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Thromb Haemost 2000; 84(03): 449-452
DOI: 10.1055/s-0037-1614043
Commentary
Schattauer GmbH

Hypofibrinogenaemia with Compound Heterozygosity for Two γ Chain Mutations – γ 82 Ala→Gly and an Intron Two GT→AT Splice Site Mutation

Jane Wyatt
2   From the Molecular Pathology Laboratory, Canterbury Health Laboratories, Christchurch Hospital, Christchurch, New Zealand
,
Stephen O. Brennan
2   From the Molecular Pathology Laboratory, Canterbury Health Laboratories, Christchurch Hospital, Christchurch, New Zealand
,
Stephen May
1   Pathlab, Medical Laboratory, Hamilton, New Zealand
,
Peter M. George
2   From the Molecular Pathology Laboratory, Canterbury Health Laboratories, Christchurch Hospital, Christchurch, New Zealand
› Author AffiliationsWe thank Silvia Parkin for coagulation studies. This investigation was supported by the Canterbury Medical Research Foundation and Lottery Health.
Further Information

Publication History

Received 22 February 2000

Accepted after revision 14 April 2000

Publication Date:
14 December 2017 (online)

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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
 

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