Antithrombin cambridge II (Ala384Ser): clinical, functional and haplotype analysis of 18 families.
Thirty-one individuals from 18 unrelated families with antithrombin deficiency have been identified as having a single point mutation within codon 384 (13268 GCA-->TCA) resulting in an alanine to serine substitution. Six families (11 individuals) were identified by the screening of individuals with thromboembolic disease or with a family history of thromboembolic disease, whilst the remaining 12 families (20 individuals) were identified by screening of asymptomatic blood donors. Four individuals had a history of venous thrombotic disease, a further 2 gave a history of superficial thrombophlebitis but the remaining 25 individuals were asymptomatic. Affected individuals demonstrated normal immunological levels of antithrombin but a decrease in anti-IIa activity in the presence of heparin. Haplotype analysis was used to examine the possibility of a founder effect to explain the high frequency of this non-CpG mutation. 29/31 individuals showed a single common "core" haplotype, the only variation existing in the number of copies of an (ATT)n repeat polymorphism--13, 14, 15 or 17. The results suggest that at most there are four independent origins for this mutation.
Perry
D J
DJ
Department of Haematology, Royal Free Hospital and School of Medicine, London, UK. djp@rfhsm.ac.uk
Daly
M E
ME
Tait
R C
RC
Walker
I D
ID
Brown
K
K
Beauchamp
N J
NJ
Preston
F E
FE
Gyde
H
H
Harper
P L
PL
Carrell
R W
RW
D000409:Alanine / Q000235:genetics; D000990:Antithrombin III / Q000235:genetics*; D020152:Antithrombin III Deficiency; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D017354:Point Mutation; D011110:Polymorphism, Genetic; D012694:Serine / Q000235:genetics; D013923:Thromboembolism / Q000235:genetics*
D012694:Serine; D000990:Antithrombin III; D000409:Alanine