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State-of-the-Art Molecular Genetics and Genomics in Russia

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 33671

Special Issue Editors


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Guest Editor
1. Yurov’s Laboratory of Molecular Genetics and Cytogenomics of the Brain Mental Health Research Center, 117152 Moscow, Russia
2. Laboratory of Molecular Cytogenetics of Neuropsychiatric Diseases, Veltischev Research and Clinical Institute for Pediatrics of the Pirogov Russian National Research Medical University, 125412 Moscow, Russia
Interests: medical genomics; genome instability; chromosomes; cytogenetics; bioinformatics; brain; neurodegenerative diseases; psychiatric diseases; intellectual disability
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Research Centre of Medical Genetics, 115522 Moscow, Russia
Interests: rare diseases; medical genetics; medical genomics; cancer genetics; molecular basis of hereditary disorders

Special Issue Information

Dear Colleagues,

This Topical Collection “State-of-the-Art Medical Genetics and Genomics in Russia” aims to publish papers from Russia including international collaborative papers on all aspects of medical genetics and genomics. Topics include, but are not limited to, the following:

  • Molecular basis of hereditary disorders;
  • Cytogenomics;
  • Genetics of rare diseases;
  • Epigenetics;
  • Chromosomal disorders;
  • Cancer genetics;
  • Functional genomics;
  • Pharmacogenetics and pharmacogenomics;
  • Systems genomics;
  • Genome instability;
  • DNA structure, damage and repair;
  • Somatic mosaicism;
  • Structural genome variations;
  • Post-genomic technologies;
  • Omics technologies;

Prof. Dr. Ivan Y. Iourov
Prof. Dr. Sergei I. Kutsev
Guest Editors

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Keywords

  • medical genetics
  • medical genomics
  • cytogenetics/cytogenomics
  • molecular genetics
  • epigenetics
  • cancer genetics
  • bioinformatics
  • genome instability
  • pharmacogenomics
  • human genomics
  • DNA structure and repair
  • chromosomal biology

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Published Papers (15 papers)

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Research

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15 pages, 322 KiB  
Article
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 - 6 Apr 2023
Cited by 1 | Viewed by 2096
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  
Article
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 Goldshteinadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2023, 24(7), 6351; https://doi.org/10.3390/ijms24076351 - 28 Mar 2023
Cited by 2 | Viewed by 2375
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  
Article
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 1903
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  
Article
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 5 | Viewed by 1706
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  
Article
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 4 | Viewed by 3392
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  
Article
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 4 | Viewed by 1494
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  
Article
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 2 | Viewed by 2003
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 MRSAST239 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  
Article
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 8 | Viewed by 2428
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  
Communication
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 - 1 Dec 2022
Cited by 1 | Viewed by 1688
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  
Article
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 20 | Viewed by 1869
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, pperm ≤ 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  
Article
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 1905
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  
Article
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 2743
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

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22 pages, 1401 KiB  
Review
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 7 | Viewed by 2789
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  
Case 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
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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  
Case 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 2257
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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