Sazhenova E A, Vasilyeva O Yu, Fedotov D A, Kankanam Pathiranage M B, Lobanov A D, Sambyalova A Yu, Khramova E E, Rychkova L V, Vasilyev S A, Lebedev I N
Scientific Research Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russia.
Tomsk State University, Tomsk, Russia.
Vavilovskii Zhurnal Genet Selektsii. 2025 Jun;29(3):440-447. doi: 10.18699/vjgb-25-47.
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.
性早熟（PP，OMIM 176400，615346）是一种常染色体显性疾病，由下丘脑 - 垂体 - 性腺轴的过早重新激活引起。遗传、表观遗传和环境因素在决定青春期时间方面起决定性作用。近年来，KISS1、KISS1R、MKRN3和DLK1基因中的遗传变异已被确定为性早熟的遗传原因。MKRN3和DLK1基因是印记基因，因此，诸如DNA甲基化等改变这些基因表达的表观遗传修饰也可能导致性早熟的发生。本研究的目的是确定临床表现为性早熟的女孩中DLK1和MKRN3基因印记中心的甲基化指数。在一组45名临床表现为性早熟且核型正常的女孩（年龄7.2±1.9岁）中，使用亚硫酸氢钠处理DNA后通过靶向大规模平行测序分析DLK1和MKRN3基因印记中心的甲基化指数。对照组由无性早熟的女孩组成（n = 15，年龄7.9±1.6岁）。两组之间未观察到显著的年龄差异（p>0.8）。对DLK1和MKRN3基因印记中心甲基化指数的分析显示，性早熟患者与对照组之间无显著差异。然而，在孤立性肾上腺初现患者组中，观察到MKRN3基因印记中心的甲基化指数增加（72±7.84对56.92±9.44%，p = 0.005）。在中枢性性早熟患者组中，3.8%的患者显示DLK1基因印记中心的甲基化指数降低，11.5%的先证者MKRN3基因印记中心的甲基化指数降低。因此，本研究表明，不仅遗传变异，而且DLK1和MKRN3基因印记中心甲基化指数的改变也可能导致性早熟的发生。
