Molecular Genetic Analysis of Russian Patients with Coagulation Factor FVII Deficiency.

Coagulation factor VII (proconvertin) is one of the proteins starting the blood coagulation cascade. Plasma FVII concentration is regulated by different factors. A low level of FVII could also be a result of FVII deficiency (MIM# 227500), the rare autosomal recessive inherited disease caused by pathogenic variants in the F7 gene. The aim of this study was to describe a mutation spectrum of the F7 gene and genotype-phenotype relationship in patients with FVII deficiency in Russia for the first time. We studied the primary structure of the F7 gene of 54 unrelated patients with FVII deficiency by direct Sanger sequencing. Pathogenic variants in the F7 gene were detected in 37 (68.5%) of them. We identified 24 different mutations located mostly in the serine protease domain. Five pathogenic variants had never been reported before. A major mutation in the Russian population was c.1391delC (p. Pro464Hisfs*32), linked with rs36209567 and rs6046 functional polymorphisms, that is widely distributed in East Europe. As in other countries, the F7 genotypes poorly correlated with the severity of clinical manifestations but were quite well associated with FVII levels. Minor alleles of functional polymorphisms rs510335, rs5742910, rs561241, rs36209567, and rs6046 could also participate in the F7 genotype and influence FVII levels.

Hb Ryazan: An Elongated C-Terminal ß-Chain Due to a New Frameshift Mutation, HBB: c.396delG p.Val133Trpfs*25.

We identified a novel abnormal hemoglobin variant caused by a frameshift mutation at nucleotide position 396 in exon 3 of the ß-globin gene (HBB): NM_000518:c.396delG. This variant causes an emergence of alternative amino acid sequence starting at codon 133 and a new stop codon formed in the 3' untranslated region (3'UTR) of the HBB gene at amino acid position 158. This ß-globin gene variant was identified in a woman with a long history of hemolytic anemia. We named this variant Hb Ryazan after the proband's city of origin.

Spectrum of Causative Mutations in Patients with Hemophilia A in Russia.

Hemophilia A (HA) is one of the most widespread, X-linked, inherited bleeding disorders, which results from defects in the F8 gene. Nowadays, more than 3500 different pathogenic variants leading to HA have been described. Mutation analysis in HA is essential for accurate genetic counseling of patients and their relatives. We analyzed patients from 273 unrelated families with different forms of HA. The analysis consisted of testing for intron inversion (inv22 and inv1), and then sequencing all functionally important F8 gene fragments. We identified 101 different pathogenic variants in 267 patients, among which 35 variants had never been previously reported in international databases. We found inv22 in 136 cases and inv1 in 12 patients. Large deletions (1-8 exons) were found in 5 patients, and we identified a large insertion in 1 patient. The remaining 113 patients carried point variants involving either single nucleotide or several consecutive nucleotides. We report herein the largest genetic analysis of HA patients issued in Russia.

Factor XII deficiency: a clinical and molecular genetic study.

Factor XII deficiency is a rare inherited disorder caused by clotting factor XII (FXII, F12) deficiency. It is often asymptomatic but can have both thrombotic and haemorrhagic symptoms. The aim of this study was to describe the spectrum of F12 gene mutations in a Russian population and learn more about the relationship between F12 variants and clinical phenotypes. We obtained and analysed genetic and clinical data from 33 apparently unrelated patients with FXII plasma levels below 60% and genetic data from 26 healthy controls with no history of FXII deficiency. Forty mutant alleles and six different deleterious substitutions were identified. Of these substitutions, three were major in the Russian population (c.-62C > T, c.-57G > C and c.1532-1G > A, total frequency 92.5%) and the three others (p.615 del C, c.1180_1181delCA, and CD218 TAT- > CAT p.Tyr218His) were rare and novel in the world population. Eight patients with mild FXII deficiency were found to be homozygous for a hypomorphic variant of functional polymorphism C46T and have no other deleterious substitutions in the F12 gene. Contrary to data in the literature, our study showed that mild haemorrhagic manifestations are common among patients with FXII deficiency.

New electroactive asymmetrical chalcones and therefrom derived 2-amino- / 2-(1H-pyrrol-1-yl)pyrimidines, containing an N-[ω-(4-methoxyphenoxy)alkyl]carbazole fragment: synthesis, optical and electrochemical properties.

In this paper we present a synthetic approach to six new D-π-A-D conjugated chromophores containing the N-[ω-(4-methoxyphenoxy)alkyl]carbazole fragment. Such readily functionalizable heterocycle as carbazole was used as a main starting compound for their preparation. The investigation of the optical properties has shown that the positive solvatochromism is inherent to the chromophores containing an electron-withdrawing prop-2-en-1-one fragment, while the compounds containing a 2-aminopyrimidine moiety exhibit both positive and negative solvatochromism. The fluorescence quantum yields were experimentally determined for some of the synthesized chromophores; e.g., 1-(5-arylthiophen-2-yl)ethanones quantum yields were found to lie in an interval of 60-80%. Electrochemical oxidation of the synthesized chromophores has resulted in the formation of colored thin oligomeric films that became possible due to the presence of carbazole or pyrrole fragments with free electron-rich positions.