vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-25-47vavilov-4610Research ArticleМЕДИЦИНСКАЯ ГЕНЕТИКАMEDICAL GENETICSИндекс метилирования генов DLK1 и MKRN3 при преждевременном половом созреванииMethylation index of the DLK1 and MKRN3 genes in precocious pubertyСаженоваЕ. А.SazhenovaE. A.

Томск

Tomsk

elena.sazhenova@medgenetics.ruВасильеваО. Ю.VasilyevaO. Yu.

Томск

Tomsk

ФедотовД. А.FedotovD. A.

Томск

Tomsk

Канканам ПатиранагеМ. Б.Kankanam PathiranageM. B.

Томск

Tomsk

ЛобановА. Д.LobanovA. D.

Tomsk

СамбяловаА. Ю.SambyalovaА. Yu.

Иркутск

Irkutsk

ХрамоваЕ. Е.KhramovaE. E.

Иркутск

Irkutsk

РычковаЛ. В.RychkovaL. V.

Иркутск

Irkutsk

ВасильевС. А.VasilyevS. А.

Томск

Tomsk

ЛебедевИ. Н.LebedevI. N.

Томск

Tomsk

Научно-исследовательский институт медицинской генетики, Томский национальный исследовательский медицинский центр Российской академии наукРоссияScientific Research Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of SciencesRussian FederationНациональный исследовательский Томский государственный университетРоссияTomsk State UniversityRussian FederationСибирский государственный медицинский университет Министерства здравоохранения Российской ФедерацииРоссияSiberian State Medical UniversityRussian FederationНаучный центр проблем здоровья семьи и репродукции человекаРоссияScientific Center for Family Health and Human Reproduction ProblemsRussian FederationНаучно-исследовательский институт медицинской генетики, Томский национальный исследовательский медицинский центр Российской академии наук; Национальный исследовательский Томский государственный университетРоссияScientific Research Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of Sciences; Tomsk State UniversityRussian FederationНаучно-исследовательский институт медицинской генетики, Томский национальный исследовательский медицинский центр Российской академии наук; Сибирский государственный медицинский университет Министерства здравоохранения Российской ФедерацииРоссияScientific Research Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of Sciences; Siberian State Medical UniversityRussian Federation202503062025293440447Copyright © Саженова Е.А., Васильева О.Ю., Федотов Д.А., Канканам Патиранаге М.Б., Лобанов А.Д., Самбялова А.Ю., Храмова Е.Е., Рычкова Л.В., Васильев С.А., Лебедев И.Н., 20252025Саженова Е.А., Васильева О.Ю., Федотов Д.А., Канканам Патиранаге М.Б., Лобанов А.Д., Самбялова А.Ю., Храмова Е.Е., Рычкова Л.В., Васильев С.А., Лебедев И.Н.Sazhenova E.A., Vasilyeva O.Y., Fedotov D.A., Kankanam Pathiranage M.B., Lobanov A.D., Sambyalova А.Y., Khramova E.E., Rychkova L.V., Vasilyev S.А., Lebedev I.N.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/4610

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.

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 modifications, 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.

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The authors declare that there are no conflicts of interest present.