Blood, 15 March 2001, Vol. 97, No. 6, pp. 1549-1554
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Characterization of a novel autosomal dominant bleeding disorder
in a large kindred from east Texas
Shao-Qing Kuang,
Sumera Hasham,
Martin D. Phillips,
David Wolf,
Ying Wan,
Perumal Thiagarajan, and
Dianna M. Milewicz
From the Department of Internal Medicine,
University of Texas-Houston Medical School, Houston, TX, and Centeon
L.L.C., King of Prussia, PA.
A large east Texas family with autosomal dominant inheritance of a
novel bleeding disorder has been identified. The disorder is
characterized clinically 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 affected 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 antithrombin III (AT3) mutation that resulted in
a constitutively active AT3 in the absence of heparin binding. Linkage studies using DNA from the family and an intragenic polymorphic marker
within the AT3 gene showed that the disease mapped to this locus. The coding region and intron/exon junctions of AT3
were sequenced using the proband's DNA, but this analysis failed
to identify a mutation. Additional family members were recruited for
the study, and 16 polymorphic markers around the AT3 gene were analyzed. Using 2 recombinants, the critical interval for the
defective gene was narrowed to approximately 1.5 Mb, centromeric to
AT3. The factor V (FV) gene was mapped into the
disease interval and sequenced; there were no mutations found.
Elucidation of the genetic defect causing the bleeding disorder in this
family may reveal a novel protein involved in the coagulation cascade.
