Factor X Frankfurt I: molecular and functional characterization of a hereditary factor X deficiency (Gla+25 to Lys).
A family with hereditary factor X deficiency is presented. One member, a 25-year-old man, showed a mild bleeding tendency. His factor X activity (extrinsic: 56%; intrinsic: 55%; Russell's viper venom: 57%) and his level of circulating factor X antigen (55% of normal) were markedly reduced. Analysis of his factor X gene revealed a single point mutation within exon II resulting in the substitution of +25 Gla (GAA) by Lys (AAA). The mutation was determined by gene analysis to be heterozygous in this patient, his mother and one of his brothers. Clotting assays of factor X purified from the plasma of the index patient revealed an activity of 89% of normal upon activation with Russell's viper venom, 77% of normal in the intrinsic and 81% of normal in the extrinsic coagulation pathway. The mutation responsible for the substitution of Lys for Gla+25 was introduced into an expression plasmid containing a wild type factor X cDNA and expressed in a mammalian cell line. Factor X antigen levels in the cell lysates and in the supernatant were identical in the mutant and wild type constructs. The specific activity of the factor X expressed from the mutant construct was 3% compared with the wild type construct. These data demonstrate that the substitution of Lys for Gla+25 results not only in a reduced level of factor X in the affected family members, but also in a substantial loss of specific factor X activity.
Nöbauer-Huhmann
I M
IM
Universitätsklinik Wien, Internal Medicine I, Department of Hematology and Hemostaseology, Vienna, Austria.
Höller
W
W
Krinninger
B
B
Turecek
P L
PL
Richter
G
G
Scharrer
I
I
Forberg
E
E
Watzke
H H
HH
D000328:Adult; D019943:Amino Acid Substitution; D005170:Factor X / Q000235:genetics*; D005171:Factor X Deficiency / Q000235:genetics*; D005808:Genes, Recessive; D006801:Humans; D008239:Lysine; D008297:Male; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
D005170:Factor X; D008239:Lysine