10.31857/S001667582105009X

For more than 100 years of existence of Wilson–Konovalov disease as an independent nosological form, the etiology and pathogenesis of this disease have been studied from different points of view—both clinical and genetic. However, to this day, new information is emerging not only about mutations in the ATP7B gene itself but also about modifying factors affecting the clinical picture of the disease. From a genetic point of view, the influence of modifier genes is undeniable, because owing to their action (protective or compensatory), some forms of Wilson–Konovalov disease can be explained and it is possible to further use this knowledge in the framework of personalized patient treatment. In this review, the authors consider the influence of various modifiers (intra- and extra-gene) on the course and manifestation of the clinical forms of Wilson–Konovalov disease. The authors show the possible mechanisms for the occurrence of milder or more severe forms of Wilson–Konovalov disease with the participation of certain genes.

Более чем за 100 лет после выделения болезни Вильсона–Коновалова в самостоятельную нозологическую форму этиология и патогенез этого заболевания изучены с разных точек зрения – как врачами-клиницистами, так и генетиками. Однако и по нынешний день появляются все новые сведения не только о мутациях в самом гене ATP7B, но и о модифицирующих факторах, влияющих на клиническую картину заболевания. С генетической точки зрения влияние генов-модификаторов неоспоримо, ведь за счет их действия (протективного или компенсирующего) можно объяснить клиническую вариабельность болезни Вильсона–Коновалова и возможно в дальнейшем использовать эти знания в рамках персонализированного лечения пациента. В настоящем обзоре рассматривается влияние различных модификаторов (внутри- и внегенных) на течение и проявление клинических форм болезни Вильсона–Коновалова. Авторами обозначены возможные механизмы возникновения более мягких или более тяжелых форм болезни Вильсона–Коновалова при участии определенных генов.

Саркопения - это прогрессирующая генерализованная патология скелетных мышц многофакторной природы. Настоящий обзор посвящен анализу молекулярно-генетических маркеров, которые могут вносить вклад в формирование риска развития саркопении и в изменчивость диагностически значимых для данного заболевания признаков. По данным GWAS для полиморфных вариантов 369 генов установлены ассоциации с фенотипом «мышечная масса». Согласно информации, представленной в базе DisGeNet об ассоциированных с саркопенией генах, и в Gene Ontology - о генах, участвующих в регуляции процессов атрофии (GO:0014737, GO:0014732, GO:0014736) и регенерации (GO:0014839) мышц, 69 генов могут рассматриваться в качестве генов-кандидатов саркопении. Гены, ассоциированные с мышечной массой, и гены-кандидаты саркопении обладают плейотропными свойствами, вовлечены в регуляцию широкого спектра биологических процессов (включая метаболизм гормонов, углеводов, липидов, протеина; ответ на стимулы (половые гормоны, нутриенты), регуляция экспрессии генов, протеин/серинкиназной активности и MAPK-сигнального пути); ассоциированы с коморбидными с саркопений заболеваниями многофакторной природы, чувствительны или определяют ответ на лекарственные средства, гормоны, нутриены (включая креатин, кортикостероиды, альдостерон, антагонисты альдостерона, метформин, белковые добавки)...

The ""Mendelian code"" hypothesis postulates a relationship between Mendelian (monogenic) and common pathologies. In this hypothesis, polymorphisms in the genes of Mendelian diseases may have a significant contribution to predisposition to common diseases in which the same biochemical pathways may be involved. In this review a group of genes encoding various proteins participating in the DNA repair, with a particular focus on the BRCA1-associated genome surveillance complex (BASC), is presented through the prism of the ""Mendelian code"" hypothesis. Here we discuss (1) their main functions in the repair of DNA double-strand breaks (ATM, MRE11, NBN, RAD50, BRCA1, and BLM) and mismatch repair (MSH2, MSH6, MLH1, PMS2, RF-C, and PCNA); (2) the mitochondrial involvement of these proteins; (3) the involvement of BASC proteins in the development of an adaptive immune response. For 13 out of 16 BASC protein encoding genes, mutations leading to monogenic diseases have already been described; for 11, there are associations with common diseases or individual biological processes. Patients with mutations in the genes of the BASC complex and patients with severe combined immunodeficiency share similar symptoms. Polymorphisms within DNA repair genes may play a role in the development of common diseases through the involvement of the immune response. The pleiotropic effects of these genes suggest their participation in the development of various conditions, both in health and pathology.

Генетическая компонента многофакторных заболеваний интенсивно изучается на протяжении многих лет, но до сих пор в этой области остается очень много вопросов. В последние годы появились исследования в области “менделевского кода” – гипотезы, постулирующей существование связи между менделевскими (моногенными) и многофакторными патологиями: полиморфные варианты в генах менделевских заболеваний могут оказаться значимыми для многофакторных патологий, в которых задействованы те же биохимические пути. В настоящем обзоре через призму гипотезы “менделевского кода” представлен взгляд на группу генов, которые могут оказаться перспективными генами-кандидатами широкого спектра патологических состояний, а именно, генов белков систем репарации ДНК. В качестве примера рассмотрены белки BRСA1-ассоциированного комплекса наблюдения за геномом (BASC). Обсуждаются основные функции белков этого комплекса в процессах репарации двухцепочечных разрывов ДНК (ATM, MRE11, NBN, RAD50, BRCA1, BLM) и мисматч-репарации (MSH2, MSH6, MLH1, PMS2, RF-C, PCNA); вовлеченность этих белков в функционирование митохондрий; участие белков BASC в развитии адаптивного иммунного ответа...

Patients with cystic fibrosis (CF) need costly medical care and adequate therapy with expensive medicinal products. Tigerase® is the first biosimilar of dornase alfa, developed by the lead Russian biotechnology company GENERIUM. The aim of the manuscript to present post hoc sub-analysis of patients' data with cystic fibrosis and severe pulmonary impairment of a larger comparative study (phase III open label, prospective, multi-centre, randomized study (NCT04468100)) of a generic version of recombinant human DNase Tigerase to the only comparable drug, Pulmozym.

Understanding the mechanisms underlying the connection between somatic mosaicism and cardiovascular disease is likely essential for the future of personalized medicine. This article is aimed at providing data on somatic mosaicism in human carotid atherosclerosis. An advanced carotid atherosclerotic plaque and white blood cells were collected simultaneously from each patient (eight Slavic males, aged 67 ± 3.8 years [mean ± SD]) to assess the spectrum of germline and somatic genetic variants. Exome sequencing of DNA from the samples was performed with the SureSelect Clinical Research Exome Enrichment Kit (Agilent Technologies) and HiSeq 1500 (Illumina). The dataset contains germline and somatic single-nucleotide variants and small indels identified in the advanced carotid atherosclerotic plaque and white blood cells of each patient. This dataset does not include copy number variants owing to a lack of suitable tools for reliable calculation of copy numbers from exome sequencing data on cancer-unrelated samples. The dataset should help to understand somatic mosaicism in cardiovascular diseases and to identify copy number variants by means of more appropriate newer tools in the future.

Wilson's disease is a rare autosomal recessive disorder of copper metabolism. The copper accumulation in the viscera appears due to the functional impairment of copper-transporting ATPase, which is encoded by the ATP7B gene. In this study, PBMCs of a patient with two ATP7B mutations were reprogrammed. The first mutation is a missense mutation p.H1069Q, which is the most frequent mutation in the human population. At the same time, the second one is a frameshift mutation p.Lys1013fs. The generated iPSC line had a normal karyotype, maintained the original genotype, expressed pluripotency markers, and demonstrated the ability to differentiate into derivatives of the three germ layers.

Comparative analysis of multilocus imprinting disturbances (MLIDs) in miscarriages from women with sporadic (SPL) and recurrent pregnancy loss (RPL) and identification of variants in the imprinting control gene NLRP7 that may lead to MLIDs.

Alzheimer's disease (AD) is a neurodegenerative disorder, and represents the most common cause of dementia. In this study, we performed several different analyses to detect loci involved in development of the late onset AD in the Russian population. DNA samples from 472 unrelated subjects were genotyped for 63 SNPs using iPLEX Assay and real-time PCR. We identified five genetic loci that were significantly associated with LOAD risk for the Russian population (TOMM40 rs2075650, APOE rs429358 and rs769449, NECTIN rs6857, APOE ε4). The results of the analysis based on comparison of the haplotype frequencies showed two risk haplotypes and one protective haplotype. The GMDR analysis demonstrated three significant models as a result: a one-factor, a two-factor and a three-factor model. A protein-protein interaction network with three subnetworks was formed for the 24 proteins. Eight proteins with a large number of interactions are identified: APOE, SORL1, APOC1, CD33, CLU, TOMM40, CNTNAP2 and CACNA1C. The present study confirms the importance of the APOE-TOMM40 locus as the main risk locus of development and progress of LOAD in the Russian population. Association analysis and bioinformatics approaches detected interactions both at the association level of single SNPs and at the level of genes and proteins.

Split reporter protein-based genetic section systems are widely used to identify and characterize protein-protein interactions (PPI). The assembly of split markers that antagonize toxins, rather than required for synthesis of missing metabolites, facilitates the seeding of high density of cells and selective growth. Here we present a newly developed split chloramphenicol acetyltransferase (split-CAT) -based genetic selection system. The N terminus fragment of CAT is fused downstream of the protein of interest and the C terminus fragment is tethered upstream to its postulated partner. We demonstrate the system's advantages for the study of PPIs. Moreover, we show that co-expression of a functional ubiquitylation cascade where the target and ubiquitin are tethered to the split-CAT fragments results in ubiquitylation-dependent selective growth. Since proteins do not have to be purified from the bacteria and due to the high sensitivity of the split-CAT reporter, detection of challenging protein cascades and post-translation modifications is enabled. In addition, we demonstrate that the split-CAT system responds to small molecule inhibitors and molecular glues (GLUTACs). The absence of ubiquitylation-dependent degradation and deubiquitylation in E. coli significantly simplify the interpretation of the results. We harnessed the developed system to demonstrate that like NEDD4, UBE3B also undergoes self-ubiquitylation-dependent inactivation. We show that self-ubiquitylation of UBE3B on K665 induces oligomerization and inactivation in yeast and mammalian cells respectively. Finally, we showcase the advantages of split-CAT in the study of human diseases by demonstrating that mutations in UBE3B that cause Kaufman oculocerebrofacial syndrome exhibit clear E. coli growth phenotypes.

Primary autosomal recessive microcephaly and Seckel syndrome spectrum disorders (MCPH-SCKS) include a heterogeneous group of autosomal recessive inherited diseases characterized by primary (congenital) microcephaly, the absence of visceral abnormalities, and a variable degree of cognitive impairment, short stature and facial dysmorphism. Recently, biallelic variants in the nuclear pore complex (NPC) component nucleoporin 85 gene (NUP85) were reported to cause steroid-resistant nephrotic syndrome (SRNS). Here, we report biallelic variants in NUP85 in two pedigrees with an MCPH-SCKS phenotype spectrum without SRNS, thereby expanding the phenotypic spectrum of NUP85-linked diseases. Structural analysis predicts the identified NUP85 variants cause conformational changes that could have an effect on NPC architecture or on its interaction with other NUPs. We show that mutant NUP85 is, however, associated with a reduced number of NPCs but unaltered nucleocytoplasmic compartmentalization, abnormal mitotic spindle morphology, and decreased cell viability and proliferation in one patient's cells. Our results also indicate the link of common cellular mechanisms involved in MCPH-SCKS spectrum disorders and NUP85-associated diseases. In addition to the previous studies, our results broaden the phenotypic spectrum of NUP85-linked human disease and propose a role for NUP85 in nervous system development.

Metabolic syndrome (MetS) is characterized by abdominal obesity, hyperglycaemia, dyslipidaemia and hypertension. FTO gene has been implicated in the pathogenesis of obesity, but the available scientific data concerning their relationship to antipsychotic drug-induced obesity and metabolic syndrome is still incomplete and inconsistent, which indicates that continuing the investigation of this gene's role is necessary.

Recent studies have focused on the potential role of epicardial adipose tissue (EAT) in the development of coronary artery disease (CAD). ABCA1 and ABCG1 transporters regulate cell cholesterol content and reverse cholesterol transport. We aimed to determine whether DNA methylation and mRNA levels of the ABCA1 and ABCG1 genes in EAT and subcutaneous adipose tissue (SAT) were associated with CAD.

Chromosomal mosaicism is a hallmark of early human embryo development. The last decade yielded an enormous amount of information about diversity and prevalence of mosaicism in preimplantation embryos due to progress in preimplantation genetic testing of aneuploidies (PGT-A) based exclusively on molecular karyotyping of trophectoderm biopsy. However, the inner cell mass karyotype is still missing for mosaic embryos affecting the success rate of assisted reproductive medicine. Here, a classification model of chromosomal mosaicism is proposed based on the analysis of the primary zygote karyotype, the timing and types of primary and secondary chromosome segregation errors, and the distribution of mosaic cell clones between different embryonic and extraembryonic compartments of the blastocyst. Five basic principles for mosaicism analysis are introduced, namely, the estimation of the primary zygote karyotype, the investigation of additional sample point, the requirement of the second time point analysis, the delineating of reciprocity of chromosome segregation, and comprehensive chromosome screening at the single-cell level. The suggested model allows the prediction of the inner cell mass karyotype of the blastocyst and its developmental potential based on information from trophectoderm biopsy and non-invasive PGT-A using blastocoele fluid sample or spent culture medium as additional sample and time points for analysis and considering the reciprocity as a basic process in chromosome segregation errors between daughter cells in postzygotic cell divisions.