Fibrinogen Gene Mutations Accounting for Congenital Afibrinogenemia

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Abstract
This article reviews recent progress made in understanding the molecular basis of congenital afibrinogenemia, an autosomal recessive coagulation disorder characterized by the complete absence of detectable fibrinogen. We have identified the first causative mutations for this disorder in a non-consanguineous Swiss family; these were homozygous deletions of approximately 11 kb of the fibrinogen alpha chain (FGA) gene. Haplotype data implied that the deletions occurred on distinct ancestral chromosomes, suggesting that this region may be susceptible to deletion by a common mechanism. All the deletions were identical to the base pair, and probably resulted from non-homologous (illegitimate) recombination. In a subsequent study of 13 unrelated patients with congenital afibrinogenemia we analyzed the FGA gene in order to identify the causative mutations, and to determine the prevalence of the 11-kb FGA deletion. Although this deletion was found in an additional unrelated patient, the most common mutation was at the donor splice site of FGA intron 4 (IVS4 + 1 G > T). Three frameshift mutations, two nonsense mutations, and one other splice site mutation were also characterized. Other studies identified one further FGA nonsense mutation, two FGB missense mutations, and one FGG nonsense mutation, all in homozygosity in a single patient. In conclusion, the majority of patients have truncating mutations in the FGA gene although, intuitively, all three fibrinogen genes could be predicted to be equally implicated. These results will facilitate molecular diagnosis of the disorder, permit prenatal diagnosis for families who so desire, and pave the way for new therapeutic approaches such as gene therapy.