title: Hypoglycosylation is a common finding in antithrombin deficiency in the absence of a SERPINC1 gene defect.
abstract: Essentials We investigated the molecular base of antithrombin deficiency in cases without SERPINC1 defects. 27% of cases presented hypoglycosylation, transient in 62% and not restricted to antithrombin. Variations in genes involved in N-glycosylation underline this phenotype. These results support a new form of thrombophilia. Click here to listen to Dr Huntington's perspective on thrombin inhibition by the serpins
  
  
  
  Background Since the discovery of antithrombin deficiency, 50 years ago, few new thrombophilic defects have been identified, all with weaker risk of thrombosis than antithrombin deficiency. Objective To identify new thrombophilic mechanisms. Patients/methods We studied 30 patients with antithrombin deficiency but no defects in the gene encoding this key anticoagulant (SERPINC1). Results A high proportion of these patients (8/30: 27%) had increased hypoglycosylated forms of antithrombin. All N-glycoproteins tested in these patients (α1-antitrypsin, FXI and transferrin) had electrophoretic, HPLC and Q-TOF patterns indistinguishable from those of the congenital disorders of glycosylation (rare recessive multisystem disorders). However, all except one had no mental disability. Moreover, intermittent antithrombin deficiency and hypoglycosylation was recorded in five out of these eight patients, all associated with moderate alcohol intake. Genetic analysis, including whole exome sequencing, revealed mutations in different genes involved in the N-glycosylation pathway. Conclusions Our study provides substantial and novel mechanistic insights into two disease processes, with potential implications for diagnosis and clinical care. An aberrant N-glycosylation causing a recessive or transient antithrombin deficiency is a new form of thrombophilia. Our data suggest that congenital disorders of glycosylation are probably underestimated, especially in cases with thrombosis as the main or only clinical manifestation.
authors.affiliation: Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.|Grupo de investigación CB15/00055 del Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: M E
authors.initials: ME
authors.lastname: de la Morena-Barrio
authors.affiliation: Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.|Grupo de investigación CB15/00055 del Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Martínez-Martínez
authors.affiliation: Hospital Puerta del Mar, Cádiz, Spain.
authors.forename: C
authors.initials: C
authors.lastname: de Cos
authors.affiliation: The John Paul II Hospital, Kraków, Poland.|Institute of Cardiology, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: E
authors.initials: E
authors.lastname: Wypasek
authors.affiliation: Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Roldán
authors.affiliation: The John Paul II Hospital, Kraków, Poland.|Institute of Cardiology, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Undas
authors.affiliation: Department of Neurology, Laboratory for Genetic, Endocrine and Metabolic Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: van Scherpenzeel
authors.affiliation: Department of Neurology, Laboratory for Genetic, Endocrine and Metabolic Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: D J
authors.initials: DJ
authors.lastname: Lefeber
authors.affiliation: Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Toderici
authors.affiliation: Serviço de Hematologia do Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
authors.forename: T
authors.initials: T
authors.lastname: Sevivas
authors.affiliation: Grupo de Hemostasiam Trombosis, Arteriosclerosis y Biología Vascular, Centro de Investigación, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
authors.forename: F
authors.initials: F
authors.lastname: España
authors.affiliation: Center for Metabolic Diseases, Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Jaeken
authors.affiliation: Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.|Grupo de investigación CB15/00055 del Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Corral
authors.affiliation: Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.|Grupo de investigación CB15/00055 del Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Vicente
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000906:Antibodies / Q000737:chemistry*; D000925:Anticoagulants / Q000737:chemistry; D000990:Antithrombin III / Q000737:chemistry / Q000235:genetics*; D000991:Antithrombins / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D059472:Exome; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006023:Glycoproteins / Q000737:chemistry; D006031:Glycosylation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D013030:Spain; D019851:Thrombophilia / Q000235:genetics* / Q000276:immunology / Q000628:therapy; D013927:Thrombosis; D055815:Young Adult
chemical_list: D000906:Antibodies; D000925:Anticoagulants; D000991:Antithrombins; D006023:Glycoproteins; C542513:SERPINC1 protein, human; D000990:Antithrombin III
keywords: antithrombin III deficiency; congenital disorders of glycosylation; glycoproteins; thrombophilia; venous thrombosis