Blood, Vol. 95 No. 5 (March 1), 2000:
pp. 1709-1713
Hypofibrinogenemia in an individual with 2 coding (
82
A
G and B
235 PL) and 2 noncoding
mutations
Stephen O. Brennan,
Andrew P. Fellowes,
James M. Faed, and
Peter M. George
From the Molecular Pathology Laboratory, Canterbury Health
Laboratories, Christchurch Hospital, Christchurch, New Zealand, and
Blood Transfusion Service, Dunedin Hospital, Dunedin, New Zealand.
We investigated the molecular basis of hypofibrinogenemia in a man
with a normal thrombin clotting time. Protein analysis indicated equal
plasma expression of 2 different B
alleles, and DNA
sequencing confirmed heterozygosity for a new B235 P
L mutation. Protein analysis also revealed a novel 
D chain, present
at a ratio of 1:2 relative to the A chain. Mass
spectrometry indicated a 14 d decrease in the
D-chain mass, and DNA sequencing showed this was
caused by a novel 82 AG substitution. DNA
sequencing established heterozygosity for 2 further mutations: TC in
intron 4 of the A
gene and AC in the 3' noncoding region of
the B gene. Studies on the man's daughter, together with plasma
expression levels, discounted both the A and B mutations as the
cause of the low fibrinogen, suggesting that the 82 mutation caused
the hypofibrinogenemia. This was supported by analysis of 31 normal
controls in whom the B mutations were found at polymorphic levels,
with an allelic frequency of 5% for the B235 mutation and 42% for
the B 3' untranslated mutation. The 82 mutation was,
however, unique to the propositus. Residue 82 is located in the
triple helix that separates the E and D domains, and aberrant packing
of the helices may explain the decreased fibrinogen concentration.
