Identification of simultaneous mutation of fibrinogen α chain and protein C genes in a Japanese kindred

Abstract

Summary. Afibrinogenaemia usually induces a bleeding tendency during infancy, whereas protein C deficiency increases susceptibility to thrombosis in children or adolescence. Mutations of these genes have been, therefore, established as independent risk factors for coagulation disorders. We describe the homozygous mutation of the fibrinogen a chain gene and additional heterozygous mutation of the protein C gene in a male infant who showed prolonged umbilical bleeding after birth. On examination, the plasma fibrinogen was undetectable, and the activity and antigen level of protein C were reduced. The patient showed no fibrinogen Aa chain as well as Bb and c chains by Western blotting. The sequencing analysis showed the homozygous deletion of 1238 bases from intron 3 at position 2008 to intron 4 at position 3245 in the fibrinogen a chain gene. Both parents were heterozygous carriers of this mutation. In this patient, an additional mutation was also detected in the protein C gene: the heterozygous deletion of exon 7 at position 6161-6163 or 6164-6166, resulting the deletion of one amino acid (Lys150 or 151). His mother was also a carrier of this mutation. As the simultaneous mutation of the fibrinogen a chain and protein C genes has not been previously reported, the influence of the interaction between these two mutations on the clinical manifestations of this patient should be carefully monitored for a long period.

Congenital afibrinogenaemia caused by uniparental isodisomy of chromosome 4 containing a novel 15-kb deletion involving fibrinogen Aα-chain gene

“…13,14 Interestingly, all deletions involve FGA and the deletion breakpoints have similar locations. In particular, the 5 0 breakpoint of the 15-kb deletion is located in the FGA intron 4, like the 3 0 end of the 1238-bp deletion, while both the 3 0 breakpoints of the 15-and of the 11-kb deletions are localised in the FGA -FGB intergenic region (Figure 2a).…”

“…4 The majority of gene alterations underlying congenital afibrinogenaemia are point mutations (two small insertions, six small deletions, four missense, eight splicing, and 11 nonsense mutations), almost equally spread over the fibrinogen genes. 5 -13 Only two large deletions, an 11-kb deletion representing the first causative deletion identified in afibrinogenaemia 14 and a very recently reported 1238-bp deletion, 13 have been identified and both are located in FGA.…”

Mutations in the fibrinogen gene cluster accounting for congenital afibrinogenemia: an update and report of 10 novel mutations

“…The first, a deletion of 1.2 kb (EX_4del) eliminating the entire FGA exon 4, with breakpoints situated in FGA introns 3 and 4, was identified in homozygosity in a Japanese patient [Watanabe et al, 2003]. The second, a deletion of 15 kb, with breakpoints situated in FGA intron 4 and in the FGA-FGB intergenic region (EX5_EX6del) was identified in a Thai patient .…”

siRNA down-regulation of FGA mRNA in HepG2 cells demonstrated that heterozygous abnormality of the Aα-chain gene does not affect the plasma fibrinogen level

“…Thus, we hypothesized that in normal liver, FGA mRNA was more than two-fold higher than FGB and/or FGG mRNA, and if FGA mRNA was decreased by almost half by a mutation with FGA mRNA decay, plasma fibrinogen was not decreased and was maintained in the normal range. To examine the hypothesis, we quantitated mRNA levels for three normal livers and a human hepatocyte cell We showed plasma fibrinogen concentration for probands with afibrinogenemia causing homozygote FGAΔ1238bp mutation and compound heterozygotes including FGAΔ1238bp mutation, and their heterozygous family members in Table 1 [10][11][12][13][14]. Plasma fibrinogen levels of all heterozygous individuals were almost normal, and 1 of 16 people had <1.5 g/l by either the functional method or immunological determination method.…”

“…Six families, including our two cases, with FGAΔ1238 have only been found in Far Eastern countries, one in China [11] and five in Japan [10,[12][13][14], and regarding which parents and family members have a heterozygous genetic abnormality, the plasma fibrinogen concentrations were all normal (Table 1). According to our observation and the coincident reports, we hypothesize these phenomena as follows.…”