SERPINC1 gene mutations in antithrombin deficiency.
Existing evidence suggests that in most cases antithrombin deficiency can be explained by mutations in its gene, SERPINC1. We investigated the molecular background of antithrombin deficiency in a single centre family cohort study. We included a total of 21 families comprising 15 original probands and sixty-six relatives, 6 of who were surrogate probands for the genetic analysis. Antithrombin activity and antigen levels were measured. The heparin-antithrombin binding ratio assay was used to distinguish between the different subtypes of type II antithrombin deficiency. SERPINC1 mutations were detected by direct sequencing of all 7 exons and regulatory regions, and multiplex ligation-dependent probe amplification. Eighty-six per cent of the families had a detrimental SERPINC1 gene mutation that segregated in the family. We detected 13 different SERPINC1 gene mutations of which 5 were novel. Among all these mutations, 44% was associated with type I deficiency, whereas the remainder was associated with type II heparin binding site (11%), type II pleiotropic effect (33%), type II reactive site (6%) or had the antithrombin Cambridge II mutation (6%). The current study reports several novel SERPINC1 mutations, thereby adding to our knowledge of the molecular background of antithrombin deficiency. Finally, our results point out the importance of future research outside the conventional SERPINC1 gene approach.
Department of Laboratory Medicine, University Medical Centre Groningen, Groningen, the Netherlands.
René
0000-0001-8749-8347
R
Mulder
Division of Haemostasis and Thrombosis, Department of Haematology, University Medical Centre Groningen, Groningen, the Netherlands.|Department of Haematology, Erasmus University Medical Centre, Rotterdam, the Netherlands.
F Nanne
FN
Croles
Department of Laboratory Medicine, University Medical Centre Groningen, Groningen, the Netherlands.
André B
AB
Mulder
Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
James A
JA
Huntington
Division of Haemostasis and Thrombosis, Department of Haematology, University Medical Centre Groningen, Groningen, the Netherlands.
Karina
K
Meijer
Department of Laboratory Medicine, University Medical Centre Groningen, Groningen, the Netherlands.
Michaël V
MV
Lukens
D000293:Adolescent; D000328:Adult; D000368:Aged; D000990:Antithrombin III / Q000235:genetics*; D020152:Antithrombin III Deficiency / Q000235:genetics*; D058833:Antithrombin Proteins / Q000235:genetics; D002675:Child, Preschool; D004274:DNA, Recombinant / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D055815:Young Adult
D058833:Antithrombin Proteins; D004274:DNA, Recombinant; C542513:SERPINC1 protein, human; D000990:Antithrombin III

MLPA
; 
SERPINC1
; antithrombin; antithrombin deficiency; sequencing