AIP.
  
  
  CONCLUSIONS
  We describe an increased glycosylation of VDBP in porphyric livers. Normal glycosylation was recovered upon liver gene therapy in a mouse model of porphyria or after liver transplantation in severely afflicted patients with AIP. Moreover, quantification of glycosylated VDBP by our ELISA immunoassay or LC-MS protocol in patients undergoing PBGD-gene therapy (www.aipgene.org) may be used as a marker indicating improvement or normalization of the patient's hepatic metabolism. This article is part of a Special Issue entitled: HUPO 2014.
authors.affiliation: Hepatology Area, Centre for Applied Medical Research, University of Navarra, Spain.
authors.forename: Irantzu
authors.initials: I
authors.lastname: Serrano-Mendioroz
authors.affiliation: Hepatology Area, Centre for Applied Medical Research, University of Navarra, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Sampedro
authors.affiliation: Hepatology Area, Centre for Applied Medical Research, University of Navarra, Spain; Proteomics and Bioinformatics Laboratory, CIMA, University of Navarra, ProteoRed-ISCIII, Spain.
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Mora
authors.affiliation: Hepatology Area, Centre for Applied Medical Research, University of Navarra, Spain.
authors.forename: Itsaso
authors.initials: I
authors.lastname: Mauleón
authors.affiliation: Proteomics and Bioinformatics Laboratory, CIMA, University of Navarra, ProteoRed-ISCIII, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Segura
authors.affiliation: Research Center, Hospital Universitario 12 de Octubre, University Complutense of Madrid, Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Enríquez de Salamanca
authors.affiliation: Porphyria Centre Sweden, Centre for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Pauline
authors.initials: P
authors.lastname: Harper
authors.affiliation: Porphyria Centre Sweden, Centre for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Eliane
authors.initials: E
authors.lastname: Sardh
authors.affiliation: Hepatology Area, Centre for Applied Medical Research, University of Navarra, Spain; Proteomics and Bioinformatics Laboratory, CIMA, University of Navarra, ProteoRed-ISCIII, Spain; CIBEREHD, University Clinic Navarra, Instituto de Salud Carlos III, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
authors.forename: Fernando José
authors.initials: FJ
authors.lastname: Corrales
authors.affiliation: Hepatology Area, Centre for Applied Medical Research, University of Navarra, Spain; CIBEREHD, University Clinic Navarra, Instituto de Salud Carlos III, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain. Electronic address: afontanellas@unav.es.
authors.forename: Antonio
authors.initials: A
authors.lastname: Fontanellas
mesh_terms: D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002853:Chromatography, Liquid; D005260:Female; D006031:Glycosylation; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D017118:Porphyria, Acute Intermittent / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014809:Vitamin D-Binding Protein / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D014809:Vitamin D-Binding Protein
keywords: Acute intermittent porphyria; Biomarker; Glycosylation; Liquid chromatography–mass spectrometry; Vitamin D binding protein