ESPEYB21 7. Puberty Clinical Guidance and Studies (8 abstracts)
7.5. Rare variants in the MECP2 gene in girls with central precocious puberty: a translational cohort study
Canton APM , Tinano FR , Guasti L , Montenegro LR , Ryan F , Shears D , de Melo ME , Gomes LG , Piana MP , Brauner R , Espino-Aguilar R , Escribano-Muñoz A , Paganoni A , Read JE , Korbonits M , Seraphim CE , Costa SS , Krepischi AC , Jorge AAL , David A , Kaisinger LR , Ong KK , Perry JRB , Abreu AP , Kaiser UB , Argente J , Mendonca BB , Brito VN , Howard SR & Latronico AC
Lancet Diabetes Endocrinol. 2023 Aug;11(8):545-554. doi: 10.1016/S2213-8587(23)00131-6. PMID: 37385287. https://www.sciencedirect.com/science/article/pii/S2213858723001316?via%3Dihub
Brief Summary: This international cohort study of 404 patients identified rare likely damaging variants in the gene MECP2 in patients with central precocious puberty. Translational experiments showed that GnRH neurons in mice express Mecp2.
Over the last few years, several studies have provided insight into the epigenetic regulation of the onset of puberty1-3. DNA methylation, histone post-translational modifications and non-coding RNAs have a crucial role in the regulation of the transcriptional machinery of neurons involved in reactivating the GnRH pulse generator around puberty. Identification of genetic causes of central precocious puberty has confirmed the role of epigenetic mechanisms in the control of puberty4,5. This study provides additional insights into the function of chromatin organisation in GnRH neurons.
MECP2 is an X-linked gene encoding for a chromatin-associated protein. Loss of function mutations of MECP2 usually cause Rett syndrome, which is a severe neurodevelopmental disorder associated with early onset of puberty.
Between 2020 and 2022, 404 patients with sporadic or familial idiopathic central precocious puberty (95% girls and 5% boys) were included in this genetic study. Whole-exome sequencing was used for 62 patients and targeted gene sequencing for 71 patients. Additionally, 271 patients with isolated central precocious puberty were screened for MECP2 by Sanger sequencing.
Three rare heterozygous likely damaging coding variants in MECP2 were identified in five girls. These patients presented microcephaly and/or neurocognitive phenotype but criteria for Rett syndrome were not met. Additionally, one rare heterozygous 3′UTR MECP2 insertion was identified in two unrelated girls with sporadic central precocious puberty. None of them manifested Rett syndrome. Three of the four MECP2 variants were located in the coding region and were predicted to be damaging by in-silico approaches. MECP2 variants were classified as likely pathogenic in 3 of the 7 girls and variant of unknown significance in 4 girls using ACMG criteria. Analysis of the UK Biobank data did not identify an association between precocious menarche and rare protein variants in MECP2, although data on age at thelarche and pubarche were not available. Authors showed that Mecp2 is expressed in the hypothalamus including the arcuate, suprachiasmatic, and paraventricular nuclei, and in the median eminence of pubertal female mice. Co-immunostaining showed that 70% of GnRH neurons expressed Mecp2.
In summary, this study suggest a potential X-linked form of central precocious puberty associated with rare variants in MECP2, a key component of human DNA methylation regulation expressed in GnRH neurons.
References: 1. Lomniczi, A., Aylwin, C., Vigh-Conrad, K. The Emerging Role of Chromatin Remodeling Factors in Female Pubertal Development. Neuroendocrinology 2019; 109(3):208-217. 2. Toro, C. A., Wright, H., Aylwin, C. F., Ojeda, S. R. & Lomniczi, A. Trithorax dependent changes in chromatin landscape at enhancer and promoter regions drive female puberty. Nat. Commun. 2018; 9: 57. 3. Tomikawa J, Uenoyama Y, Ozawa M, Fukanuma T, Takase K, Goto T, Abe H, Ieda N, Minabe S, Deura C, Inoue N, Sanbo M, Tomita K, Hirabayashi M, Tanaka S, Imamura T, Okamura H, Maeda K, Tsukamura H. Epigenetic regulation of Kiss1 gene expression mediating estrogen-positive feedback action in the mouse brain. Proc Natl Acad Sci U S A. 2012;109(20):E1294-301. 4. Abreu AP, Dauber A, Macedo DB, Noel SD, Brito VN, Gill JC, Cukier P, Thompson IR, Navarro VM, Gagliardi PC, Rodrigues T, Kochi C, Longui CA, Beckers D, de Zegher F, Montenegro LR, Mendonca BB, Carroll RS, Hirschhorn JN, Latronico AC, Kaiser UB. Central precocious puberty caused by mutations in the imprinted gene MKRN3. N Engl J Med. 2013;368(26):2467-75. 5. Dauber A, Cunha-Silva M, Macedo DB, Brito VN, Abreu AP, Roberts SA, Montenegro LR, Andrew M, Kirby A, Weirauch MT, Labilloy G, Bessa DS, Carroll RS, Jacobs DC, Chappell PE, Mendonca BB, Haig D, Kaiser UB, Latronico AC. Paternally Inherited DLK1 Deletion Associated With Familial Central Precocious Puberty. J Clin Endocrinol Metab. 2017;102(5):1557-1567.
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ESPE Yearbook of Paediatric Endocrinology
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