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2022

Назаренко М.С., Королёва Ю.А., Зарубин А.А., Слепцов А.А.
Молекулярная биология. 2022. Т. 56. № 2. С. 227-243.
DOI: 10.31857/S0026898422020136

Нарушение регуляции экспрессии микроРНК связано с предрасположенностью ко многим заболеваниям, в том числе к атеросклеротическому поражению коронарных и сонных артерий и развитию таких осложнений, как ишемическая болезнь сердца, инфаркт миокарда, хроническая ишемия головного мозга, ишемический инсульт. В последнее время появляется все больше работ, в которых анализируется регулом микроРНК, включающий сеть регуляторных элементов экспрессии собственно микроРНК и мишеней, находящихся под их контролем. В обзоре рассмотрена экспрессия микроРНК и изменения метилирования ДНК в области генов микроРНК в артериях человека при их атеросклеротическом поражении, а также проанализирована связь однонуклеотидных полиморфизмов и вариаций числа копий участков ДНК в области генов микроРНК с клиническими осложнениями атеросклероза.

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Kucher A.N., Koroleva Iu.A., Zarubin A.A., Nazarenko M.S.
Molecular biology. 2022. 56(1), 29-45.
DOI: 10.1134/S0026893322010034

The pandemic of coronavirus disease 2019 (COVID-19) warrants the identification of factors that may determine both risk and severity of infection. The factors include microRNAs that have a wide regulatory potential and hence are particularly interesting. The review focuses on the potential roles of human microRNAs and the viral genome as well as microRNAs in SARS-CoV-2 infection and clinical features of COVID-19. The review summarizes the information about the human microRNAs that are thought to specifically bind to the SARS-CoV-2 genome and considers their expression levels in various organs (cells) in both healthy state and pathologies that are risk factors for severe COVID-19. Potential mechanisms whereby SARS-CoV-2 may affect the clinical features of COVID-19 are discussed in brief. The mechanisms include blocking of human microRNAs and RNA-binding proteins, changes in gene expression in infected cells, and possible epigenetic modifications of the human genome with the participation of coronavirus microRNAs.

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Кучер А.Н., Королёва Ю.А., Зарубин А.А., Назаренко М.С.
Молекулярная биология. 2022. Т. 56. № 1. С. 35-54.
DOI: 10.31857/S0026898422010049

The pandemic of coronavirus disease 2019 (COVID-19) warrants the identification of factors that may determine both risk and severity of infection. The factors include micro RNAs that have a wide regulatory potential and hence are particularly interesting. The review focuses on the potential roles of human microRNAs and the viral genome as well as microRNAs in SARS-CoV-2 infection and clinical features of COVID-19. The review summarizes the information about the human microRNAs that are thought to specifically bind to the SARS-CoV-2 genome and considers their expression levels in various organs (cells) in both healthy state and pathologies that are risk factors for severe COVID-19. Potential mechanisms whereby SARS-CoV-2 may affect the clinical features of COVID-19 are discussed in brief. The mechanisms include blocking of human microRNAs and RNA-binding proteins, changes in gene expression in infected cells, and possible epigenetic modifications of the human genome with the participation of coronavirus microRNAs.

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Essers R., Acharya G., Al-Nasiry S., Brunner H., Deligiannis S.P., Fonova E.A., Hoischen A., Kurg A., Lebedev I.N. , Macville M.V.E., Nikitina T.V., Salumets A., Sazhenova E.A., Stevens S.J.C., Tolmacheva E.N., Zamani Esteki M.
Nederlands Tijdschrift voor Obstetrie & Gynaecologie. 2022. 135(3), 153-154.
De prevalentie van een miskraam is 15,3%, waarbij 80% plaatsvindt in het eerste trimester.1 Aan 60% van de gevallen ligt een chromosomale afwijking ten grondslag2, terwijl dit voor levendgeborenen minder dan 1% is wanneer er geen prenatale diagnostiek verricht is.3 Dit is de eerste studie waarbij een analyse van het haplotype gebaseerd op SNP’s wordt toegepast op biopten van twee specifieke locaties van de miskraam. Het onderzoek betreft vroege miskramen (~7 weken) en er wordt een vergelijking gemaakt tussen sporadische en herhaalde miskramen (n=91). Het doel is om de prevalentie en het effect van (mozaïek) genetische afwijkingen binnen deze groepen vast te stellen.

Karamysheva T.V., Gayner T.A., Elisaphenko E.A., Trifonov V.A., Zakirova E.G., Orishchenko K.E., Prokhorovich M.A., Lopatkina M.E., Skryabin N.A., Lebedev I.N., Rubtsov N.B.
Biomedicines. 2022. 10: 3255
DOI: 10.3390/biomedicines10123255

Detection and precise genomic mapping of balanced chromosomal abnormalities in patients with impaired fertility or a clinical phenotype represent a challenge for current cytogenomics owing to difficulties with precise breakpoint localization in the regions enriched for DNA repeats and high genomic variation in such regions. Here, we present a comprehensive cytogenomic approach to breakpoint mapping in a rare paracentric inversion on 10q (in a patient with oligoasthenoteratozoospermia and necrozoospermia) that does not affect other phenotype traits. Multicolor banding, chromosomal microarray analysis, chromosome microdissection with reverse painting, and single-copy sequencing of the rearranged chromosome were performed to determine the length and position of the inverted region as well as to rule out a genetic imbalance at the breakpoints. As a result, a paracentric 19.251 Mbp inversion at 10q22.2q23.3 was described. The most probable location of the breakpoints was predicted using the hg38 assembly. The problems of genetic counseling associated with enrichment for repeats and high DNA variability of usual breakpoint regions were discussed. Possible approaches for cytogenomic assessment of couples with balanced chromosome rearrangements and problems like reproductive failures were considered and suggested as useful part of effective genetic counseling.

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Salakhov R.R., Golubenko M.V., Valiakhmetov N.R., Pavlyukova E.N., Zarubin A.A., Babushkina N.P., Kucher A.N., Sleptcov A.A., Nazarenko M.S.
International Journal of Molecular Sciences. 2022. 23: 15845
DOI: 10.3390/ijms232415845
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.
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Tikhonov D.G., Golubenko M.V., Sivtseva T.M., Zakharova R.N., Semenov S.I., Okhotina M.M. , Salakhov R.R., Klimova T.M., Osakovsky V.L.
Opera Medica et Physiologica. 2022. 9(2), 28-34
DOI: 10.24412/2500-2295-2022-2-28-34

The study of mitochondrial DNA (mtDNA), particularly the hypervariable segment (HVS1) region, is widely used to reconstruct a population's history, structure, and origin. The origin of the Sakha people living in the north-east of Russia has been discussed for more than 300 years, but up to the present time many aspects of their ethnogenesis remain unclear. In order to clarify the migration routes of the ancient ancestors of the Sakha, we analyzed the mitotypes of 69 unrelated representatives of this ethnic group, whose belonging to the ethnic group was traced to the third generation. In the studied Sakha group, we identified 33 mitotypes, the distribution of which by haplogroups approximately coincides with the data of other studies. The results of a comparative study of Sakha mitotypes according to EMPOP data and literature sources revealed a wide distribution of the identified mtDNA HVS1 haplotypes in many populations of Eurasia. A comparison of the obtained mitotypes with the results of mtDNA sequencing of ancient samples shows that most of the mtDNA lines of modern Sakha have long been located on the territory of Yakutia. West Eurasian and East Asian mtDNA lines were incorporated into the Sakha genome at different times in different ways. The results obtained contribute to a better understanding of the routes of ancient migrations of the ancestors of the Sakha population. © 2022, Lobachevsky State University of Nizhny Novgorod. All rights reserved.

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Li P., Dupont B., Hu Q., Crimi M., Shen Y., Lebedev I., Liehr T.
Human Genetics and Genomics Advances. 2022. 3(4):100139, 1-14
DOI: 10.1016/j.xhgg.2022.100139

Human ring chromosomes (RCs) are rare diseases with an estimated newborn incidence of 1/50,000 and an annual occurrence of 2,800 patients globally. Over the past 60 years, banding cytogenetics, fluorescence in situ hybridization (FISH), chromosome microarray analysis (CMA), and whole-genome sequencing (WGS) has been used to detect an RC and further characterize its genomic alterations. Ring syndrome featuring sever growth retardation and variable intellectual disability has been considered as general clinical presentations for all RCs due to the cellular losses from the dynamic mosaicism of RC instability through mitosis. Cytogenomic heterogeneity ranging from simple complete RCs to complex rearranged RCs and variable RC intolerance with different relative frequencies have been observed. Clinical heterogeneity, including chromosome-specific deletion and duplication syndromes, gene-related organ and tissue defects, cancer predisposition to different types of tumors, and reproductive failure, has been reported in the literature. However, the patients with RCs reported in the literature accounted for less than 1% of its occurrence. Current diagnostic practice lacks laboratory standards for analyzing cellular behavior and genomic imbalances of RCs to evaluate the compound effects on patients. Under-representation of clinical cases and lack of comprehensive diagnostic analysis make it a challenge for evidence-based interpretation of clinico-cytogenomic correlations and recommendation of follow-up clinical management. Given recent advancements in genomic technologies and organized efforts by international collaborations and patient advocacy organizations, the prospective of standardized cytogenomic diagnosis and evidence-based clinical management for all patients with RCs could be achieved at an unprecedented global scale.

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Paderina, D.Z.; Boiko, A.S.; Pozhidaev, I.V.; Mednova, I.A.; Goncharova, A.A.; Bocharova, A.V.; Fedorenko, O.Y.; Kornetova, E.G.; Semke, A.V.; Bokhan, N.A.; Loonen, A.J. Ivanova, S. A.
Genes. 2022, 13(8): 1312.
DOI: 10.3390/genes13081312

Background: Metabolic syndrome is widespread in patients with schizophrenia receiving long-term antipsychotic therapy. Dopamine D2 receptors play an important role in mediating both the therapeutic actions of antipsychotics and their side effects. The present study examined the association of two polymorphisms of the DRD2 gene with metabolic syndrome in patients with schizophrenia.

Methods: We examined 517 patients from several regions of Siberia (Russia) with a clinical diagnosis of schizophrenia. Genotyping of two single nucleotide polymorphisms rs1799732 and rs4436578 of the dopamine D2 receptor gene (DRD2) was performed in a population of 471 patients. The results were analyzed using chi-square tests.

Results: Functional polymorphism rs1799732 of the DRD2 gene is associated with drug-induced metabolic syndrome in women with schizophrenia.

Conclusions: Our results show that the DRD2 gene may be involved in the pathogenesis of metabolic disorders in patients with schizophrenia. Further analysis of possible genetic markers will allow for personalized treatment with minimal side effects and optimal efficacy. This which seems relevant in light of the recent focus on improving the quality of life and ensuring a high level of social adaptation of patients with schizophrenia.

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Zhalsanova I.Z., Ravzhaeva E. G.,.Postrigan A. E., Seitova G. N., Zhigalina D. I., Udalova V. Yu., Danina M. M., Kanivets I. V., Skryabin N. A.
International Journal of Molecular Sciences. 2022. 23: 10606
DOI: 10.3390/ijms231810606

Rafiq syndrome (RAFQS) is a congenital disorder of glycosylation (CDG) that is caused by mutations in the MAN1B1 gene and characterized by impaired protein and lipid glycosylation. RAFQS is characterized by a delay in intellectual and motor development, facial and other dysmorphism, truncal obesity, behavior problems, and hypotonia. We describe a Russian patient with delayed intellectual and motor development, a lack of speech, disorientation in space and time, impaired attention and memory, and episodes of aggression. Screening for lysosomal, amino acid, organic acid, and mitochondrial disorders was normal. The patient was referred for the targeted sequencing of the ""Hereditary Metabolic Disorders"" panel. The genetic testing revealed two heterozygous pathogenic variants in the MAN1B1 gene: the previously reported c.1000C > T (p.Arg334Cys) and the novel c.1065 + 1 G > C. Thus, the patient's clinical picture and genetic analysis confirmed RAFQS in the patient.

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Gervas P., Molokov A., Babyshkina N., Pisareva L., Choynzonov E., Cherdyntseva N., Kiselev A., Zarubin A., Yumov E.
Asian Pacific Journal of Cancer Prevention. 2022. 23(6), 2027-2033.
DOI: 10.31557/APJCP.2022.23.6.2027

Background: Germline alterations in BRCA1, BRCA2, and other genes are responsible for early-onset breast cancer. However, up to 20% of molecular tests report genetic variant of unknown significance (VUS) or novel variants that have never been previously described and their clinical significance are unknown. This study aimed to reclassify variant of unknown significance (VUS) or novel variants by using the ActiveDriveDB database that annotates variants through the lens of sites of post-translational modifications (PTM).

Methods: Our study included thirty-eighth young Buryat BC patients, belonging to the Mongoloid race and anthropologically to the Central Asia. Genomic DNA was extracted from the peripheral blood lymphocytes using the phenol/chloroform method. DNA library were prepared using the Hereditary Cancer SolutionTM kit (Sophia GENETICS, Switzerland) to cover 27 genes, such as ATM, APC, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FAM175A, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PIK3CA, PMS2, PMS2CL, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53, and XRCC2. Paired-end sequencing (2 x 150 bp) was conducted using NextSeq 500 system (Illumina, USA).

Results: We re-examined 135 rare variants (41 VUS, 25 conflicting, 64 benign and 5 new variants). We identified 10 out of 135 (7.4%) mutations that affected the sites of post-translational modification in proteins. Of 135 rare mutations, 1 benign variant was reclassified as network-rewiring - motif loss mutation, 3 VUS and 1 new variant were reclassified as distal PTM- mutations, 2 new and 1 benign variant were classified as proximal PTM- mutations and 1 benign and 1 conflicting variant were classified as direct PTM- mutations.

Conclusions: For the first time, 7.4% (10 out of 135) of mutations that affected the sites of post-translational modification in proteins were identified among early-onset breast cancer women of Mongoloid origin.

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Fedorenko O.Yu., Paderina D.Z., Kornetova E.G., Poltavskaya E.G., Pozhidaev I.V., Goncharova A.A., Bokhan N.A., Ivanova S.A., Freidin M.B., Bocharova A.V., Loonen A.J.M.
Diagnostics. 2022. 12(7): 1521
DOI: 10.3390/diagnostics12071521

Background: Tardive dyskinesia (TD) is an extrapyramidal side effect of the long-term use of antipsychotics. In the present study, the role of glutamatergic system genes in the pathogenesis of total TD, as well as two phenotypic forms, orofacial TD and limb-truncal TD, was studied.

Methods: A set of 46 SNPs of the glutamatergic system genes (GRIN2A, GRIN2B, GRIK4, GRM3, GRM7, GRM8, SLC1A2, SLC1A3, SLC17A7) was studied in a population of 704 Caucasian patients with schizophrenia. Genotyping was performed using the MassARRAY Analyzer 4 (Agena Bioscience™). Logistic regression analysis was performed to test for the association of TD with the SNPs while adjusting for confounders.

Results: No statistically significant associations between the SNPs and TD were found after adjusting for multiple testing. Since three SNPs of the SLC1A2 gene demonstrated nominally significant associations, we carried out a haplotype analysis for these SNPs. This analysis identified a risk haplotype for TD comprising CAT alleles of the SLC1A2 gene SNPs rs1042113, rs10768121, and rs12361171. Nominally significant associations were identified for SLC1A3 rs2229894 and orofacial TD, as well as for GRIN2A rs7192557 and limb-truncal TD.

Conclusions: Genes encoding for mGlu3, EAAT2, and EAAT1 may be involved in the development of TD in schizophrenia patients.

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Nazarenko M.S., Viakhireva I.V., Skoblov M.Y., Soloveva E.V., Sleptcov A.A., Nazarenko L.P.
International Journal of Molecular Sciences. 2022. 23(16): 9234.
DOI: 10.3390/ijms23169234

Meier-Gorlin syndrome (MGS) is a rare genetic developmental disorder that causes primordial proportional dwarfism, microtia, the absence of or hypoplastic patellae and other skeletal anomalies. Skeletal symptoms overlapping with other syndromes make MGS difficult to diagnose clinically. We describe a 3-year-old boy with short stature, recurrent respiratory infections, short-rib dysplasia, tower head and facial dysmorphisms who was admitted to the Tomsk Genetic Clinic to verify a clinical diagnosis of Jeune syndrome. Clinical exome sequencing revealed two variants (compound heterozygosity) in the ORC6 gene: c.2T>C(p.Met1Thr) and c.449+5G>A. In silico analysis showed the pathogenicity of these two mutations and predicted a decrease in donor splicing site strength for c.449+5G>A. An in vitro minigene assay indicated that variant c.449+5G>A causes complete skipping of exon 4 in the ORC6 gene. The parents requested urgent prenatal testing for MGS for the next pregnancy, but it ended in a miscarriage. Our results may help prevent MGS misdiagnosis in the future. We also performed in silico and functional analyses of ORC6 mutations and developed a restriction fragment length polymorphism and haplotype-based short-tandem-repeat assay for prenatal genetic testing for MGS. These findings should elucidate MGS etiology and improve the quality of genetic counselling for affected families.

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Yan K., Bormuth I, Bormuth O., Svetlana Tutukova , Ana Renner, Paraskevi Bessa , Theres Schaub, Marta Rosário, Victor Tarabykin.
Cerebral Cortex. 2022, 1–16
DOI: 10.1093/cercor/bhac170

Abnormal development of corpus callosum is relatively common and causes a broad spectrum of cognitive impairments in humans. We use acallosal Neurod2/6-deficient mice to study callosal axon guidance within the ipsilateral cerebral cortex. Initial callosal tracts form but fail to traverse the ipsilateral cingulum and are not attracted towards the midline in the absence of Neurod2/6. We show that the restoration of Ephrin-A4 (EfnA4) expression in the embryonic neocortex of Neurod2/6-deficient embryos is sufficient to partially rescue targeted callosal axon growth towards the midline. EfnA4 cannot directly mediate reverse signaling within outgrowing axons, but it forms co-receptor complexes with TrkB (Ntrk2). The ability of EfnA4 to rescue the guided growth of a subset of callosal axons in Neurod2/6-deficient mice is abolished by the co-expression of dominant negative TrkBK571N (kinase-dead) or TrkBY515F (SHC-binding deficient) variants, but not by TrkBY816F (PLCγ1-binding deficient). Additionally, EphA4 is repulsive to EfnA4-positive medially projecting axons in organotypic brain slice culture. Collectively, we suggest that EfnA4-mediated reverse signaling acts via TrkB-SHC and is required for ipsilateral callosal axon growth accuracy towards the midline downstream of Neurod family factors.

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Nikitina T.V., Lebedev I.N.
Cells. 2022. 11(12): 1923
DOI: 10.3390/cells11121923

Miscarriage affects approximately 15% of clinically recognized pregnancies, and 1-3% of couples experience pregnancy loss recurrently. Approximately 50-60% of miscarriages result from chromosomal abnormalities, whereas up to 60% of euploid recurrent abortions harbor variants in candidate genes. The growing number of detected genetic variants requires an investigation into their role in adverse pregnancy outcomes. Since placental defects are the main cause of first-trimester miscarriages, the purpose of this review is to provide a survey of state-of-the-art human in vitro trophoblast models that can be used for the functional assessment of specific abnormalities/variants implicated in pregnancy loss. Since 2018, when primary human trophoblast stem cells were first derived, there has been rapid growth in models of trophoblast lineage. It has been found that a proper balance between self-renewal and differentiation in trophoblast progenitors is crucial for the maintenance of pregnancy. Different responses to aneuploidy have been shown in human embryonic and extra-embryonic lineages. Stem cell-based models provide a powerful tool to explore the effect of a specific aneuploidy/variant on the fetus through placental development, which is important, from a clinical point of view, for deciding on the suitability of embryos for transfer after preimplantation genetic testing for aneuploidy.

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