Factor 8 (F8) gene mutation profile of Turkish hemophilia A patients with inhibitors.
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.
Fidanci
Inanç D
ID
Department of Molecular Biology and Genetics, Boğaziçi University, Istanbul, Turkey.
Kavakli
Kaan
K
Uçar
Canan
C
Timur
Cetin
C
Meral
Adalet
A
Kilinç
Yurdanur
Y
Sayilan
Hülya
H
Kazanci
Elif
E
Cağlayan
S Hande
SH
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
D020413:3' Untranslated Regions; D019774:Blood Coagulation Factor Inhibitors; C078147:F8 protein, human; D005169:Factor VIII