Characterization of a novel autosomal dominant bleeding disorder in a large kindred from east Texas

A large east Texas family with autosomal dominant inheritance of a novel bl eeding disorder has been identified. The disorder is characterized clinical ly by easy bruising, life-threatening bleeding with trauma or surgery, and menorrhagia in affected women. Laboratory studies demonstrated prolongation of the prothrombin time and activated partial thromboplastin time in affec ted individuals. Paradoxically, assays of known coagulation factors are all within normal limits. To determine the molecular basis of this disease, a candidate gene linkage analysis in this kindred was done. Initially it was hypothesized that the cause of the disease in this family could be an antit hrombin III (AT3) mutation that resulted in a constitutively active AT3 in the absence of heparin binding. Linkage studies using DNA from the family a nd an intragenic polymorphic marker within the AT3 gene showed that the dis ease mapped to this locus. The coding region and intron/exon junctions of A T3 were sequenced using the proband's DMA, but this analysis failed to iden tify a mutation. Additional family members were recruited for the study, an d 16 polymorphic markers around the AT3 gene were analyzed. Using 2 recombi nants, the critical interval for the defective gene was narrowed to approxi mately 1.5 Mb, centromeric to AT3. The factor V (FV) gene was mapped into t he disease interval an were no mutations found. Elucidation of the genetic defect causing the bleeding disorder in this family may reveal a novel prot ein involved in the coagulation cascade. (Blood. 2001;97:1549-1554) (C) 200 1 by The American Society of Hematology.