SFEBES2022 Poster Presentations Neuroendocrinology and Pituitary (72 abstracts)
Variants in Methyl-CpG-binding protein 2 (MECP2) are associated with X-Linked Central Precocious Puberty
Jordan E Read 1 , Ana Pinheiro-Machado Canton 2 , Flávia Tinano 2 , Leonardo Guasti 1 , Luciana Ribeiro Montenegro 2 , Fiona Ryan 3 , Deborah Shears 4 , Alyssa Paganoni 1 , Marta Korbonits 1 , Alexander Jorge 2 , Alessia David 5 , Berenice Bilharinho Mendonca 2 , Vinicius Nahime Brito 2 , Ana Claudia Latronico 2 & Sasha R Howard 1
1Queen Mary University of London, London, United Kingdom; 2University of São Paulo, São Paulo, Brazil; 3Oxford Children’s Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom; 4Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom; 5Imperial College Healthcare NHS Trust, London, United Kingdom
Whilst several key genetic contributors to the phenotype of central precocious puberty (CPP) have been recognized, many familial cases remain without a clear genetic aetiology. Methyl-CpG-binding protein 2 (MECP2) is a chromatin-associated transcriptional regulator, which plays an essential role in neuronal maturation. It is encoded by the MECP2 gene, located at chromosome Xq28, which is highly expressed in brain tissues. Loss-of-function mutations in MECP2 are usually associated with Rett syndrome, a severe neurodevelopment disorder with female predominance characterized by developmental regression and intellectual disability. Early puberty has been demonstrated in girls with Rett syndrome. We investigated whether MECP2 defects might be associated with idiopathic CPP with or without mild neurodevelopmental abnormalities. A cohort of 331 multiethnic idiopathic CPP patients (38% familial) was investigated for MECP2 allelic variants by high-throughput sequencing. Immunohistochemistry and immunofluorescence studies were performed in pubertal female mice to determine Mecp2 expression in hypothalamic nuclei. Three rare heterozygous exonic MECP2 variants were identified in 5 girls from 4 unrelated families with CPP: a de novo p.Arg97Cys variant in monozygotic twin sisters with CPP and microcephaly; a de novo p.Ser176Arg variant in one girl with sporadic CPP, obesity and autism; and a p.Ala6_Ala8dup insertion in two unrelated girls with sporadic CPP, all predicted likely damaging by in silico proteomic tools. Patients did not manifest typical features of Rett syndrome. In female mice, experiments identified abundant Mecp2 staining in hypothalamic nuclei (arcuate, suprachiasmatic, and paraventricular) and co-localization of Mecp2 and GnRH within GnRH neurons, demonstrating Mecp2 expression in key hypothalamic nuclei responsible for GnRH regulation. We propose MECP2 as a novel candidate for CPP that may regulate pubertal timing via transcriptional modification of GnRH secretion. Further studies aim to functionally characterize in vitro the effect of these MECP2 variants of interest and ascertain their role in modulation of GnRH secretion.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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