1. На главную
  2. Электронные версии
  3. Генетика
  4. T. 59, № 12, 2023

Генетика, 2023, T. 59, № 12, стр. 1360-1371

Генетика и эпигенетика преждевременного полового созревания

Е. А. Саженова 1, *, С. А. Васильев 1, Л. В. Рычкова 2, Е. Е. Храмова 2, И. Н. Лебедев 1

1 Научно-исследовательский институт медицинской генетики, Томский национальный исследовательский медицинский центр Российской академии наук
634050 Томск, Россия

2 Научный центр проблем здоровья семьи и репродукции человека
664003 Иркутск, Россия

* E-mail: elena.sazhenova@medgenetics.ru

Поступила в редакцию 02.06.2023
После доработки 05.07.2023
Принята к публикации 12.07.2023

Аннотация

Центральное преждевременное половое созревание (ППС) вызвано преждевременной реактивацией гипоталамо-гипофизарно-гонадной оси. В определении сроков полового созревания решающую роль играют генетические, эпигенетические и экологические факторы. В последние годы варианты в генах KISS1, KISS1R, MKRN3 и DLK1 были идентифицированы как наследственные причины ППС. Гены MKRN3 и DLK1 являются импринтированными, в связи с чем эпигенетические модификации, изменяющие экспрессию данных генов, также рассматриваются в качестве причины преждевременного полового созревания. При прогрессировании ППС эпигенетические факторы, такие как метилирование ДНК, посттрансляционные модификации гистонов и некодирующие РНК, могут опосредовать взаимосвязь между влиянием генетических вариантов и окружающей среды. ППС связано и с другими краткосрочными и долгосрочными неблагоприятными последствиями для здоровья. Это является основанием для исследований, направленных на понимание генетических и эпигенетических причин ППС. Цель настоящего обзора – обобщение данных литературы о молекулярно-генетических и эпигенетических механизмах формирования ППС.

Ключевые слова: центральное преждевременное половое созревание, гонадотропин-рилизинг-гормон (ГнРГ), гипоталамо-гипофизарно-гонадная ось (ГПГ), геномный импринтинг, DLK1, KISS1, KISS1R, MKRN3.

Список литературы

  1. Дедов И.И., Семичева Т.В., Петеркова В.А. Половое развитие детей: норма и патология. М.: Колор Ит. Студио, 2002. 232 с.

  2. US Department of Health and Human Services. Third National Health and Nutrition Examination Survey, 1988–1994 // Hyattsville. MD: National Center for Health Statistics, Centers for Disease Control and Prevention. 1999. https://www.academia.edu/6706974/ Third_National_Health_and_Nutrition_Examination_Survey

  3. Bleil M.E., Booth-LaForce C., Benner A.D. Race disparities in pubertal timing: Implications for cardiovascular disease risk among African American women // Popul. Res. Policy Rev. 2017. V. 36. P. 717–738. https://doi.org/10.1007/s11113-017-9441-5

  4. Петеркова В.А., Алимова И.Л., Башнина Е.Б. и др. Клинические рекомендации “преждевременное половое развитие” // Проблемы эндокринологии. 2021. Т. 67. № 5. С. 84–103. https://doi.org/10.14341/probl12821

  5. Kim Y.J., Kwon A., Jung M.K. et al. Incidence and prevalence of central precocious puberty in Korea: An epidemiologic study based on a national database // J. Pediatr. 2019. V. 208. P. 221–228.

  6. Eckert-Lind C., Busch A.S., Petersen J.H. et al. Worldwide secular trends in age at pubertal onset assessed by breast development among girls: A systematic review and meta-analysis // JAMA Pediatr. 2020. V. 174. № 4. P. e195881. https://doi.org/10.1001/jamapediatrics.2019.5881

  7. Brauner E.V., Busch A.S., Eckert-Lind C. et al. Trends in the incidence of central precocious puberty and normal variant puberty among children in Denmark, 1998 to 2017 // JAMA Netw. Open. 2020. V. 3. № 10. P. e2015665. https://doi.org/10.1001 /jamanetworkopen.2020.15665

  8. Maione L., Bouvattier C., Kaiser U.B. Central precocious puberty: Recent advances in understanding the etiology and in the clinical approach // Clin. Endocrinol. 2021. V. 95. № 4. P. 542–555. https://doi.org/10.1111/cen.14475

  9. Soriano-Guillen L., Corripio R., Labarta K. et al. Central precocious puberty in children living in Spain: incidence, prevalence, and influence of adoption and immigration // J. Clin. Endocrinol. Metab. 2010. V. 95. № 9. P. 4305–4313.

  10. Zhu J., Kusa T.O., Chan Y.M. Genetics of pubertal timing // Curr. Opin. Pediatr. 2018. V. 30. P. 532–540. https://doi.org/10.1097/MOP.0000000000000642

  11. Valadares L.P., Meireles C.G., De Toledo I.P. et al. MKRN3 mutations in central precocious puberty: A systematic review and meta-analysis // J. Endocr. Soc. 2019. V. 3. P. 979–995. https://doi.org/10.1210/js.2019-00041

  12. Varimo T., Wang Y., Miettinen P.J. et al. Circulating miR-30b levels increase during male puberty // Eur. J. Endocrinol. 2021. V. 184. № 5. P. K11–K14.

  13. Shim Y.S., Lee H.S., Hwang J.S. Genetic factors in precocious puberty // Clin. Exp. Pediatr. 2022. V. 65. № 4. P. 172–181. https://doi.org/10.3345/cep.2021.00521

  14. http://igc.otago.ac.nz – каталог импринтированных генов и родительских эффектов у человека и животных.

  15. Renfree M.B., Hore T.A., Shaw G. Evolution of genomic imprinting: Insights from marsupials and monotremes // Annu. Rev. Genomics Hum. Genet. 2009. V. 10. P. 241–262.

  16. Tucci V., Isles A.R., Kelsey G., Ferguson-Smith A.C. Genomic imprinting and physiological processes in mammals // Cell. 2019. V. 176. № 5. P. 952–965. https://doi.org/10.1016/j.cell.2019.01.043

  17. Eggermann T., Davies J.H., Tauber M. et al. Growth restriction and genomic imprinting-overlapping phenotypes support the concept of an imprinting network // Genes (Basel). 2021. V. 12. № 4. P. e585. https://doi.org/10.3390/genes12040585

  18. Canton A.P., Krepischi A.C., Montenegro L.R. et al. Insights from the genetic characterization of central precocious puberty associated with multiple anomalies // Hum. Reprod. 2021. V. 36. № 2. P. 506–518. https://doi.org/10.1093/humrep/deaa306

  19. Fontana L., Bedeschi M.F., Maitz S. et al. Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders // Epigenetics. 2018. V. 13. № 9. P. 897–909. https://doi.org/10.1080/15592294.2018.1514230

  20. Sparago A., Verma A., Patricelli M.G. et al. The phenotypic variations of multi-locus imprinting disturbances associated with maternal-effect variants of NLRP5 range from overt imprinting disorder to apparently healthy phenotype // Clin. Epigenetics. 2019. V. 11. P. e190. https://doi.org/10.1186/s13148-019-0760-8

  21. Sazhenova E.A., Nikitina T.V., Vasilyev S.A. et al. NLRP7 variants in spontaneous abortions with multilocus imprinting disturbances from women with recurrent pregnancy loss // J. Assist. Reprod. Genet. 2021. V. 38. № 11. P. 2893–2908. https://doi.org/10.1007/s10815-021-02312-z

  22. Faienza M.F., Urbano F., Moscogiuri L.A. et al. Genetic, epigenetic and enviromental influencing factors on the regulation of precocious and delayed puberty // Front. Endocrinol. (Lausanne). 2022. V. 13. P. e1019468. https://doi.org/10.3389/fendo.2022.1019468

  23. Brito V.N., Canton A.P., Seraphim C.E. et al. The congenital and acquired mechanisms implicated in the etiology of central precocious puberty // Endocr. Rev. 2023. V. 44. № 2. P. 193–221. https://doi.org/10.1210/endrev/bnac020

  24. Cantas-Orsdemir S., Garb J.L., Allen H.F. Prevalence of cranial MRI findings in girls with central precocious puberty: A systematic review and meta-analysis // J. Pediatr. Endocrinol. Metab. 2018. V. 31. № 7. P. 701–710. https://doi.org/10.1515/jpem-2018-0052

  25. Imperial R., Toor O.M., Hussain A. et al. Comprehensive pancancer genomic analysis reveals (RTK)-RAS-RAF-MEK as a key dysregulated pathway in cancer: its clinical implications // Semin. Cancer Biol. 2019. V. 54. P. 14–28. https://doi.org/10.1016/j.semcancer.2017.11.016

  26. Savas Erdeve S., Ocal G., Berberoglu M. et al. The endocrine spectrum of intracranial cysts in childhood and review of the literature // J. Pediatr. Endocrinol. Metab. 2011. V. 24. № 11–12. P. 867–875. https://doi.org/10.1515/jpem.2011.263

  27. Almutlaq N., O’Neil J., Fuqua J.S. Central precocious puberty in spina bifida children: guidelines for the care of people with spina bifida // J. Pediatr. Rehabil. Med. 2020. V. 13. № 4. P. 557–563.

  28. Vurallı D., Ozon A., Gonc E.N. et al. Gender-related differences in etiology of organic central precocious puberty // Turk. J. Pediatr. 2020. V. 62. № 5. P. 763–769. https://doi.org/10.24953/turkjped.2020.05.007

  29. Фархутдинова Л.М. Преждевременное половое созревание центрального происхождения // Архив внутренней медицины. 2017. № 4. С. 245–251.

  30. Витебская А.В., Амшинская Д.Р., Шуминов О.В. Гонадотропинзависмое преждевременное половое созревание у девочек. Описание клинических случаев // Сеченовский вестник. 2017. Т. 1. № 27. С. 36–40.

  31. Gangat M., Radovick S. Precocious puberty // Minerva Pediatr. 2020. V. 72. № 6. P. 491–500. https://doi.org/10.23736/S0026-4946.20.05970-8

  32. Campbell R.E., Coolen L.M., Hoffman G.E., Hrabovszky E. Highlights of neuroanatomical discoveries of the mammalian gonadotropin-releasing hormone system // J. Neuroendocrinol. 2022. V. 34. № 5. P. e13115. https://doi.org/10.1111/jne.13115

  33. Vazquez M.J., Toro C.A., Castellano J.M et al. SIRT1 mediates obesity- and nutrient-dependent perturbation of pubertal timing by epigenetically controlling Kiss1 expression // Nat. Commun. 2018. V. 9. № 1. P. e4194. https://doi.org/10.1038/s41467-018-06459-9

  34. De Roux N., Genin E., Carel J.C. et al. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54 // Proc. Natl Acad. Sci. USA. 2003. V. 100. № 19. P. 10972–10976.

  35. Seminara S.B., Messager S., Chatzidaki E.E. et al. The GPR54 gene as a regulator of puberty // N. Engl. J. Med. 2003. V. 349. № 17. P. 1614–1627.

  36. Teles M.G., Bianco S.D., Brito V.N. et al. AGPR54-activating mutation in a patient with central precocious puberty // N. Engl. J. Med. 2008. V. 358. № 7. P. 709–715.

  37. Pagani S., Calcaterra V., Acquafredda G. et al. MKRN3 and KISS1R mutations in precocious and early puberty // Ital. J. Pediatr. 2020. V. 46. № 1. P. e39. https://doi.org/10.1186/s13052-020-0808-6

  38. Hu K.L., Chang H.M., Zhao H.C. et al. Potential roles for the kisspeptin/kisspeptin receptor system in implantation and placentation // Hum. Reprod. Update. 2019. V. 25. № 3. P. 326–343. https://doi.org/10.1093/humupd/dmy046

  39. Abreu A.P., Toro C.A., Song Y.B. et al. MKRN3 inhibits the reproductive axis through actions in kisspeptin-expressing neurons // J. Clin. Invest. 2020. V. 130. № 8. P. 4486–4500. https://doi.org/10.1172/JCI136564

  40. Gomes L.G., Cunha-Silva M., Crespo R.P. et al. DLK1 is a novel link between reproduction and metabolism // J. Clin. Endocrinol. Metab. 2019. V. 104. № 6. P. 2112–2120.

  41. Perry J.R., Day F., Elks C.E. et al. Parent-of-origin specific allelic associations among 106 genomic loci for age at menarche // Nature. 2014. V. 514. P. 92–97.

  42. Dauber A., Cunha-Silva M., Macedo D.B. et al. Paternally inherited DLK1 deletion associated with familial central precocious puberty // J. Clin. Endocrinol. Metab. 2017. V. 102. № 5. P. 1557–1567. https://doi.org/10.1210/jc.2016-3677

  43. Moon Y.S., Smas C.M., Lee K. et al. Mice lacking paternally expressed Pref-1/Dlk1 display growth retardation and accelerated adiposity // Mol. Cell. Biol. 2002. V. 22. № 15. P. 5585–5592. https://doi.org/10.1128/MCB.22.15.5585-5592.2002

  44. Li C., Han T., Li Q. et al. MKRN3-mediated ubiquitination of Poly(A)-binding proteins modulates the stability and translation of GNRH1 mRNA in mammalian puberty // Nucl. Acids Res. 2021. V. 49. № 7. P. 3796–3813.

  45. Yellapragada V., Liu X., Lund C. et al. MKRN3 interacts with several proteins implicated in puberty timing but does not influence GNRH1 expression // Front. Endocrinol. (Lausanne). 2019. V. 10. P. e48. https://doi.org/10.3389/fendo.2019.00048

  46. Garcia J.P., Guerriero K.A., Keen K.L. et al. Kisspeptin and neurokinin B signaling network underlies the pubertal increase in GnRH release in female rhesus monkeys // Endocrinology. 2017. V. 158. № 10. P. 3269–3280. https://doi.org/10.1210/en.2017-00500

  47. Kanber D., Giltay J., Wieczorek D. et al. A paternal deletion of MKRN3, MAGEL2 and NDN does not result in Prader–Willi syndrome // Eur. J. Hum. Genet. 2009. V. 17. № 5. P. 582–590.

  48. Jeong H.R., Lee H.J., Shim Y.S. et al. Serum Makorin ring finger protein 3 values for predicting Central precocious puberty in girls // Gynecol. Endocrinol. 2019. V. 35. P. 732–736. https://doi.org/10.1080/09513590.2019.1576615

  49. Fanis P., Skordis N., Toumba M. et al. Central precocious puberty caused by novel mutations in the promoter and 5′-UTR region of the imprinted MKRN3 // Front. Endocrinol. (Lausanne). 2019. V. 10. P. e677. https://doi.org/10.3389/fendo.2019.00677

  50. Maione L., Naule L., Kaiser U.B. Makorin RING finger protein 3 and central precocious puberty // Curr. Opin. Endocr. Metab. Res. 2020. V. 14. P. 152–159. https://doi.org/10.1016/j.coemr.2020.08.003

  51. Aycan Z., Savas-Erdeve S., Çetinkaya S. et al. Investigation of MKRN3 mutation in patients with familial central precocious puberty // J. Clin. Res. Pediatr. Endocrinol. 2018. V. 10. P. e223–e229. https://doi.org/10.4274/jcrpe.5506

  52. Зубкова Н.А., Колодкина А.А., Макрецкая Н.А. и др. Клиническая и молекулярно-генетическая характеристика 3 семейных случаев гонадотропинзависимого преждевременного полового развития, обусловленного мутациями в гене MKRN3 // Проблемы эндокринологии. 2021. Т. 7. № 3. С. 55–61.

  53. Patti G., Malerba F., Calevo M.G. et al. Pubertal timing in children with Silver–Russell syndrome compared to those born small for gestational age // Front. Endocrinol. (Lausanne). 2022. V. 24. № 13. P. e975511. https://doi.org/10.3389/fendo.2022.975511

  54. Ioannides Y., Lokulo-Sodipe K., Mackay D. et al. Temple syndrome: Improving the recognition of an underdiagnosed chromosome 14 imprinting disorder: an analysis of 51 published cases // J. Med. Genet. 2014. V. 51. P. 495–501.

  55. Juriaans A.F., Kerkhof G.F., Mahabier E.F. et al. Syndrome: Clinical findings, body composition and cognition in 15 patients // J. Clin. Med. 2022. V. 11. № 21. P. e6289. https://doi.org/10.3390/jcm11216289

  56. Flippo C., Kolli V., Andrew M. et al. Precocious puberty in a boy with bilateral leydig cell tumors due to a somatic gain-of-function LHCGR variant // J. Endocr. Soc. 2022. V. 6. P. e10. https://doi.org/10.1210/jendso/bvac127

  57. Partsch C.J., Japing I., Siebert R. et al. Central precocious puberty in girls with Williams syndrome // J. Pediatr. 2002. V. 141. № 3. P. 441–444.

  58. Kozel B.A., Barak B., Kim C.A. et al. Williams syndrome // Nat. Rev. Dis. Primers. 2021. V. 7. № 1. P. e42. https://doi.org/10.1038/s41572-021-00276-z

  59. Nizon M., Andrieux J., Rooryck C. et al. Phenotype-genotype correlations in 17 new patients with an Xp11.23p11.22 microduplication and review of the literature // Am. J. Med. Genet. A. 2015. V. 167A. № 1. P. 111–122. https://doi.org/10.1002/ajmg.a.36807

  60. Smith A., Leask K., Tomlin P., Donnai D. A familial dysmorphic condition with hypotonia, seizures and precocious puberty // Clin. Dysmorph. 2008. V. 17. P. 161–164.

  61. Luckie T.M., Danzig M., Zhou S. et al. A multicenter retrospective review of pediatric Leydig cell tumor of the testis // J. Pediatr. Hematol. Oncol. 2019. V. 41. № 1. P. 74–76. https://doi.org/10.1097/mph.0000000000001124

  62. Menon K.M., Menon B. Structure, function and regulation of gonadotropin receptors – a perspective // Mol. Cell. Endocrinol. 2012. V. 356. № 1–2. P. 88–97. https://doi.org/10.1016/j.mce.2012.01.021

  63. Lomniczi A., Ojeda S.R. The emerging role of epigenetics in the regulation of female puberty // Endocr. Dev. 2016. V. 29. P. 1–16. https://doi.org/10.1159/000438840

  64. Feinberg A.P. The key role of epigenetics in human disease prevention and mitigation // N. Engl. J. Med. 2018. V. 378. № 14. P. 1323–1334. https://doi.org/10.1056/NEJMra1402513

  65. Wright H., Aylwin C.F., Toro C.A. et al. Polycomb represses a gene network controlling puberty via modulation of histone demethylase Kdm6b expression // Sci. Rep. 2021. V. 11. № 1. P. e1996. https://doi.org/10.1038/s41598-021-81689-4

  66. Lomniczi A., Wright H., Castellano J.M. et al. Epigenetic regulation of puberty via zinc finger protein-mediated transcriptional repression // Nat. Commun. 2015. V. 6. P. e10195. https://doi.org/10.1038/ncomms10195

  67. Toro C.A., Wright H., Aylwin C.F. et al. Trithorax dependent changes in chromatin landscape at enhancer and promoter regions drive female puberty // Nat. Commun. 2018. V. 9. № 1. P. e57. https://doi.org/10.1038/s41467-017-02512-1

  68. Messina A., Langlet F., Chachlaki K. et al. A microRNA switch regulates the rise in hypothalamic GnRH production before puberty // Nat. Neurosci. 2016. V. 19. № 6. P. 835–844. https://doi.org/10.1038/nn.4298

  69. Heras V., Sangiao-Alvarellos S., Manfredi-Lozano M. et al. Hypothalamic miR-30 regulates puberty onset via repression of the puberty-suppressing factor Mkrn3 // PLoS Biol. 2019. V. 17. № 11. P. e3000532. https://doi.org/10.1371/journal.pbio.3000532

  70. Canton A.P., Krepischi A.C., Montenegro L.R. et al. Insights from the genetic characterization of central precocious puberty associated with multiple anomalies // Hum. Reprod. 2021. V. 25. № 36. P. 506–518. https://doi.org/10.1093/humrep/deaa306

  71. Le Goff L.J., Cachin O., Rappaport R. Precocious puberty associated with Silver’s syndrome // Arch. Fr. Pediatr. 1977. V. 34. № 9. P. 899–905.

  72. Wakeling E.L., Brioude F., Lokulo-Sodipe O. et al. Diagnosis and management of Silver–Russell syndrome: first international consensus statement // Nat. Rev. Endocrinol. 2017. V. 13. № 2. P. 105–124. https://doi.org/10.1038/nrendo.2016.138

  73. Grosvenor S.E., Davies J.H., Lever M. et al. A patient with multilocus imprinting disturbance involving hypomethylation at 11p15 and 14q32, and phenotypic features of Beckwith–Wiedemann and Temple syndromes // Am. J. Med. Genet. A. 2022. V. 188. № 6. P. 1896–1903. https://doi.org/10.1002/ajmg.a.62717

  74. Docherty L.E., Rezwan F.I., Poole R.L. Mutations in NLRP5 are associated with reproductive wastage and multilocus imprinting disorders in humans // Nat. Commun. 2015. V. 6. P. e8086. https://doi.org/10.1038/ncomms9086

  75. Саженова Е.А., Никитина Т.В., Скрябин Н.А. и др. Эпигенетический статус импринтированных генов в плаценте при привычном невынашивании беременности // Генетика. 2017. Т. 53. № 3. С. 364–377. https://doi.org/10.7868/S0016675817020096

  76. Anvar Z., Chakchouk I., Demond H. et al. DNA methylation dynamics in the female germline and maternal-effect mutations that disrupt genomic imprinting // Genes (Basel). 2021. V. 12. № 8. P. e1214. https://doi.org/10.3390/genes12081214

  77. Pignata L., Cecere F., Verma A. et al. Novel genetic variants of KHDC3L and other members of the subcortical maternal complex associated with Beckwith–Wiedemann syndrome or Pseudohypoparathyroidism 1B and multi-locus imprinting // Clin. Epigenetics. 2022. V. 14. P. e71. https://doi.org/10.1186/s13148-022-01292-w

  78. Begemann M., Rezwan F.I., Beygo J. et al. Maternal variants in NLRP and other maternal effect proteins are associated with multilocus imprinting disturbance in offspring // J. Med. Genet. 2018. V. 55. № 7. P. 497–504. https://doi.org/10.1136/jmedgenet-2017-105190

  79. Monteagudo-Sanchez A., Hernandez Mora J.R., Simon C. et al. The role of ZFP57 and additional KRAB-zinc finger proteins in the maintenance of human imprinted methylation and multi-locus imprinting disturbances // Nucl. Acids Res. 2020. V. 48. № 20. P. 11394–11407. https://doi.org/10.1093/nar/gkaa837

  80. Bessa D.S., Maschietto M., Aylwin C.F. et al. Methylome profiling of healthy and central precocious puberty girls // Clin. Epigenetics. 2018. V. 10. № 1. P. e146. https://doi.org/10.1186/s13148-018-0581-1

  81. Holland A., Manning K., Whittington J. The paradox of Prader–Willi syndrome revisited: Making sense of the phenotype // EBioMedicine. 2022. V. 78. P. e103952. https://doi.org/10.1016/j.ebiom.2022.103952

Дополнительные материалы отсутствуют.

Инструменты

следующая статья выпуска предыдущая статья выпуска содержание выпуска

Генетика

Архивы выпусков Информация о журнале Отправить рукопись в журнал