The prothrombin Denver patient has two different prothrombin point mutations resulting in Glu-300-->Lys and Glu-309-->Lys substitutions.
Dysprothrombinaemia is a rare, congenital cause of bleeding. Fewer than 25 families who express a functional prothrombin (factor II) defect have been reported. The original patient with prothrombin Denver had a severe haemophilia-like bleeding disorder treated with weekly prophylactic factor replacement. Analysis of factor II activity and antigen in the patient showed a factor II activity of 5 units/dl and factor II antigen of 21 units/dl. Genomic DNA from the patient, mother and brother was obtained from peripheral blood white cells. Oligonucleotides were constructed, and prothrombin exons were amplified via polymerase chain reaction (PCR). The entire sequence of the thrombin portion of the molecule (exons VIII-XIV) and that of exons I-II and IV-VII was determined. This moderately severe dysprothrombinaemia was found to be associated with compound heterozygosity for two different Glu-->Lys point mutations, at amino acid positions 300 and 309. Assays of plasma from the prothrombin Denver proband suggested that the functional defect was in the activation of zymogen to enzyme.
Lefkowitz
J B
JB
Department of Pathology, University Hospital Clinical Laboratory, University of Colorado School of Medicine, Denver, USA.
Haver
T
T
Clarke
S
S
Jacobson
L
L
Weller
A
A
Nuss
R
R
Manco-Johnson
M
M
Hathaway
W E
WE
D000293:Adolescent; D019943:Amino Acid Substitution / Q000235:genetics; D001483:Base Sequence; D015153:Blotting, Western; D006474:Hemorrhagic Disorders / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D017354:Point Mutation / Q000235:genetics*; D011516:Prothrombin / Q000235:genetics*
D011516:Prothrombin