Hypofibrinogenemia in an individual with 2 coding (γ82 A→G and Bβ235 P→L) and 2 noncoding mutations

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 beta alleles, and DNA sequencing confirmed heterozygosity for a new B beta 235 P-->L mutation, Protein analysis also revealed a novel gamma(D) chain, present at a ratio of 1:2 relative to the gamma(A) chain. Mass spectrometry indicated a 14 d decrease in the gamma(D)-chain mass, and DNA sequencing showed this was caused by a novel gamma 82 A-->G substitution. DNA sequencing established heterozygosity for 2 further mutations: T-->C in intron 4 of the A alpha gene and A-->C in the 3' noncoding region of the B beta gene. Studies on the man's daughter, together with plasma expression levels, discounted both the A alpha and B beta mutations as the cause of the low fibrinogen, suggesting that the gamma 82 mutation caused the hypofibrinogenemia, This was supported by analysis of 31 normal controls in whom the B beta mutations were found at polymorphic levels, with an allelic frequency of 5% for the B beta 235 mutation and 42% for the B beta 3' untranslated mutation. The gamma 82 mutation was, however, unique to the propositus. Residue gamma 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. (C) 2000 by The American Society of Hematology.