MOLECULAR CHARACTERIZATION OF HEMOPHILIA A IN SOUTHEAST BULGARIA
Sukarova Stefanovska E1, Tchakarova P2, Petkov GH2, 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, POB 428, Skopje 1000, Republic of Macedonia; Tel.: +389-2-3235-411; Fax: +389-2-3115-434;E-mail: gde@manu.edu.mk
page: 55

INTRODUCTION

 

Hemophilia A is a common X-linked bleeding disorder affecting 1/5,000 males worldwide [1]. It is caused by mutations in the factor VIII (FVIII) gene, leading to a deficiency of, or to a dysfunctional FVIII, an essential cofactor in the factor X activation complex. This gene consists of 26 exons (approximately 9 kb mRNA) and encodes a 2,351 amino acid precursor protein. This comprises of a leader peptide, three A domains, a B domain and two C domains. The A domains are flanked by small acidic regions (a1-3) in the sequence: A1-a1-A2-a2- B-a3-A3-C1-C2 [2]. During secretion, circulation in plasma and activation of the precursor protein undergoes a series of cleavages that result in the active heterotrimeric FVIII [3]. Factor VIII deficiency is heterogeneous in clinical severity and at the molecular level. The most common molecular defect is an intron 22 inversion which occurs in up to 45% of severely hemophilic patients. This is caused by recombination between a sequence within intron 22 of the FVIII gene and one of the two homologous regions telomeric to the gene [4]. Another recurrent mutation is the intron 1 inversion which has a frequency of up to 5% of molecular defects detected in hemophilic patients of different ethnic groups [5]. Other mutations 56 are mainly single nucleotide substitutions spread throughout the coding region of the gene, and are peculiar to the individual families [6]. A comprehensive FVIII mutation database and sequence resource site (HAMSTeRS) is available at http:// europium. csc.mrc.ac.uk. Knowledge of the causative molecular defect has become an important tool in hemophilia care with respect to prediction of the clinical course and safe genetic counseling of relatives.




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