Balkan Journal of Medical Genetics

MOLECULAR CHARACTERIZATION OF IRANIAN PATIENTS WITH INHERITED COAGULATION FACTOR VII DEFICIENCY
Shahbazi S1,*, Mahdian R2, Karimi K3, Mashayekhi A1
*Corresponding Author: Dr. Shirin Shahbazi, Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Al-e-Ahmad and Chamran Cross, POB 14115-111Tehran, Iran. Tel: +98-21-82-884-556. Fax: +98-21- 82-884-555. E-mail: sh.shahbazi@modares.ac.ir
page: 19

INTRODUCTION

Coagulation factor VII (FVII) is a vitamin K-dependent serine protease that has a key role in the initiation of the coagulation cascade. This factor circulates in the blood at a concentration of 0.5 μg/mL and its severe reduction leads to rare autosomal recessive bleeding disorder, FVII deficiency [1,2]. The F7 gene maps to the long arm of chromosome 13 (13q34) and contains nine exons [1,3]. It is expressed as two major transcripts, A and B, each ~3.1 kb long, that encode polypeptides of 466 and 444 residues, respectively [4]. The pre proteins are synthesized with either 60 or 38 amino acid leader sequences that yield a unique mature single chain protein of 406 amino acids with a molecular weight of ~50 kDa. Exons 1a, 1b and a fraction of exon 2 encode the leader sequences, the rest of exon 2 and exons 3 to 8 encode the mature protein [5]. Upon blood vessel injury, tissue factor is exposed to the circulation and interacts with FVII and activates it by cleavage between Arg152 and Ile153. The activated FVII (FVIIa) consists of a 254-residue heavy chain that contains a catalytic domain and is linked by a disulfide bond to a 152-residue light chain that contains two epidermal growth factor-like (EGF-like) domains [6]. The most common FVII deficiency symptoms consist of soft tissue, mucocutaneous, joint and gastrointestinal hemorrhage. The hereditary form of the disease shows considerable phenotypic heterogeneity ranging from lethal to mild or even asymptomatic types. As a result, prevalence and incidence of FVII deficiency is not entirely determined [7]. Studies show that the incidence of clinically significant FVII deficiencies is estimated to be 1/500,000 [8]. However, the disease is more frequent where consanguineous marriages are commonplace [9]. The severity of hemorrhagic symptoms is not directly related to the level of plasma FVII coagulant activity [2,10]. In a study on 717 patients, Herrmann et al. [11] reported that about 60.0% of FVII deficient patients were asymptomatic who were diagnosed following an abnormal prothrombin time (PT) test. They also mentioned that the causative mutations responsible for FVII deficiency are spread throughout the F7 gene with no well-defined hot-spots. More than 250 mutations have been reported with FVII deficiency with missense mutations as the most frequent type. Exon 8 is the largest exon of the F7 gene that accommodates the highest number of mutations [12]. The most severe cases are either homozygous or compound heterozygous resulting in FVII:C levels less than 2.0% of normal. Occasionally, heterozygous carriers display hemorrhagic symptoms that can be severe in rare cases. Recently, a heterozygous patient was reported with severe spontaneous intra cranial bleeding. He was a previously healthy 19-year-old patient, without any reported hemorrhagic symptoms, even following tonsillectomy in childhood [13]. We here report on the characterization of the mutations in eight patients from eight unrelated families in Iran. We also intended to elucidate the effect of each mutation on their corresponding mRNA expression.

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