@entity6805 in an individual with 2 coding (gamma XXXX and Bbeta @entity72378 ) and 2 noncoding mutations.

@entity1 @entity72378 @entity14552 @entity6407 @entity6805 @entity72379
We investigated the molecular basis of @entity6805 in a @entity1 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 @entity72378 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 @entity72379 substitution. DNA sequencing established heterozygosity for 2 further mutations: @entity14552 in intron 4 of the Aalpha gene and @entity6407 in the 3' noncoding region of the Bbeta gene. Studies on the @entity1 's daughter, together with plasma expression levels, discounted both the Aalpha and Bbeta mutations as the cause of the low fibrinogen, suggesting that the gamma82 mutation caused the @entity6805 . 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 Bbeta235 mutation and 42% for the Bbeta 3' untranslated mutation. The gamma82 mutation was, however, unique to the propositus. Residue gamma82 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. (Blood. 2000;95:1709-1713)
