Congenital afibrinogenaemia is a rare autosomal recessive coagulation disorder. Here we describe the genetic defect in the fibrinogen A alpha-chain underlying afibrinogenaemia in a Chinese family. The proposita had a life-long bleeding tendency, both her parents and paternal grandparents had a consa
nguineous marriage. The blood-clotting indices of the proposita and her father were prolonged, and their functional and immunologic fibrinogen was absent. To identify the mutations of fibrinogen genes in this family, all the exons and exon-intron boundaries of the three fibrinogen genes (FGA, FGB, FGG) were amplified by polymerase chain reaction, and direct sequencing of polymerase chain reaction products was performed, then the restriction endonuclease (RsaI) analysis was used to confirm the mutation. A homozygous C --> T mutation was found at nucleotide 3108 in exon 4 of the FGA gene of the proposita and her father; it is a null mutation predicting to produce severely truncated A alpha-chains because of the presence of premature termination at the Gln 150 codon (or truncated at the 131 residues according to the mature A alpha-chain). Her mother and some other family members were heterozygous. The g.3108C --> T (Gln150 --> stop) nonsense mutation in the FGA gene is a novel genetic defect of congenital afibrinogenaemia that, to our knowledge, has not been described previously.
Ko YL, etal., Hum Genet. 2006 Mar;119(1-2):84-91. Epub 2005 Dec 14.
To determine the genetic risk factors for venous thromboembolism (VTE), this study examined 14 genetic variants from 10 hemostatic genes in 186 Taiwanese VTE patients and the same number of matched controls, which demonstrated FGA (encoding alpha fibrinogen) Th
r312Ala polymorphism was the only variant significantly associated with VTE. Nine genetic polymorphisms on the fibrinogen cluster region of chromosome 4q28 were further studied, in which four FGA polymorphisms were found in strong linkage disequilibrium and were significantly associated with VTE by genotype and allele frequency analyses. Haplotype analysis showed significantly different FGA haplotype frequencies between VTE patients and controls with the haplotype F1, containing -1051G, -3A, 312Ala and TaqI duplication alleles, significantly associated with susceptibility to VTE (P = 0.001). Haplotype-pair analysis results also indicated a strong association of the haplotype-pair F1F1 with VTE in various VTE patient subgroups. In vitro functional analysis indicated that FGA -1051G, -3A and TaqI duplication alleles enhanced significantly the transcription level of FGA; however, control subjects with FGA genotypes containing these alleles had no elevated plasma fibrinogen levels. In conclusion, our experimental data indicated that functional genetic variants in FGA are risk factors for VTE in Taiwanese populations. Determination of FGA genotypes will likely contribute to primary prevention of this condition.
Neerman-Arbez M, etal., Eur J Hum Genet. 1999 Dec;7(8):897-902.
Congenital afibrinogenaemia is an autosomal recessive disorder characterised by the complete absence of detectable fibrinogen. We previously identified the first known causative mutations for this disorder in a non-consanguineous Swiss family. The four affected male individuals (two brothers and the
ir first two cousins) were shown to have homozygous deletions of approximately 11 kb of the fibrinogen alpha chain (FGA) gene. Haplotype data suggested that the deletions occurred on three distinct ancestral chromosomes, implying that the FGA region of the fibrinogen locus is susceptible to deletion by a common mechanism, but the sequences responsible for the recombination remained to be identified. Here, we report the detailed characterisation of the deletion by nucleotide sequence analysis of all three deletion junctions and comparison with normal sequences. We found that all three deletions were identical to the base-pair and probably resulted from non-homologous (illegitimate) recombination. The centromeric and telomeric deletion junctions featured both a 7 bp direct repeat, AACTTTT, situated in FGA intron 1 and in the FGA-FGB intergenic sequence and a number of inverted repeats which could be involved in the generation of secondary structures. Analysis with closely linked flanking polymorphic markers revealed the existence of at least two haplotypes, further suggesting independent origins of the deletions in this family.
