Summary
We investigated the molecular basis of hypofibrinogenaemia in a woman with a history
of recurrent, pregnancy-associated bleeding, and miscarriage. She had a Clauss fibrinogen
of 0.9 mg/ml and SDS PAGE of purified fibrinogen showed a normal pattern of chains.
However careful inspection of reverse phase chain separation profiles showed apparent
homozygosity for a more hydrophilic form of the γ chain. DNA Sequencing showed only
heterozygosity for a CGT→GGT (Ala→Gly) mutation at codon γ82, but further sequencing showed an additional GT
splice sequence mutation at the 5’ end of intron 2 of the γ gene. Translation of mRNA
containing this intron would result in premature truncation explaining the phenotypic
homozygosity of the γ82 Ala→Gly substitution. The patient’s sister had a mild bleeding
disorder with hypofibrinogenaemia and she too was a compound heterozygote for the
γ mutations. Her nephew had only the novel splice site mutation, while her mother
and daughter inherited only the γ82 Ala→Gly substitution.
Key words
Fibrinogen - hypofibrinogenaemia - mutation - compound heterozygote
