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

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 CT change in codon 2159 found in four (8%) of the patients. Four mutations [ATGAGG (Met Arg), exon 1, codon 19; GCTCCT (AlaPro), exon 3, codon 78; TGCGGC (CysGly), exon 24, codon 2174, and TATGAT (TyrAsp), 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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