title: Non-inversion factor VIII mutations in 80 hemophilia A families including 24 with alloimmune responses.
abstract: Heteroduplex screening identified 74 small mutations in the factor VIII genes of 72 families with hemophilia A. In addition, patients from 3 families with high titer inhibitors had partial gene deletions and 5 unrelated families that were negative for heteroduplex formation had a mutation on direct sequencing. The latter had mild hemophilia A with an inhibitor, and sequencing their exon 23 fragments found a transition predicting a recurrent Arg2150 to His. Of 69 distinct mutations (including the 3 partial gene deletions), 47 are novel. Of small mutations, 51 were missense (one possibly a normal variant and two that could also alter splicing) at 39 sites, 13 were small deletions or insertions (3 inframe and one a normal variant in an intron), 13 were nonsense at 12 sites and 2 altered intron splice junctions. In 24 families, at least one affected member had evidence for an alloimmune response to factor VIII: of these, 11 were associated with missense mutations. In 14 families, de novo origin was demonstrated.
authors.affiliation: Puget Sound Blood Center and the Department of Medicine, University of Washington, Seattle 98104-1256, USA.
authors.forename: Miao-Liang
authors.initials: ML
authors.lastname: Liu
authors.forename: Shelley
authors.initials: S
authors.lastname: Nakaya
authors.forename: Arthur R
authors.initials: AR
authors.lastname: Thompson
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D019943:Amino Acid Substitution; D003062:Codon / Q000235:genetics; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005169:Factor VIII / Q000235:genetics* / Q000276:immunology; D005260:Female; D017353:Gene Deletion; D006467:Hemophilia A / Q000235:genetics* / Q000276:immunology; D020180:Heteroduplex Analysis; D006801:Humans; D007518:Isoantibodies / Q000276:immunology*; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D009692:Nucleic Acid Heteroduplexes / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics
chemical_list: D003062:Codon; D018389:Codon, Nonsense; D007518:Isoantibodies; D009692:Nucleic Acid Heteroduplexes; D022821:RNA Splice Sites; D005169:Factor VIII