title: Factor 8 (F8) gene mutation profile of Turkish hemophilia A patients with inhibitors.
abstract: Factor VIII (FVIII) replacement therapy is ineffective in hemophilia A patients who develop alloantibodies (inhibitors) against FVIII. The type of factor 8 (F8) gene mutation, genes in the major histocompatibility complex loci, and also polymorphisms in IL-10 and tumor necrosis factor-alpha are the major predisposing factors for inhibitor formation. The present study was initiated to reveal the F8 gene mutation profile of 30 severely affected high-responder patients with inhibitor levels of more than 5 Bethesda U (BU)/ml and four low-responder patients with inhibitors less than 5 BU/ml. Southern blot and PCR analysis were performed to detect intron 22 and intron 1 inversions, respectively. Point mutations were screened by DNA sequence analysis of all coding regions, intron/exon boundaries, promoter and 3' UTR regions of the F8 gene. The prevalent mutation was the intron 22 inversion among the high-responder patients followed by large deletions, small deletions, and nonsense mutations. Only one missense and one splicing error mutation was seen. Among the low-responder patients, three single nucleotide deletions and one intron 22 inversion were found. All mutation types detected were in agreement with the severe hemophilia A phenotype, most likely leading to a deficiency of and predisposition to the development of alloantibodies against FVIII. It is seen that Turkish hemophilia A patients with major molecular defects have a higher possibility of developing inhibitors.
authors.affiliation: Department of Molecular Biology and Genetics, Boğaziçi University, Istanbul, Turkey.
authors.forename: Inanç D
authors.initials: ID
authors.lastname: Fidanci
authors.forename: Kaan
authors.initials: K
authors.lastname: Kavakli
authors.forename: Canan
authors.initials: C
authors.lastname: Uçar
authors.forename: Cetin
authors.initials: C
authors.lastname: Timur
authors.forename: Adalet
authors.initials: A
authors.lastname: Meral
authors.forename: Yurdanur
authors.initials: Y
authors.lastname: Kilinç
authors.forename: Hülya
authors.initials: H
authors.lastname: Sayilan
authors.forename: Elif
authors.initials: E
authors.lastname: Kazanci
authors.forename: S Hande
authors.initials: SH
authors.lastname: Cağlayan
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D019774:Blood Coagulation Factor Inhibitors; D005169:Factor VIII / Q000032:analysis / Q000235:genetics*; D006467:Hemophilia A / Q000097:blood / Q000235:genetics*; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D009154:Mutation; D011110:Polymorphism, Genetic; D014421:Turkey
chemical_list: D020413:3' Untranslated Regions; D019774:Blood Coagulation Factor Inhibitors; C078147:F8 protein, human; D005169:Factor VIII