Genetic defect responsible for the dysfunctional protein: factor IXLong
Beach
J Ware, L Davis, D Frazier, SP Bajaj and DW Stafford
Department of Biology, University of North Carolina, Chapel Hill 27599-
3280.
DNA sequence analysis of the gene coding for the variant protein, factor
IXLong Beach (FIXLB), has identified a transition mutation in an otherwise
normal factor IX (FIX) gene. Genomic DNA clones spanning 35 kilobase (kb)
pairs of the FIXLB gene were isolated. A gene analysis strategy that
specifically characterized exons and their flanking intron sequences
predicted the entire amino acid sequence of FIXLB. A thymine to cytosine
transition causes the substitution of a threonine codon (ACA) for an
isoleucine codon (ATA) in exon VIII of the FIXLB gene. This mutation
results in an amino acid substitution at residue 397 of the FIX zymogen and
the phenotypic display of hemophilia-B. Previous studies revealed that
activated purified FIXLB (FIXaLB) had normal Ca2+, phospholipid, and factor
VIIIa binding characteristics. However, FIXaLB activated factor X or factor
VII (with their cofactors Ca2+ and phospholipid) at significantly reduced
rates, suggesting that the defect in FIXaLB lies near or within the
catalytic triad of the FIX heavy chain. Identification of an amino acid
substitution near the carboxy-terminus of the FIXaLB heavy chain supports
the earlier characterization of this variant protein. Moreover, our data
identify a residue in the catalytic domain of FIXa essential for normal
function.
Volume 72,
Issue 2,
pp. 820-822,
08/01/1988
Copyright © 1988 by The American Society of Hematology
