Severe hypodysfibrinogenemia in compound heterozygotes of the fibrinogen AalphaIVS4 + 1G>T mutation and an AalphaGln328 truncation (fibrinogen Keokuk).
Two siblings with hypofibrinogenemia have lifelong trauma-related bleeding. Recently, the brother experienced recurrent thrombosis after cryoprecipitate infusions following surgery. The sister had 6 miscarriages. Plasma clots in each were resistant to compression and fibrinolysis and were soluble in 5 M urea. Examination by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) revealed only the presence of crosslinked gamma-gamma fibrin chain dimers without high polymers of alpha n. Fibrin clots contained an abnormal 35-kDa constituent recognized by an antibody to the mature fibrinogen Aalpha-chain residues 241-476 but not by antibodies to Aalpha219-348 or Aalpha349-406. DNA analysis revealed a heterozygous CAA-->TAA mutation at the codon for amino acid 328 of the Aalpha gene in these siblings and 2 asymptomatic family members. The Gln328stop mutation (fibrinogen Keokuk) predicted a 46% truncation and the production of a 35-kDa Aalpha chain. Analysis of purified fibrinogen revealed expression of the abnormal Aalpha chain in 4 family members but found no normal fibrinogen in the 2 hypofibrinogenemic patients. This paradox was resolved when they and their asymptomatic mother were found to be heterozygous for a second Aalpha mutation, a GT-->TT splice site mutation in intron 4 (IVS4 + 1 G> T). However, compound heterozygosity for both mutations was required for the expression of severe hypodysfibrinogenemia and for clinical symptoms.
Lefebvre
Phil
P
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Velasco
Pauline T
PT
Dear
Amy
A
Lounes
Karim C
KC
Lord
Susan T
ST
Brennan
Stephen O
SO
Green
David
D
Lorand
Laszlo
L
D001778:Blood Coagulation Disorders / Q000235:genetics*; D019281:Dimerization; D005060:Europe / Q000208:ethnology; D005190:Family; D005260:Female; D005337:Fibrin / Q000235:genetics; D005340:Fibrinogen / Q000235:genetics / Q000302:isolation & purification; D015241:Fibrinogens, Abnormal / Q000235:genetics*; D006580:Genetic Carrier Screening; D006487:Hemostasis / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D017354:Point Mutation; D017384:Sequence Deletion; D014481:United States
D015241:Fibrinogens, Abnormal; D005337:Fibrin; D005340:Fibrinogen