title: A common ancestral mutation (C128X) occurring in 11 non-Jewish families from the UK with factor XI deficiency.
abstract: Factor XI (FXI) deficiency is a mild bleeding disorder that is particularly common in Ashkenazi Jews, but has been reported in all populations. In Jews, two FXI gene (F11) mutations (a stop codon in exon 5, E117X, type II, and a point mutation in exon 9, F283L, type III) are particularly common, but in other populations a variety of different mutations have been described. In the Basque region of France one mutation, C38R in exon 3, was found in eight of 12 families studied, haplotype analysis suggesting a founder effect. In the course of screening 78 unrelated individuals (including 15 Jewish and 12 Asian) we have found 10 Caucasian non-Jewish patients with the mutation C128X in exon 5. Individuals were investigated because of a personal or family history of bleeding, or finding a prolonged activated partial thromboplastin time. Individuals negative for the type II and type III mutations were screened by a combination of SSCP and heteroduplex analysis. The C128X mutation was found in 10 families (one previously described). Among three individuals with severe FXI deficiency, one was homozygous for the C128X mutation, and two were compound heterozygotes for the C128X and another mutation; other individuals were carriers of the C128X mutation. This is a nonsense mutation producing a truncated protein; individuals have FXI antigen levels concordant with FXI coagulant activity. Haplotype analysis of 11 families, including a further kindred previously reported from the USA, but which originally came from the UK (in which the index patient was homozygous for C128X), suggests a founder effect.
authors.affiliation: Department of Clinical Haematology, Manchester Royal Infirmary, Manchester, UK. paula.bolton-maggs@man.ac.uk
authors.forename: P H B
authors.initials: PH
authors.lastname: Bolton-Maggs
authors.forename: H
authors.initials: H
authors.lastname: Peretz
authors.forename: R
authors.initials: R
authors.lastname: Butler
authors.forename: R
authors.initials: R
authors.lastname: Mountford
authors.forename: S
authors.initials: S
authors.lastname: Keeney
authors.forename: L
authors.initials: L
authors.lastname: Zacharski
authors.forename: A
authors.initials: A
authors.lastname: Zivelin
authors.forename: U
authors.initials: U
authors.lastname: Seligsohn
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D005091:Exons; D005173:Factor XI Deficiency / Q000208:ethnology / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D017720:Molecular Epidemiology; D010375:Pedigree; D006113:United Kingdom / Q000453:epidemiology / Q000208:ethnology; D044465:White People / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense