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

DISCUSSION

Identification of underlying gene alterations and their expression changes can be a prerequisite for the proper evaluation and management of the FVII deficiency. In our study, we found three homozygous patients, two of them had consanguineous parents, while the third patient was an adopted child with no available records regarding his family of origin. We also characterized molecular changes in two compound heterozygous and three heterozygous patients. Mutation detection in patient 2 revealed the 10824C>A homozygous substitution that causes the P303T defect in FVII protein. This mutation was previously detected in an Iranian patient [16]. It has been shown that residues P303, L305 and M306 are involved in tissue factor (TF) binding [17]. Another homozygous mutation was found in patient 5, C91S that was previously identified in an English patient [18]. Since C91 is engaged in disulfide bond formation, this mutation could be a basis of severe dysfunction of the enzyme. However, patient 5 did not exhibit severe complications such as hemarthrosis or gastrointestinal bleeding. Further studies are needed to explore the role played by different factors in determining the phenotypic variation of each mutation. The highest prothrombin time (PT) and partial thromboplastin time (PTT) (34 and 44 min., respectively) were found in patient 6 homozygous for a rather frequent gene defect, the R304Q mutation. The R304Q mutation was first found in a heterozygous state in a patient with no clinical bleeding tendency by O’Brien et al. [19]. Variability in the degree of severity and phenotypic expression is commonly observed in patients with R304Q mutation. This mutation was found in symptomatic patients from Latin America, but the patients from Germany were asymptomatic while carrying R304Q [11]. This kind of variations in phenotypic outcome of a given genotype can be affected by environmental factors and genetic modifier loci. Previous studies revealed that the substitution R304Q had adverse effects on the enzyme’s activity and TF interaction [19]. We also detected the R304Q variation in Patient 8. He was identified as a compound heterozygote for R304Q as well as IVS7+7A>G alterations. The IVS7+7A>G is a common mutation reported in various populations [20,21]. It has been shown that IVS7+7A>G was responsible for the lowest relative FVII levels although they did not observe any changes in the mRNA structure [21]. We also detected the IVS7+7A>G transcript with a normal pattern in this patient. Another compound heterozygous case in our study was patient 7. Both mutations in this patient were located on exon 8, S282R and H348R. The mutation S282R was reported previously by Peyvandi et al. [22] in a compound heterozygous Iranian patient, while the other defective allele remained “unknown.” H348R was previously reported in homozygous and compound heterozygous Indian patients [23,24]. As stated earlier, some individuals with heterozygous F7 mutations may show bleeding manifestations. In our study, two patients were heterozygous for A244V transition, which was associated with decreased FVII activity levels. A244V was previously reported by Tamary et al. [25] in Iranian-Jewish patients with an allele frequency of 1:40. They detected a heterozygous A244V substitution in 10 out of 23 symptomatic patients affected by this mutation [25]. The only asymptomatic patient that we tested was patient 4, a 54-year-old man diagnosed on pre anesthesia blood analysis. Further molecular investigation revealed a heterozygous genotype with the 64G>A missense mutation. This mutation was previously reported in a Turkish family [26]. The 64G>A is located at the last nucleotide of exon 1a and is known as V(–39)I or V(–17)I. As reported by Wulff and Herrmann [26], the homozygous form of this mutation could cause the severe manifestations such as postpartal (after birth) cephalic hematomas. It should be noted that in communities with a preference for consanguineous marriages, mutation detection of asymptomatic or mild cases could be of great importance in genetic counseling. The cDNA sequencing revealed no expression of mRNA carrying the 64A allele. This may be due to inefficient splicing or mRNA decay. However, the F7 cDNA sequencing in A244V, S282K, H348Q and R304Q implied that their transcripts were expressed at detectable levels. Therefore, it could be concluded that the reduction of FVII protein activity following these mutations is not related to the changes at mRNA level. In conclusion, in the present study, we found eight different F7 gene mutations, four of them were the first to be reported from Iran. This report reinforces the genetic and phenotypic heterogeneity of FVII deficiency, and provides evidence regarding the expression of the pathogenic mutations at the mRNA level. We propose that the reduction of FVII protein activity subsequent to missense mutations does not reflect the degradation of mRNA. We also wanted to bring the mutation detection in asymptomatic patients to the attention of genetic counselors.

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