ESPE Abstracts (2018) 89 FC13.1

aDepartment of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; bDepartment of Pediatrics, Iasis Hospital, Paphos, Cyprus; cUniversity of Wroclaw, Wroclaw, Poland; dDivision of Pediatric Endocrinology, Makarios III Hospital, Nicosia, Cyprus; eAristotle University of Thessaloniki Faculty of Medicine, Department of Health Sciences, Papageorgiou General Hospital, 4th Clinic of Pediatrics, Thessaloniki, Greece; fDevelopmental Endocrinology Research Group, School of Medicine, University of Glasgow, Glasgow, UK; g1st Pediatric Department, Aristotle University of Thessaloniki, Thessaloniki, Greece; hDepartment of Pediatric Endocrinology, Paedi Center for specialized Pediatrics, Nicosia, Cyprus; iCyprus School of Molecular Medicine, Nicosia, Cyprus

Central precocious puberty (CPP) results from premature activation of the hypothalamic-pituitary-gonadal axis through the activation of the gonadotropin releasing hormone (GnRH). Gain-of-function mutations of the KISS1 and KISS1R genes or loss-of-function mutations of the makorin RING-finger protein 3 (MKRN3) have been linked with CPP. Moreover intronic and intragenic variants harbouring the imprinted loci of MKRN3-MAGEL2 and DLK1 genes have been associated to age of menarche. In the present study, a cohort of 75 index girls with CPP were screened for mutations in the coding sequence of the MKRN3, KISS1, KISS1R, DLK1 and MAGEL2 genes. All patients had pubertal basal and/or GnRH-stimulated LH levels and advanced bone age. Genotypic analysis of the KISS1R gene did not reveal any genetic defect. Three, seven and one single nucleotide polymorphisms (SNPs) were found in the KISS1, DLK1 and MAGEL2 genes, respectively. The minor allele frequencies (MAF) for these SNPs were similar to that found in the general population. However, two novel and one known MKRN3 gene mutations were identified in two familial and three sporadic cases of CPP. The pathogenicity of the novel missense mutation at the protein level was verified by in silico structural analysis. The novel nonsense and the known frameshift mutations resulted in truncated proteins. As expected the MKRN3 mutations identified in this study were also identified in the unaffected fathers following an imprinted mode of inheritance. Age at puberty onset was earlier among the patients with MKRN3 mutations compared to those without MKRN3 mutations. Our results confirm the role of MKRN3 in the onset of pubertal development and support the fundamental role of this gene in the suppression of the hypothalamic GnRH neurons. Furthermore, these results indicate the involvement of additional genes in the regulation of pubertal timing in humans and screening using high throughput genetic analyses is under investigation.

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