title: Molecular basis of severe factor XI deficiency in seven families from the west of France. Seven novel mutations, including an ancient Q88X mutation.
abstract: Inherited factor (F)XI deficiency is a rare disorder in the general population, though it is commonly found in individuals of Ashkenazi Jewish ancestry. In particular, two mutations--a stop mutation (type II) and a missense mutation (type III)--which are responsible for FXI deficiency, predominate. The bleeding tendency associated with plasma FXI deficiency in patients is variable, with approximately 50% of patients exhibiting excessive post-traumatic or postsurgical bleeding. In this study, we identified the molecular basis of FXI deficiency in 10 patients belonging to six unrelated families of the Nantes area in France and one family of Lebanese origin. As in Ashkenazi Jewish or in French Basque patients, we have identified a new ancient mutation in exon 4 resulting in Q88X, specific to patients from Nantes, that can result in a severely truncated polypeptide. Homozygous Q88X was found in a severely affected patient with an inhibitor to FXI and in three other unrelated families, either as homozygous, heterozygous or compound heterozygous states. Other identified mutations are two nonsense mutations in the FXI gene, in exon 7 and 15, resulting in R210X and C581X, respectively, which were identified in three families. A novel insertion in exon 3 (nucleotide 137 + G), which causes a stop codon, was characterized. Finally, sequence analysis of all 15 exons of the FXI gene revealed three missense mutations resulting in G336R and G350A (exon 10) and T575M (exon 15). Two mutations (T575M and G350A) with discrepant antigen and functional values are particularly interesting because most of the described mutations are associated with the absence of secreted protein.
authors.affiliation: Laboratoire de Biochimie et Biologie Moléculaire, Hôpital Raymond Poincaré, Garches, France. florence.quelin@rpc.ap-hop-paris.fr
authors.forename: F
authors.initials: F
authors.lastname: Quélin
authors.forename: M
authors.initials: M
authors.lastname: Trossaërt
authors.forename: M
authors.initials: M
authors.lastname: Sigaud
authors.forename: P D E
authors.initials: PD
authors.lastname: Mazancourt
authors.forename: E
authors.initials: E
authors.lastname: Fressinaud
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D018389:Codon, Nonsense; D018388:Codon, Terminator / Q000235:genetics; D004252:DNA Mutational Analysis; D005172:Factor XI / Q000235:genetics*; D005173:Factor XI Deficiency / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D005602:France; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree
chemical_list: D018389:Codon, Nonsense; D018388:Codon, Terminator; D005172:Factor XI