title: Identification of an ancient haemophilia A splice site mutation.
abstract: BACKGROUND
  To date, numerous mutations resulting in haemophilia A are known and recorded at HAMSTeRS. We identified a new splice site mutation in intron 6 of the F8 gene (T to G transition at position -14; c.788-14T>G) in seven not knowingly related patients, who all suffer from mild haemophilia A. RNA analysis of blood cells indicated that this mutation leads to the preferred generation of a transcript lacking the complete exon 7 (without frameshift).
  
  
  METHODS
  To determine whether the mutation represented a founder mutation we analyzed intragenic (intronic) and extragenic short tandem repeat (STR) regions and constructed haplotypes in the 7 patients and 128 apparently healthy male control individuals.
  
  
  RESULTS
  In the 128 healthy control individuals, 109 different haplotypes were found. Surprisingly, also the 7 patients carried 3 different haplotypes. However, by genealogy reconstruction using BATWING we could identify an ancestral haplotype on which the mutation apparently occurred. This haplotype - DXS9897:12-DXS1073:21-HA472:64-DXS1108:26 - was frequent and was found in three patients, but was also present in four control individuals who did not carry the splice site mutation.
  
  
  CONCLUSIONS
  Our data indicate that the splice site mutation occurred in an individual carrying a relatively common haplotype. While the mutation was passed on through generations, the haplotypes identified in the seven patients derived from this founder haplotype but were changed by later mutations in the STR regions.
authors.affiliation: Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Austria. sylvia-elisabeth.reitter@meduniwien.ac.at
authors.forename: Sylvia
authors.initials: S
authors.lastname: Reitter-Pfoertner
authors.forename: Arndt
authors.initials: A
authors.lastname: von Haeseler
authors.forename: Birgit
authors.initials: B
authors.lastname: Horvath
authors.forename: Raute
authors.initials: R
authors.lastname: Sunder-Plassmann
authors.forename: Vera
authors.initials: V
authors.lastname: Tiedje
authors.forename: Ingrid
authors.initials: I
authors.lastname: Pabinger
authors.forename: Christine
authors.initials: C
authors.lastname: Mannhalter
mesh_terms: D001317:Austria / Q000453:epidemiology; D005169:Factor VIII / Q000378:metabolism*; D005260:Female; D018703:Founder Effect; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics*; D006467:Hemophilia A / Q000453:epidemiology / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007438:Introns / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics*
chemical_list: D022821:RNA Splice Sites; C078147:F8 protein, human; D005169:Factor VIII