Publication Date:
2000-03-01
Description:
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 Bβ alleles, and DNA sequencing confirmed heterozygosity for a new Bβ235 P→L mutation. Protein analysis also revealed a novel γD chain, present at a ratio of 1:2 relative to the γA chain. Mass spectrometry indicated a 14 d decrease in the γD-chain mass, and DNA sequencing showed this was caused by a novel γ82 A→G substitution. DNA sequencing established heterozygosity for 2 further mutations: T→C in intron 4 of the A gene and A→C in the 3′ noncoding region of the Bβ gene. Studies on the man's daughter, together with plasma expression levels, discounted both the A and Bβ mutations as the cause of the low fibrinogen, suggesting that the γ82 mutation caused the hypofibrinogenemia. This was supported by analysis of 31 normal controls in whom the Bβ mutations were found at polymorphic levels, with an allelic frequency of 5% for the Bβ235 mutation and 42% for the Bβ 3′ untranslated mutation. The γ82 mutation was, however, unique to the propositus. Residue γ82 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.
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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