Research

15 pages, 322 KiB

Open AccessArticle

The Study of the Association of Polymorphisms in LSP1, GPNMB, PDPN, TAGLN, TSPO, and TUBB6 Genes with the Risk and Outcome of Ischemic Stroke in the Russian Population

by Andrey V. Khrunin, Gennady V. Khvorykh, Anna S. Arapova, Anna E. Kulinskaya, Evgeniya A. Koltsova, Elizaveta A. Petrova, Ekaterina I. Kimelfeld and Svetlana A. Limborska

Int. J. Mol. Sci. 2023, 24(7), 6831; https://doi.org/10.3390/ijms24076831 - 06 Apr 2023

Viewed by 1513

Abstract

To date, there has been great progress in understanding the genetic basis of ischemic stroke (IS); however, several aspects of the condition remain underexplored, including the influence of genetic factors on post-stroke outcomes and the identification of causative loci. We proposed that an [...] Read more.

To date, there has been great progress in understanding the genetic basis of ischemic stroke (IS); however, several aspects of the condition remain underexplored, including the influence of genetic factors on post-stroke outcomes and the identification of causative loci. We proposed that an analysis of the results obtained from animal models of brain ischemia could be helpful. To this end, we developed a bioinformatic approach for exploring single-nucleotide polymorphisms (SNPs) in human orthologs of rat genes expressed differentially after induced brain ischemia. Using this approach, we identified and analyzed 11 SNPs from 6 genes in 553 Russian individuals (331 patients with IS and 222 controls). We assessed the association of SNPs with the risk of IS and IS outcomes. We found that the SNPs rs858239 (GPNMB), rs907611 (LSP1), and rs494356 (TAGLN) were associated with different parameters of IS functional outcomes. In addition, the SNP rs1261025 (PDPN) was associated significantly with IS itself (p = 0.0188, recessive model). All these associations were demonstrated for the first time. Analysis of the literature suggests that they should be characterized as being inflammation related. This supports the pivotal role of inflammation in both the incidence of stroke and post-stroke outcomes. We believe the findings reported here will help with stroke prognosis in the future. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Genetics and Genomics in Russia)

23 pages, 4393 KiB

Open AccessArticle

Clinical and Functional Characteristics of the E92K CFTR Gene Variant in the Russian and Turkish Population of People with Cystic Fibrosis

by Elena Kondratyeva, Yuliya Melyanovskaya, Nataliya Bulatenko, Ksenia Davydenko, Alexandra Filatova, Anna Efremova, Mikhail Skoblov, Tatiana Bukharova, Viktoriya Sherman, Anna Voronkova, Elena Zhekaite, Stanislav Krasovskiy, Elena Amelina, Nika Petrova, Alexander Polyakov, Tagui Adyan, Marina Starinova, Maria Krasnova, Andrey Vasilyev, Oleg Makhnach, Rena Zinchenko, Sergey Kutsev, Yasemin Gokdemir, Bülent Karadag and Dmitry Goldshtein Show full author list Hide full author list

Int. J. Mol. Sci. 2023, 24(7), 6351; https://doi.org/10.3390/ijms24076351 - 28 Mar 2023

Cited by 1 | Viewed by 1822

Abstract

The pathogenic variant E92K (c.274G > A) of the CFTR gene is rare in America and Europe, but it is common for people with cystic fibrosis from Russia and Turkey. We studied the effect of the E92K genetic variant on the CFTR function. [...] Read more.

The pathogenic variant E92K (c.274G > A) of the CFTR gene is rare in America and Europe, but it is common for people with cystic fibrosis from Russia and Turkey. We studied the effect of the E92K genetic variant on the CFTR function. The function of the CFTR channel was studied using the intestinal current measurements (ICM) method. The effects of CFTR modulators on the restoration of the CFTR function were studied in the model of intestinal organoids. To assess the effect of E92K on pre-mRNA splicing, the RT-PCR products obtained from patients’ intestinal organoid cultures were analyzed. Patients with the genetic variant E92K are characterized by an older age of diagnosis compared to homozygotes F508del and a high frequency of pancreatic sufficiency. The results of the sweat test and the ICM method showed partial preservation of the function of the CFTR channel. Functional analysis of CFTR gene expression revealed a weak effect of the E92K variant on mRNA-CFTR splicing. Lumacaftor (VX-809) has been shown to restore CFTR function in an intestinal organoid model, which allows us to consider the E92K variant as a promising target for therapy with CFTR correctors. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Genetics and Genomics in Russia)

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11 pages, 1220 KiB

Open AccessArticle

SAV-Pred: A Freely Available Web Application for the Prediction of Pathogenic Amino Acid Substitutions for Monogenic Hereditary Diseases Studied in Newborn Screening

by Anton D. Zadorozhny, Anastasia V. Rudik, Dmitry A. Filimonov and Alexey A. Lagunin

Int. J. Mol. Sci. 2023, 24(3), 2463; https://doi.org/10.3390/ijms24032463 - 27 Jan 2023

Cited by 3 | Viewed by 1506

Abstract

Next Generation Sequencing (NGS) technologies are rapidly entering clinical practice. A promising area for their use lies in the field of newborn screening. The mass screening of newborns using NGS technology leads to the discovery of a large number of new missense variants [...] Read more.

Next Generation Sequencing (NGS) technologies are rapidly entering clinical practice. A promising area for their use lies in the field of newborn screening. The mass screening of newborns using NGS technology leads to the discovery of a large number of new missense variants that need to be assessed for association with the development of hereditary diseases. Currently, the primary analysis and identification of pathogenic variations is carried out using bioinformatic tools. Although extensive efforts have been made in the computational approach to variant interpretation, there is currently no generally accepted pathogenicity predictor. In this study, we used the sequence–structure–property relationships (SSPR) approach, based on the representation of protein fragments by molecular structural formula. The approach predicts the pathogenic effect of single amino acid substitutions in proteins related with twenty-five monogenic heritable diseases from the Uniform Screening Panel for Major Conditions recommended by the Advisory Committee on Hereditary Disorders in Newborns and Children. In order to create SSPR models of classification, we modified a piece of cheminformatics software, MultiPASS, that was originally developed for the prediction of activity spectra for drug-like substances. The created SSPR models were compared with traditional bioinformatic tools (SIFT 4G, Polyphen-2 HDIV, MutationAssessor, PROVEAN and FATHMM). The average AUC of our approach was 0.804 ± 0.040. Better quality scores were achieved for 15 from 25 proteins with a significantly higher accuracy for some proteins (IVD, HADHB, HBB). The best SSPR models of classification are freely available in the online resource SAV-Pred (Single Amino acid Variants Predictor). Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Genetics and Genomics in Russia)

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7 pages, 523 KiB

Open AccessArticle

Caspase-3, Caspase-8 and XIAP Gene Expression in the Placenta: Exploring the Causes of Spontaneous Preterm Labour

by Vera Belousova, Oxana Svitich, Elena Timokhina, Irina Ignatko, Irina Bogomazova, Svetlana Pesegova, Tatiana Silaeva, Tatiana Kuzmina and Oxana Skorobogatova

Int. J. Mol. Sci. 2023, 24(2), 1692; https://doi.org/10.3390/ijms24021692 - 15 Jan 2023

Cited by 2 | Viewed by 1312

Abstract

A better understanding of the pathogenesis of preterm birth (PTB) will allow us to lower the PTB rate, reducing perinatal morbidity and mortality. This article presents the hypothesis that premature placenta apoptosis could be a potential cause of PTB. We evaluated gene expression [...] Read more.

A better understanding of the pathogenesis of preterm birth (PTB) will allow us to lower the PTB rate, reducing perinatal morbidity and mortality. This article presents the hypothesis that premature placenta apoptosis could be a potential cause of PTB. We evaluated gene expression involved in apoptosis: caspase-3, caspase-8, and XIAP (X-linked inhibitor of apoptosis) in the placenta during pregnancy (n = 41), at the onset of preterm labour (n = 42), after preterm (n = 44) and term (n = 32) labour. We used RNA extraction, reverse transcription, and PCR. During pregnancy the gene expression of caspase-3 and caspase-8 is low, but XIAP is higher than the caspases. At the onset of preterm labour, we observed a significantly increased expression of both caspase-8 (10.7-fold, p < 0.01) and caspase-3 (2.5-fold, p < 0.01) and XIAP (3-fold; p < 0.05) compared with expression during pregnancy. Our study showed that during pregnancy, the expression of caspase genes in the placenta is low and probably controlled by high XIAP expression. At the onset of preterm labour, the expression of caspase genes increases sharply. This may initiate the onset of preterm labour. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Genetics and Genomics in Russia)

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18 pages, 2532 KiB

Open AccessArticle

Leigh Syndrome: Spectrum of Molecular Defects and Clinical Features in Russia

by Denis Kistol, Polina Tsygankova, Tatiana Krylova, Igor Bychkov, Yulia Itkis, Ekaterina Nikolaeva, Svetlana Mikhailova, Maria Sumina, Natalia Pechatnikova, Sergey Kurbatov, Fatima Bostanova, Ochir Migiaev and Ekaterina Zakharova

Int. J. Mol. Sci. 2023, 24(2), 1597; https://doi.org/10.3390/ijms24021597 - 13 Jan 2023

Cited by 2 | Viewed by 2315

Abstract

Leigh syndrome (LS), also known as infantile subacute necrotizing encephalopathy, is the most frequent mitochondrial disorder in children. Recently, more than 80 genes have been associated with LS, which greatly complicates the diagnosis. In this article, we present clinical and molecular findings of [...] Read more.

Leigh syndrome (LS), also known as infantile subacute necrotizing encephalopathy, is the most frequent mitochondrial disorder in children. Recently, more than 80 genes have been associated with LS, which greatly complicates the diagnosis. In this article, we present clinical and molecular findings of 219 patients with LS and give the detailed description of three cases with rare findings in nuclear genes MORC2, NARS2 and VPS13D, demonstrating wide genetic heterogeneity of this mitochondrial disease. The most common cause of LS in Russian patients are pathogenic variants in the SURF1 gene (44.3% of patients). The most frequent pathogenic variant is c.845_846delCT (66.0% of mutant alleles; 128/192), which is also widespread in Eastern Europe. Five main LS genes, SURF1, SCO2, MT-ATP6, MT-ND5 and PDHA1, account for 70% of all LS cases in the Russian Federation. Using next generation sequencing (NGS) technique, we were able to detect pathogenic variants in other nuclear genes: NDUFV1, NDUFS2, NDUFS8, NDUFAF5, NDUFAF6, NDUFA10, SUCLG1, GFM2, COX10, PMPCB, NARS2, PDHB and SLC19A3, including two genes previously associated with Leigh-like phenotypes—MORC2 and VPS13D. We found 49 previously undescribed nucleotide variants, including two deep intronic variants which affect splicing. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Genetics and Genomics in Russia)

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15 pages, 1811 KiB

Open AccessArticle

Interplay of Cellular mRNA, miRNA and Viral miRNA during Infection of a Cell

by Vladimir P. Zhdanov

Int. J. Mol. Sci. 2023, 24(1), 122; https://doi.org/10.3390/ijms24010122 - 21 Dec 2022

Cited by 1 | Viewed by 1133

Abstract

The understanding of the kinetics of gene expression in cells infected by viruses is currently limited. As a rule, the corresponding models do not take viral microRNAs (miRNAs) into account. Such RNAs are, however, operative during the replication of some viruses, including, e.g., [...] Read more.

The understanding of the kinetics of gene expression in cells infected by viruses is currently limited. As a rule, the corresponding models do not take viral microRNAs (miRNAs) into account. Such RNAs are, however, operative during the replication of some viruses, including, e.g., herpesvirus. To clarify the kinetics of this category (with emphasis on the information available for herpesvirus), I introduce a generic model describing the transient interplay of cellular mRNA, protein, miRNA and viral miRNA. In the absence of viral miRNA, the cellular miRNA is considered to suppress the populations of mRNA and protein due to association with mRNA and subsequent degradation. During infection, the viral miRNA suppresses the population of cellular miRNA and via this pathway makes the mRNA and protein populations larger. This effect becomes appreciable with the progress of intracellular viral replication. Using biologically reasonable parameters, I investigate the corresponding mean-field kinetics and show the scale of the effect of viral miRNAs on cellular miRNA and mRNA. The scale of fluctuations of the populations of these species is illustrated as well by employing Monte Carlo simulations. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Genetics and Genomics in Russia)

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30 pages, 892 KiB

Open AccessArticle

In Silico Genome-Scale Analysis of Molecular Mechanisms Contributing to the Development of a Persistent Infection with Methicillin-Resistant Staphylococcus aureus (MRSA) ST239

by Olga Dmitrenko, Andrey Chaplin, Anna Balbutskaya, Tamara Pkhakadze and Sergey Alkhovsky

Int. J. Mol. Sci. 2022, 23(24), 16086; https://doi.org/10.3390/ijms232416086 - 16 Dec 2022

Cited by 1 | Viewed by 1522

Abstract

The increasing frequency of isolation of methicillin-resistant Staphylococcus aureus (MRSA) limits the chances for the effective antibacterial therapy of staphylococcal diseases and results in the development of persistent infection such as bacteremia and osteomyelitis. The aim of this study was to identify features [...] Read more.

The increasing frequency of isolation of methicillin-resistant Staphylococcus aureus (MRSA) limits the chances for the effective antibacterial therapy of staphylococcal diseases and results in the development of persistent infection such as bacteremia and osteomyelitis. The aim of this study was to identify features of the MRSA_ST239 0943-1505-2016 (SA943) genome that contribute to the formation of both acute and chronic musculoskeletal infections. The analysis was performed using comparative genomics data of the dominant epidemic S. aureus lineages, namely ST1, ST8, ST30, ST36, and ST239. The SA943 genome encodes proteins that provide resistance to the host’s immune system, suppress immunological memory, and form biofilms. The molecular mechanisms of adaptation responsible for the development of persistent infection were as follows: amino acid substitution in PBP2 and PBP2a, providing resistance to ceftaroline; loss of a large part of prophage DNA and restoration of the nucleotide sequence of beta-hemolysin, that greatly facilitates the escape of phagocytosed bacteria from the phagosome and formation of biofilms; dysfunction of the AgrA system due to the presence of psm-mec and several amino acid substitutions in the AgrC; partial deletion of the nucleotide sequence in genomic island vSAβ resulting in the loss of two proteases of Spl—operon; and deletion of SD repeats in the SdrE amino acid sequence. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Genetics and Genomics in Russia)

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14 pages, 1935 KiB

Open AccessArticle

Application of Long-Read Nanopore Sequencing to the Search for Mutations in Hypertrophic Cardiomyopathy

by Ramil R. Salakhov, Maria V. Golubenko, Nail R. Valiakhmetov, Elena N. Pavlyukova, Aleksei A. Zarubin, Nadezhda P. Babushkina, Aksana N. Kucher, Aleksei A. Sleptcov and Maria S. Nazarenko

Int. J. Mol. Sci. 2022, 23(24), 15845; https://doi.org/10.3390/ijms232415845 - 13 Dec 2022

Cited by 4 | Viewed by 1932

Abstract

Increasing evidence suggests that both coding and non-coding regions of sarcomeric protein genes can contribute to hypertrophic cardiomyopathy (HCM). Here, we introduce an experimental workflow (tested on four patients) for complete sequencing of the most common HCM genes (MYBPC3, MYH7, [...] Read more.

Increasing evidence suggests that both coding and non-coding regions of sarcomeric protein genes can contribute to hypertrophic cardiomyopathy (HCM). Here, we introduce an experimental workflow (tested on four patients) for complete sequencing of the most common HCM genes (MYBPC3, MYH7, TPM1, TNNT2, and TNNI3) via long-range PCR, Oxford Nanopore Technology (ONT) sequencing, and bioinformatic analysis. We applied Illumina and Sanger sequencing to validate the results, FastQC, Qualimap, and MultiQC for quality evaluations, MiniMap2 to align data, Clair3 to call and phase variants, and Annovar’s tools and CADD to assess pathogenicity of variants. We could not amplify the region encompassing exons 6–12 of MYBPC3. A higher sequencing error rate was observed with ONT (6.86–6.92%) than with Illumina technology (1.14–1.35%), mostly for small indels. Pathogenic variant p.Gln1233Ter and benign polymorphism p.Arg326Gln in MYBPC3 in a heterozygous state were found in one patient. We demonstrated the ability of ONT to phase single-nucleotide variants, enabling direct haplotype determination for genes TNNT2 and TPM1. These findings highlight the importance of long-range PCR efficiency, as well as lower accuracy of variant calling by ONT than by Illumina technology; these differences should be clarified prior to clinical application of the ONT method. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Genetics and Genomics in Russia)

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7 pages, 1200 KiB

Open AccessCommunication

Mlig-SKP1 Gene Is Required for Spermatogenesis in the Flatworm Macrostomum lignano

by Mikhail Biryukov, Anastasia Dmitrieva, Valeriya Vavilova, Kirill Ustyantsev, Erzhena Bazarova, Igor Sukhikh, Eugene Berezikov and Alexandr Blinov

Int. J. Mol. Sci. 2022, 23(23), 15110; https://doi.org/10.3390/ijms232315110 - 01 Dec 2022

Viewed by 1251

Abstract

In a free-living flatworm, Macrostomum lignano, an S-phase kinase-associated protein 1 (SKP1) homologous gene was identified as enriched in proliferating cells, suggesting that it can function in the regulation of stem cells or germline cells since these are the only [...] Read more.

In a free-living flatworm, Macrostomum lignano, an S-phase kinase-associated protein 1 (SKP1) homologous gene was identified as enriched in proliferating cells, suggesting that it can function in the regulation of stem cells or germline cells since these are the only two types of proliferating cells in flatworms. SKP1 is a conserved protein that plays a role in ubiquitination processes as a part of the Skp1-Cullin 1-F-box (SCF) ubiquitin ligase complex. However, the exact role of Mlig-SKP1 in M. lignano was not established. Here, we demonstrate that Mlig-SKP1 is neither involved in stem cell regulation during homeostasis, nor in regeneration, but is required for spermatogenesis. Mlig-SKP1(RNAi) animals have increased testes size and decreased fertility as a result of the aberrant maturation of sperm cells. Our findings reinforce the role of ubiquitination pathways in germ cell regulation and demonstrate the conserved role of SKP1 in spermatogenesis. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Genetics and Genomics in Russia)

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16 pages, 1682 KiB

Open AccessArticle

Matrix Metalloproteinase Gene Polymorphisms Are Associated with Breast Cancer in the Caucasian Women of Russia

by Nadezhda Pavlova, Sergey Demin, Mikhail Churnosov, Evgeny Reshetnikov, Inna Aristova, Maria Churnosova and Irina Ponomarenko

Int. J. Mol. Sci. 2022, 23(20), 12638; https://doi.org/10.3390/ijms232012638 - 20 Oct 2022

Cited by 14 | Viewed by 1455

Abstract

We conducted this study to explore the association between matrix metalloproteinase (MMP) gene polymorphisms and breast cancer (BC) risk in the Caucasian women of Russia. In total, 358 affected (BC) and 746 unaffected (cancer-free) women were included in this case-control retrospective [...] Read more.

We conducted this study to explore the association between matrix metalloproteinase (MMP) gene polymorphisms and breast cancer (BC) risk in the Caucasian women of Russia. In total, 358 affected (BC) and 746 unaffected (cancer-free) women were included in this case-control retrospective study. From BC-related genes in previous studies, ten single nucleotide polymorphisms (SNPs) in five MMP genes (MMP1, 2, 3, 8, 9) were genotyped. The BC risk was calculated by logistic regression (to evaluate the SNPs’ independent effects) and model-based multifactor dimensionality reduction (MB-MDR) (to identify SNP–SNP interactions) methods. The allelic variants’ distribution of c.836 A > G (rs17576) and c. 1721 C > G (rs2250889) MMP9 was significantly different between BC and cancer-free women: for G minor alleles, these SNPs manifested disorder protective effects (OR 0.82 and OR 0.67–0.71, respectively, p_perm ≤ 0.035). Eleven haplotypes of six SNPs MMP9 were involved in BC risk (nine haplotypes) and protective (two haplotypes) effects. All 10 SNPs of the MMP genes examined were associated with BC within the 13 SNP–SNP interaction simulated models, with a pivotal role of the two-locus (rs17577 × rs3918242) MMP9 epistatic interaction (defined as 1.81% BC entropy within more than 60% of the genetic models). Under in silico bioinformatics, BC susceptibility MMP polymorphic loci are located in functionally active genome regions and impact genes expression and splicing “regulators” in the mammary gland. The biological pathways of BC MMP candidate genes are mainly realized due to metalloendopeptidase activity and extracellular matrix organization (structure, disassembly, metabolic process, etc.). In conclusion, our data show that MMP gene polymorphisms are related to BC susceptibility in the Caucasian women of Russia. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Genetics and Genomics in Russia)

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11 pages, 977 KiB

Open AccessArticle

The Presentation of Two Unrelated Clinical Cases from the Republic of North Ossetia-Alania with the Same Previously Undescribed Variant in the COL6A2 Gene

by Sofya A. Ionova, Aysylu F. Murtazina, Inna S. Tebieva, Zalina K. Getoeva, Elena L. Dadali, Polina A. Chausova, Olga A. Shchagina, Andrey V. Marakhonov, Sergey I. Kutsev and Rena A. Zinchenko

Int. J. Mol. Sci. 2022, 23(20), 12127; https://doi.org/10.3390/ijms232012127 - 12 Oct 2022

Cited by 1 | Viewed by 1442

Abstract

Here, we described three affected boys from two unrelated families of Ossetian-Digor origin from the Republic of North Ossetia-Alania who were admitted to the Research Centre for Medical Genetics with unspecified muscular dystrophy. High-throughput sequencing was performed and revealed two novel frameshift variants [...] Read more.

Here, we described three affected boys from two unrelated families of Ossetian-Digor origin from the Republic of North Ossetia-Alania who were admitted to the Research Centre for Medical Genetics with unspecified muscular dystrophy. High-throughput sequencing was performed and revealed two novel frameshift variants in the COL6A2 gene (NM_001849.3) in a heterozygous state each in both cases: c.508_535delinsCTGTGG and c.1659_1660del (case 1) and c.1689del and c.1659_1660del (case 2). In two cases, the same nucleotide variant in the COL6A2 gene (c.1659_1660del) was observed. We have suggested that the variant c.1659_1660del may be common in the Ossetian-Digor population because two analyzed families have the same ancestry from the same subethnic group of Ossetians). The screening for an asymptomatic carriage of the nucleotide variant c.1659_1660del in 54 healthy donors from Ossetian-Digor population revealed that the estimated carrier frequency is 0.0093 (CI: 0.0002–0.0505), which is high for healthy carriers of the pathogenic variant. Molecular genetic, anamnestic data and clinical examination results allowed us to diagnose Ullrich muscular dystrophy in those affected boys. Genetic heterogeneity and phenotypic diversity of muscular dystrophies complicate diagnosis. It is important to make a differential diagnosis of such conditions and use HTS methods to determine the most accurate diagnosis. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Genetics and Genomics in Russia)

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15 pages, 3640 KiB

Open AccessArticle

Recurrent Translocations in Topoisomerase Inhibitor-Related Leukemia Are Determined by the Features of DNA Breaks Rather Than by the Proximity of the Translocating Genes

by Nikolai A. Lomov, Vladimir S. Viushkov, Sergey V. Ulianov, Alexey A. Gavrilov, Daniil A. Alexeyevsky, Artem V. Artemov, Sergey V. Razin and Mikhail A. Rubtsov

Int. J. Mol. Sci. 2022, 23(17), 9824; https://doi.org/10.3390/ijms23179824 - 29 Aug 2022

Cited by 3 | Viewed by 2221

Abstract

Topoisomerase inhibitors are widely used in cancer chemotherapy. However, one of the potential long-term adverse effects of such therapy is acute leukemia. A key feature of such therapy-induced acute myeloid leukemia (t-AML) is recurrent chromosomal translocations involving AML1 (RUNX1) or MLL (KMT2A) genes. [...] Read more.

Topoisomerase inhibitors are widely used in cancer chemotherapy. However, one of the potential long-term adverse effects of such therapy is acute leukemia. A key feature of such therapy-induced acute myeloid leukemia (t-AML) is recurrent chromosomal translocations involving AML1 (RUNX1) or MLL (KMT2A) genes. The formation of chromosomal translocation depends on the spatial proximity of translocation partners and the mobility of the DNA ends. It is unclear which of these two factors might be decisive for recurrent t-AML translocations. Here, we used fluorescence in situ hybridization (FISH) and chromosome conformation capture followed by sequencing (4C-seq) to investigate double-strand DNA break formation and the mobility of broken ends upon etoposide treatment, as well as contacts between translocation partner genes. We detected the separation of the parts of the broken AML1 gene, as well as the increased mobility of these separated parts. 4C-seq analysis showed no evident contacts of AML1 and MLL with loci, implicated in recurrent t-AML translocations, either before or after etoposide treatment. We suggest that separation of the break ends and their increased non-targeted mobility—but not spatial predisposition of the rearrangement partners—plays a major role in the formation of these translocations. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Genetics and Genomics in Russia)

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Review

Jump to: Research, Other

22 pages, 1401 KiB

Open AccessReview

Advanced Situation with Recombinant Toxins: Diversity, Production and Application Purposes

by Elena Efremenko, Aysel Aslanli and Ilya Lyagin

Int. J. Mol. Sci. 2023, 24(5), 4630; https://doi.org/10.3390/ijms24054630 - 27 Feb 2023

Cited by 5 | Viewed by 2085

Abstract

Today, the production and use of various samples of recombinant protein/polypeptide toxins is known and is actively developing. This review presents state-of-the-art in research and development of such toxins and their mechanisms of action and useful properties that have allowed them to be [...] Read more.

Today, the production and use of various samples of recombinant protein/polypeptide toxins is known and is actively developing. This review presents state-of-the-art in research and development of such toxins and their mechanisms of action and useful properties that have allowed them to be implemented into practice to treat various medical conditions (including oncology and chronic inflammation applications) and diseases, as well as to identify novel compounds and to detoxify them by diverse approaches (including enzyme antidotes). Special attention is given to the problems and possibilities of the toxicity control of the obtained recombinant proteins. The recombinant prions are discussed in the frame of their possible detoxification by enzymes. The review discusses the feasibility of obtaining recombinant variants of toxins in the form of protein molecules modified with fluorescent proteins, affine sequences and genetic mutations, allowing us to investigate the mechanisms of toxins’ bindings to their natural receptors. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Genetics and Genomics in Russia)

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23 pages, 8710 KiB

Open AccessCase Report

Enterotype-Dependent Probiotic-Mediated Changes in the Male Rat Intestinal Microbiome In Vivo and In Vitro

by Nikolay Kolzhetsov, Natalia Markelova, Maria Frolova, Olga Alikina, Olga Glazunova, Lubov Safonova, Irina Kalashnikova, Vladimir Yudin, Valentin Makarov, Anton Keskinov, Sergey Yudin, Daria Troshina, Viktoria Rechkina, Viktoria Shcherbakova, Konstantin Shavkunov and Olga Ozoline

Int. J. Mol. Sci. 2024, 25(8), 4558; https://doi.org/10.3390/ijms25084558 - 22 Apr 2024

Viewed by 231

Abstract

Beneficial properties of lactic acid bacteria have been known long ago, but particular interest in probiotics has arisen in the last two decades due to the understanding of the important role of intestinal microflora in human life. Thus, the ability of probiotics to [...] Read more.

Beneficial properties of lactic acid bacteria have been known long ago, but particular interest in probiotics has arisen in the last two decades due to the understanding of the important role of intestinal microflora in human life. Thus, the ability of probiotics to support healthy homeostasis of gut microbiomes has received particular attention. Here, we evaluated the effect of a probiotic consisting of Bifidobacterium longum and Lacticaseibacillus paracasei on the gut microbiome of male rats, assessed their persistence in the fecal biota, and compared probiotic-mediated changes in vitro and in vivo. As expected, microbiomes of two enterotypes were identified in the feces of 21 animals, and it turned out that even a single dose of the probiotic altered the microbial composition. Upon repeated administration, the E1 biota temporarily acquired properties of the E2 type. Being highly sensitive to the intervention of probiotic bacteria at the phylum and genus levels, the fecal microbiomes retained the identity of their enterotypes when transferred to a medium optimized for gut bacteria. For the E2 biota, even similarities between probiotic-mediated reactions in vitro and in vivo were detected. Therefore, fecal-derived microbial communities are proposed as model consortia to optimize the response of resident bacteria to various agents. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Genetics and Genomics in Russia)

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12 pages, 31748 KiB

Open AccessCase Report

Genetic Heterogeneity of X-Linked Ichthyosis in the Republic of North Ossetia–Alania, Case Series Report

by Tatyana A. Vasilyeva, Andrey V. Marakhonov, Inna S. Tebieva, Vitaly V. Kadyshev, Artem O. Borovikov, Zhanna G. Markova, Alyona L. Chukhrova, Evgeny K. Ginter, Sergey I. Kutsev and Rena A. Zinchenko

Int. J. Mol. Sci. 2023, 24(5), 4515; https://doi.org/10.3390/ijms24054515 - 24 Feb 2023

Viewed by 1878

Abstract

North Caucasus has always been a residence of a lot of different authentic ethnic groups speaking different languages and still living their traditional lifestyle. The diversity appeared to be reflected in the accumulation of different mutations causing common inherited disorders. X-linked ichthyosis represents [...] Read more.

North Caucasus has always been a residence of a lot of different authentic ethnic groups speaking different languages and still living their traditional lifestyle. The diversity appeared to be reflected in the accumulation of different mutations causing common inherited disorders. X-linked ichthyosis represents the second most common form of genodermatoses after ichthyosis vulgaris. Eight patients from three unrelated families of different ethnic origin, Kumyk, Turkish Meskhetians, and Ossetian, with X-linked ichthyosis from the North Caucasian Republic of North Ossetia–Alania were examined. NGS technology was implied for searching for disease-causing variants in one of the index patients. Known pathogenic hemizygous deletion in the short arm of chromosome X encompassing the STS gene was defined in the Kumyk family. A further analysis allowed us to establish that likely the same deletion was a cause of ichthyosis in a family belonging to the Turkish Meskhetians ethnic group. In the Ossetian family, a likely pathogenic nucleotide substitution in the STS gene was defined; it segregated with the disease in the family. We molecularly confirmed XLI in eight patients from three examined families. Though in two families, Kumyk and Turkish Meskhetian, we revealed similar hemizygous deletions in the short arm of chromosome X, but their common origin was not likely. Forensic STR markers of the alleles carrying the deletion were defined to be different. However, here, common alleles haplotype is hard to track for a high local recombination rate. We supposed the deletion could arise as a de novo event in a recombination hot spot in the described and in other populations with a recurrent character. Defined here are the different molecular genetic causes of X-linked ichthyosis in families of different ethnic origins sharing the same residence place in the Republic of North Ossetia–Alania which could point to the existing reproductive barriers even inside close neighborhoods. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Genetics and Genomics in Russia)

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