Prospective analysis of factor XI deficiencies in the Marseilles area identified four novel mutations among 12 consecutive unrelated families

Abstract

Hereditary factor XI (FXI) deficiency is an autosomal bleeding disorder of variable severity but without a clear relationship between bleeding and FXI levels or mutation location or both. In the present study, the molecular basis of FXI deficiency in 16 patients from 12 families originating from the Marseilles area in the south of France was studied. FXI defect was evidenced by routine laboratory tests showing prolonged activated partial thromboplastin times and decreased factor XI activities. The promotor region, exons 1-15, and the exon-intron boundaries of the FXI gene were sequenced. Four novel mutations were found; three were missense mutations (Cys212Ser, Gly350Arg and Thr381Leu resulting from heterozygote mutation in exon 7, 10 and 11, respectively), and one was a one base deletion in exon 4 that induces a frameshift creating a stop codon four residues later (Thr57Ile fsX4). Eight previously reported mutations were also found. Contrarily to the Jewish, Basques or Briton populations, no recurrent mutation was identified. This cohort also illustrates that bleeding events occur not exclusively and not systematically in severe FXI deficiency but also in patients characterized by a mild FXI deficiency.

High incidence of FXI deficiency in a Spanish town caused by 11 different mutations and the first duplication of F11: Results from the Yecla study

“…CM051916 (c.1613C>T) , responsible for the missense change p.Pro538Leu, was identified in two unrelated cases from our study (Table ). This mutation was previously described in heterozygosis in 5 patients with FXI deficiency from different European countries and in compound heterozygosis in one additional patient . Antigenic values observed in heterozygous patients previously described together with in vitro studies supported that a FXI variant may be correctly secreted but with a modest catalytic activity.…”

“…Diagnosis of FXI deficiency is usually performed in patients with bleeding that display an elongated activated partial thromboplastin time (APTT), even though there is a poor correlation between FXI levels and bleeding tendency, and APTT is not the best method to diagnose FXI deficiency . These data and recent studies finding a high number of cases with FXI deficiency among non‐Jewish populations question the rarity of this disorder …”

“…1 These data and recent studies finding a high number of cases with FXI deficiency among non-Jewish populations question the rarity of this disorder. 5,[7][8][9][10][11][12][13][14] Here, we present the result of a 20-year study performed in a Spanish town of 60 000 inhabitants that analysed the cases with prolonged APTT independently of any clinical manifestation. Our study describes a high prevalence of FXI deficiency caused by a wide spectrum of recurrent and sporadic mutations.…”

Point mutations regarded as missense mutations cause splicing defects in the factor XI gene

“…Sequences of all exons and flanking exon–intron boundaries of the F11 gene revealed a c.1693G>A substitution in exon 14 of patient 1 and two mutations in patient 2, a c.616C>T substitution in exon 7 and a c.1060G>A substitution in exon 10. All three mutations were reported previously in other FXI‐deficient patients and were defined as missense mutations [9–15] predicting an E547K substitution in patient 1 and P188S and G336R substitutions in patient 2. In the current nomenclature, the signal peptide is included and thus these mutations are designated as E565K, P206S and G354R, respectively.…”

“…In the present study, we characterized in two patients with FXI deficiency three‐point mutations in exons 7, 10 and 14 of the F11 gene. All three mutations were previously reported and were defined as missense mutations [9–15]. Surprisingly, expression of cDNA of these mutations in baby hamster kidney (BHK) cells yielded higher FXI levels than expected from the plasma levels in the patients.…”