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DOI: 10.1055/s-0037-1614043
Hypofibrinogenaemia with Compound Heterozygosity for Two γ Chain Mutations – γ 82 Ala→Gly and an Intron Two GT→AT Splice Site Mutation
We thank Silvia Parkin for coagulation studies. This investigation was supported by the Canterbury Medical Research Foundation and Lottery Health.
Publication History
Received
22 February 2000
Accepted after revision
14 April 2000
Publication Date:
14 December 2017 (online)
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.
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References
- 1 Henschen A, McDonagh J. Fibrinogen, fibrin and factor XIII. In: Blood Coagulation. Zwaal FFA, Hemker HC. eds. Amsterdam: Elsevier Science Publishers BV; 1986: 171-241.
- 2 Doolittle RF. The molecular biology of fibrin. In: The Molecular Basis of Blood Diseases. Stamatoyannopoulos G, Nienhuis AW, Majerus PW, Varmus H. eds. Philadelphia: WB Saunders Company; 1994: 701-23.
- 3 McDonagh J, Carrell N, Lee MH. Dysfibrinogenemia and other disorders of fibrinogen structure and function. In Hemostasis and thrombosis: Basic principles and clinical practice. Colman RW, Hirsh J, Marder VJ, Salzman EW. eds. Philadelphia: J. B. Lippincott Company; 1994: 314-34.
- 4 Hahn LPA, Lundberg PA, Tiger-Nnilsson AC. Congenital hypofibrinogenaemia and recurrent abortion. British Journal of Obstetrics and Gynaecology 1978; 85: 790-3.
- 5 Ridgway HJ, Brennan SO, Faed M, George PM. Fibrinogen Otago: a major a chain truncation associated with severe hypofibrinogenaemia and recurrent miscarriage. Brit J Haemaolt 1997; 98: 632-9.
- 6 Gralnick R, Coller BS, Fratantoni JC, Martinez J. Fibrinogen Bethesda III: a hypodysfibrinogenemia. Blood 1979; 53: 28-46.
- 7 Brennan SO, Fellowes AP, Faed JM, George PM. Hypofibrinogenemia in an individual with two coding (γ82 A→G and Bβ235 P→L) and two noncoding mutations. Blood 2000; 95: 1709-13.
- 8 Brennan SO, Hammonds B, George PM. Aberrant hepataic processing causes removal of activation peptide and primary polymerisation site from fibrinogen Canterbury (A α20 Val→Asp). J Clin Invest 1995; 96: 2854-8.
- 9 Brennan SO. Electrospray ionisation analysis of human fibrinogen. Thromb Haemost 1997; 78: 1055-8.
- 10 Ciulla TA, Sklar M, Hause SL. A Simple Method for DNA Purification from Peripheral Blood. Anal Biochem 1988; 174: 485-8.
- 11 Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA. Primer-Directed Enzymatic Amplification of DNA with a Thermostable DNA Polymerase. Science 1988; 239: 487-91.
- 12 Thomas A, Lamlum H, Humphries SE, Green F. Linkage disequilibrium across the fibrinogen locus as shown by five genetic polymorphisms, G/A-455 (HaeIII), C/T-148 ( HindIII/AluI), T/G+1689 (AvaII), and BclI (β-fibrinogen) and TaqI (α-fibrinogen), and their detection by PCR. Human Mutation 1994; 03: 79-81.
- 13 Baumann RE, Henschen AH. Human fibrinogen polymorphic site analysis by restriction endonuclease digestion and allele-specific polymerase chain reaction amplification: identification of polymorphisms at positions Aα312 and Bβ 448. Blood 1993; 82: 2117-24.
- 14 Baumann RE, Henschen AH. Linkage disequilibrium relationships among four polymorphisms within the human fibrinogen gene cluster. Human Genetics 1994; 94: 165-70.
- 15 Suh TT, Holmback K, Jensen NJ, Daugherty CC, Small K, Simon DI, Potter S, Degan DL. Resolution of spontaneous bleeding events but failure pregnancy in fibrinogen deficient mice. Genes and Development 1995; 09: 2020-33.
- 16 Hasselback R, Marion RB, Thomas JW. Congenital hypofibrinogenaemia in five members of a family. Canadian Medical Association Journal 1963; 88: 19-22.