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

INTRODUCTION

Hemophilia A is a common X-linked bleeding disorder affecting approximately 1 in 5,000 males worldwide. It is caused by mutations in the factor VIII (fVIII) gene leading to deficiency or dysfunctional fVIII [1]. Its clinical picture is characterized by recurrent bleeding at multiple sites. The frequency and severity of the bleeding episodes depend on the functional fVIII levels. The gene encoding fVIII is located on the long arm of the X chromosome (Xq28). It is 186 kb long and contains 26 exons, encoding 9 kb mRNA [2,3].

A wide spectrum of different gene defects has been found as a cause of hemophilia A [4]. The most common molecular defect found in 45% of the severe cases is an intron 22 inversion [5]. The inversion is mediated by the presence of three copies of the int22h homologous sequence, one located within intron 22 of the fVIII gene and the other two 400 bp telomeric to the gene. Crossover with the distal int22h sequence results in inversion type 1, and is the most common crossover event accounting for 82% of all inversions. A crossover involving the proximal int22h resulting in inversion type 2, occurs less frequently (15%). A rare type of the inversion can also be detected (1%) since the number of extragenic copies appears to be polymorphic. This crossover event results in translocation of the gene, thus causing severe hemophilia A [6].


Most of the other defects are single nucleotide substi­tutions dispersed through out the whole coding region of the fVIII gene, and are peculiar to the individual families. Efficient mutation screening methods have greatly facili­tated the analysis of the fVIII gene. The fast-growing num­ber of identified mutations has led to the understanding of the genetics of hemophilia A. Characterization of muta­tions may help to identify amino acids or regions with essential functional or structural properties, and thereby clarify the mechanism of pathogenesis.

The knowledge of the causative gene defect has also become an important instrument in hemophilia care with respect to prediction of the patientsí clinical course and safe genetic counseling of relatives [7].




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