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Blood, Vol. 95 No. 5 (March 1), 2000: pp. 1709-1713

Hypofibrinogenemia in an individual with 2 coding (gamma 82 Aright-arrow G and Bbeta 235 Pright-arrow L) 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 Bbeta alleles, and DNA sequencing confirmed heterozygosity for a new Bbeta 235 Pright-arrowL 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 Aright-arrowG substitution. DNA sequencing established heterozygosity for 2 further mutations: Tright-arrowC in intron 4 of the Aalpha gene and Aright-arrowC in the 3' noncoding region of the Bbeta gene. Studies on the man's daughter, together with plasma expression levels, discounted both the Aalpha and Bbeta 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 Bbeta mutations were found at polymorphic levels, with an allelic frequency of 5% for the Bbeta 235 mutation and 42% for the Bbeta 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.


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