НИИ
медицинской
генетики

Преждевременное половое созревание (ППС, OMIM 176400, 615346) – заболевание, которое вызвано преждевременной реактивацией гипоталамо-гипофизарно-гонадной оси. В определении сроков полового созревания ведущую роль играют генетические, эпигенетические и экологические факторы. В последние годы варианты в генах KISS1, KISS1R, MKRN3 и DLK1 были идентифицированы как генетические причины ППС. Гены MKRN3 и DLK1 являются импринтированными, в связи с чем эпигенетические модификации, такие как метилирование ДНК, изменяющее экспрессию данных генов, также могут рассматриваться в качестве причины ППС. Цель настоящего исследования – определение индекса метилирования центров импринтинга генов DLK1 и MKRN3 у девочек с клинической картиной ППС. Анализ индекса метилирования центров импринтинга генов DLK1 и MKRN3 проводили в группе из 45 девочек (возраст 7.2±1.9 года) с клинической картиной ППС и нормальным кариотипом методом таргетного массового параллельного секвенирования после обработки ДНК бисульфитом натрия. Контрольная группа состояла из девочек без ППС (n = 15, возраст 7.9±1.6 года). Различий по возрасту между группами не выявлено (p > 0.8). Анализ индекса метилирования центров импринтинга генов DLK1 и MKRN3 не показал различий между пациентами с ППС и контрольной группой. Группа пациентов с изолированным адренархе имела повышенный индекс метилирования центра импринтинга гена MKRN3 (72±7.84 против 56.92±9.44 %, p = 0.005). В группе пациентов с центральным ППС 3.8 % пациентов имели пониженный индекс метилирования центра импринтинга гена DLK1 и 11.5 % – гена MKRN3. Таким образом, показано, что не только генетические варианты, но и нарушение индекса метилирования центров импринтинга генов DLK1 и MKRN3 могут быть причиной ППС. 

Aortic aneurysm and atherosclerosis are characterized by high clinical heterogeneity. The uncertainty in their comorbidity evaluations may be related to polyetiology of these diseases and the presence of not only common but also specific risk factors, as well as the complex pathogenesis of these conditions. The aim of this review is to summarize information on the prevalence and risk factors of aortic aneurysm and atherosclerosis, explaining the possible mechanisms underlying the comorbidity of these pathologies. We conducted a search for scientific publications in Russian (eLIBRARY.RU) and international (PubMed) electronic libraries, prioritizing works published in the last 10 years. Aortic aneurysm and atherosclerosis exhibit an age-dependent pattern of prevalence. The high prevalence of atherosclerosis compared to aortic aneurysm, along with the approximately similar age ranges for the manifestation of these pathologies,is related to their comorbidity. Conversely, these diseases share some common risk factors, albeit with varying contributions to atherosclerosis and aortic aneurysm of different localizations. Type 2 diabetes mellitus and lipid metabolism profiles are examples of risk factors with multidirectional influences. To understand the reasons for the discordant estimates of comorbidity between aortic aneurysm and atherosclerosis from an epidemiological perspective, a comprehensive approach to patient characterization, including a detailed analysis of risk factors recorded in the analyzed groups, is essential.

Familial hypercholesterolaemia is a common monogenic disorder characterized by high plasma cholesterol levels leading to chronic cardiovascular disease with high risk and often early manifestation due to atherosclerotic lesions of the blood vessels. The atherosclerotic lesions in familial hypercholesterolaemia are mainly caused by pathogenic variants of the low-density lipoprotein receptor (LDLR) gene, which plays an important role in cholesterol metabolism. Normally, cholesterol-laden low-density lipoproteins bind to the LDLR receptor on the surface of liver cells to be removed from the bloodstream by internalisation with hepatocytes. In familial hypercholesterolaemia, the function of the receptor is impaired and the uptake of low-density lipoproteins is significantly reduced. As a result, cholesterol accumulates in the subendothelial space on the inner wall of blood vessels, triggering atherogenesis, the formation of atherosclerotic plaques. At present, there are no effective and universal approaches to the diagnosis and treatment of familial hypercholesterolaemia. A relevant approach to study the molecular genetic mechanisms of the disease and to obtain systems for screening chemical compounds as potential drugs is the generation of cellular models based on patient-specific induced pluripotent stem cells. The aim of our work was to derive an isogenic genetically modified induced pluripotent stem cell line by correcting the pathogenic allelic variant c.530C of the LDLR gene in the original iPSC previously obtained from a compound heterozygote patient with familial hypercholesterolaemia. The resulting isogenic iPSC line differs from the original by only one corrected nucleotide substitution, allowing us to study the direct effect of this pathogenic genetic variant on physiological changes in relevant differentiated cells. CRISPR/Cas-mediated base editing was used to correct the single nucleotide substitution. The resulting genetically modified iPSC line has pluripotency traits, a normal karyotype, a set of short tandem repeats identical to that in the original line and can be used to obtain differentiated derivatives necessary for the elaboration of relevant cell models

Precocious puberty (PP, OMIM 176400, 615346) is an autosomal dominant disorder caused by the premature reactivation of the hypothalamic-pituitary-gonadal axis. Genetic, epigenetic, and environmental factors play a decisive role in determining the timing of puberty. In recent years, genetic variants in the KISS1, KISS1R, MKRN3, and DLK1 genes have been identified as genetic causes of PP. The MKRN3 and DLK1 genes are imprinted, and therefore epigenetic fications, such as DNA methylation, which alter the expression of these genes, can also contribute to the development of PP. The aim of this study is to determine the methylation index of the imprinting centers of the DLK1 and MKRN3 genes in girls with a clinical presentation of PP. The methylation index of the imprinting centers of the DLK1 and MKRN3 genes was analyzed in a group of 45 girls (age 7.2±1.9 years) with a clinical presentation of PP and a normal karyotype using targeted massive parallel sequencing after sodium bisulfite treatment of DNA. The control group consisted of girls without PP (n = 15, age 7.9±1.6 years). No significant age differences were observed between the groups (p > 0.8). Analysis of the methylation index of the imprinting centers of the DLK1 and MKRN3 genes revealed no significant differences between patients with PP and the control group. However, in the group of patients with isolated adrenarche, an increased methylation index of the imprinting center of the MKRN3 gene was observed (72±7.84 vs 56.92±9.44 %, p = 0.005). In the group of patients with central PP, 3.8 % of patients showed a decreased methylation index of the imprinting center of the DLK1 gene, and 11.5 % of probands had a decreased methylation index of the imprinting center of the MKRN3 gene. Thus, this study demonstrates that not only genetic variants but also alterations in the methylation index of the imprinting centers of the DLK1 and MKRN3 genes can contribute to the development of PP.