Factor VII gene intronic mutation in a lethal factor VII deficiency: effects on splice-site selection

Keren Borensztajn (1) , Marie-Laure Sobrier (2) , Anne-Marie Fischer , Ouerdia Chafa (3) , Serge Amselem (2) , Jacqueline Tapon-Bretaudiére (4)

1 Risque thrombotique et mécanismes de l'hémostase
2 Génétique moléculaire et physiopathologie
3 CHU Mustapha
4 HEGP - Hôpital Européen Georges Pompidou [APHP]

Abstract In a patient with lethal factor VII (FVII) deficiency, 2 homozygous nucleotide substitutions were identified in the F7 gene: a IVS7+2T>G transversion involving the IVS7 donor splice site, followed by a mutation at nucleotide 10588 that would result in a missense variation (Arg224Gln). The mutated splice site, located within the first repeat of a minisatellite, is followed by a variable number of pseudo-sites, normally silent. To investigate the consequences of this mutation on F7 splicing, we designed normal and mutant minigenes, spanning exons 5 to 8. In cells transfected with the mutant construct, no normal splicing occurred. Only spliced transcripts including the first minisatellite repeat were observed, resulting from the activation of the most proximal wild-type pseudo-site, which would generate a truncated protein (stop codon upstream of nucleotide 10588). These findings, which suggest the existence of a mechanism selecting one single splice site among multiple cryptic sites, explain the patient's phenotype.

Domaines: Génétique humaine; Endocrinologie et métabolisme

Keren Borensztajn, Marie-Laure Sobrier, Anne-Marie Fischer, Ouerdia Chafa, Serge Amselem, et al.. Factor VII gene intronic mutation in a lethal factor VII deficiency: effects on splice-site selection. Blood, 2003, 102 (2), pp.561-563. ⟨10.1182/blood-2002-09-2951⟩. ⟨inserm-04142098⟩