MOLECULAR CHARACTERIZATION OF
HEMOPHILIA A IN THE REPUBLIC OF MACEDONIA
Sukarova-Stefanovska E1, Zisovski N2,
Muratovska O2, Kostova S3, Efremov GD1,*
*Corresponding Author: Professor Dr. Georgi D. Efremov, Research Centre for Genetic Engineering and Biotechnology, Macedonian Academy of Sciences and Arts, Bul. Krste Misirkov 2, 1000, Skopje, Republic of Macedonia; Tel: +389 2 3120 253; Fax: +389 2 3115 434; e-mail: gde@manu.edu.mk page: 27
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Abstract
Hemophilia A is an X-linked bleeding disorder caused by mutations in the factor VIII gene. The aim of this study was to determine the molecular defects underlying hemophilia A patients from the Republic of Macedonia. Molecular characterization of factor VIII was performed in 50 unrelated patients with different clinical severity. We employed Southern blot analysis for detection of an inversion in intron 22 of the factor VIII gene, and gross gene deletions or insertions; while polymerase chain reaction (PCR), followed by single strand conformation polymorphism (SSCP) or denaturation gradient gel electrophoresis (DGGE) was performed for mutation screening in the coding sequences of the factor VIII gene.
The molecular defects causing hemophilia A were determined in 34 out of 50 (68%) patients. The most frequent molecular defect was an inversion in intron 22, found in 38% of the patients, or 67.7% of the patients with a severe form of disease. Nucleotide substitutions were found in 15 hemophilia A patients with different clinical severity, mostly being found in one family only, with the exception of a C®T change in codon 2159 found in four (8%) of the patients. Four mutations [ATG®AGG (Met® Arg), exon 1, codon 19; GCT®CCT (Ala®Pro), exon 3, codon 78; TGC®GGC (Cys®Gly), exon 24, codon 2174, and TAT®GAT (Tyr®Asp), exon 25, codon 2256] were detected for the first time.
As a result of this study six prenatal diagnoses were performed.
Key words: Hemophilia A, factor VIII (fVIII) gene, inversion in intron 22, point mutations
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