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DOI: 10.1160/TH04-04-0220
Novel aberrant splicings caused by a splice site mutation (IVS1a+5g>a) in F7 gene
Publikationsverlauf
Received
07. April 2004
Accepted after revision
09. März 2005
Publikationsdatum:
11. Dezember 2017 (online)

Summary
Low FVII coagulant activity (FVII:C 8.2%) and antigen level (FVII:Ag 34.1%) in a 46-year-old Chinese male led to a diagnosis of coagulation factor VII (FVII) deficiency. Compound heterozygous mutations were identified in his F7 gene:a G to A transition in the 5’ donor splice site of intron 1a (IVS1a+5g>a) and a T to G transition at the nucleotide position 10961 in exon 8, resulting in a His to Gln substitution at amino acid residue 348. An analysis of ectopic transcripts of F7 in the leukocytes of the patient reveals that the mutation (IVS1a+5g>a) is associated with two novel aberrant patterns of splicing. The predominant alternative transcript removes exon 2, but retains intron 3, which shifts the reading frame and predicts a premature translation termination at the nucleotide positions 2–4 in intron 3. The minor alternative transcript skips both exon 2 and exon 3 (FVII Δ2, 3), leading to an in-frame deletion of the propeptide and γ-carboxylated glutamic acid (Gla) domains of mature FVII protein. In vitro expression studies of the alternative transcript FVII Δ2, 3 by transient transfection of HEK 293 cells with PcDNA 3.1(-) expression vector showed that although the mutant protein could be secreted, no pro-coagulation activity was detected. The coexistence of the two abnormal transcripts and a heterozygous mutation His348Gln, explained the patient’s phenotype.
* These authors contribute to the work equally
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References
- 1 Fair DS. Quantitation of factor VII in the plasma of normal and warfarin-treated individuals by radioimmunoassay. Blood 1983; 62: 784-91.
- 2 Bauer KA, Kass BL, ten Cate H. et al. Factor IX is activated in vivo by the tissue factor mechanism. Blood 1990; 76: 731-6.
- 3 Peyvandi F, Jenkins PV, Mannucci PM. et al. Molecular characterisation and three-dimensional structural analysis of mutations in 21 unrelated families with inherited factor VII deficiency. Thromb Haemost 2000; 84: 250-7.
- 4 Hagen FS, Gray CL, O’Hara P. et al. Characterization of a cDNA coding for human factor VII. Proc Natl Acad Sci USA 1986; 83: 2412-6.
- 5 O’Hara PJ, Grant FJ, Haldeman BA. et al. Nucleotide sequence of the gene coding for human factor VII, a vitamin K-dependent protein participating in blood coagulation. Proc Natl Acad Sci USA 1987; 84: 5158-62.
- 6 McVey JH, Boswell E, Mumford AD. et al. Factor VII deficiency and the FVII mutation database. Hum Mutat 2001; 17: 3-17.
- 7 Katsumi A, Matsushita T, Yamazaki T. et al. Severe factor VII deficiency caused by a novel mutation His348 to Gln in the catalytic domain. Thromb Haemost 2000; 83: 239-43.
- 8 Giansily-Blaizot M, Aguilar-Martinez P, Biron-Andreani C. et al. Analysis of the genotypes and phenotypes of 37 unrelated patients with inherited factor VII deficiency. Eur J Hum Genet 2001; 9: 105-12.
- 9 McVey JH, Boswell EJ, Takamiya O. et al. Exclusion of the first EGF domain of factor VII by a splice site mutation causes lethal factor VII deficiency. Blood 1998; 92: 920-6.
- 10 Wulff K, Herrmann FH. Twenty two novel mutations of the factor VII gene in factor VII deficiency. Hum Mutat 2000; 15: 489-96.
- 11 Pinotti M, Toso R, Redaelli R. et al. Molecular mechanisms of FVII deficiency: expression of mutations clustered in the IVS7 donor splice site of factor VII gene. Blood 1998; 92: 1646-51.
- 12 Shahin H, Walsh T, Sobe T. et al. Genetics of congenital deafness in the Palestinian population: multiple connexin 26 alleles with shared origins in the Middle East. Hum Genet 2002; 110: 284-9.
- 13 Lai LW, Whitehair O, Wu MJ. et al. Analysis of splice-site mutations of the alpha-galactosidase A gene in Fabry disease. Clin Genet 2003; 63: 476-82.
- 14 Gonzalez AA, Reyes ML, Carvajal CA. et al. Congenital lipoid adrenal hyperplasia caused by a novel splicing mutation in the gene for the steroidogenic acute regulatory protein. J Clin Endocrinol Metab 2004; 89: 946-51.
- 15 Lal S, Choi JH, Shaw JR. et al. A splice site mutant of maize activates cryptic splice sites, elicits intron inclusion and exon exclusion, and permits branch point elucidation. Plant Physiol 1999; 121: 411-8.
- 16 Rios M, Storry JR, Hue-Roye K. et al. Two new molecular bases for the Dombrock null phenotype. Br J Haematol 2002; 117: 765-7.
- 17 Nakai K, Sakamoto H. Construction of a novel database containing aberrant splicing mutations of mammalian genes. Gene 1994; 141: 171-7.
- 18 Takahara K, Schwarze U, Imamura Y. et al. Order of intron removal influences multiple splice outcomes, including a two-exon skip, in a COL5A1 acceptor-site mutation that results in abnormal pro-alpha1(V) N-propeptides and Ehlers-Danlos syndrome type I. Am J Hum Genet 2002; 71: 451-65.