ESPE Abstracts (2016) 86 P-P1-730

aDepartment of Molecular Genetics, Function & Therapy, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus; bPaediatric & Paediatric Endocrinology Clinic, IASIS Hospital, Paphos, Cyprus; cNMR Centre for Structural Biology, Institute of Integrative Biology, University of Liverpool, Crown Street, L69 7ZB, Liverpool, UK; dDivision of Paediatric Endocrinology, Makarios III Hospital, Nicosia, Cyprus; e1st Paediatric Department, Aristotle University of Thessaloniki, Thessaloniki, Greece; fDivision of Pediatric Endocrinology, Paedi Center for specialized Pediatrics, Nicosia, Cyprus; gSt George’s University of London Medical School at the University of Nicosia, Nicosia, Cyprus

Background: Central precocious puberty (CPP) results from premature activation of the hypothalamic-pituitary-gonadal axis and increasing evidence suggests a genetic origin. Premature activation of the GnRH secretion in CPP may arise either from gain-of-function mutations of the KISS1 and KISS1R genes or loss-of-function manner mutations of the MKRN3 gene leading to MKRN3 deficiency.

Objective and hypotheses: To identify loss-of-function mutations in the makorin RING-finger protein 3 (MKRN3) gene or gain-of-function mutations in the KISS1 and KISS1R genes that lead to CPP.

Method: We investigated potential sequence variations in the intronless MKRN3 gene and the KISS1 and KISS1R genes by Sanger sequencing in a cohort of 24 index girls with CPP. Four of these 24 index cases reported familial history of CPP. A phenotype-genotype correlation was evaluated between the MKRN3 mutated and non mutated patients.

Results: Mutational analysis of the KISS1 and KISS1R genes did not identify any genetic defect. MKRN3 mutations however were identified in one sporadic and two familial cases of CPP. The novel missense g.Gly312Asp (p.G312D) and the novel p.Glu298Term (p.E298*) nonsense mutation were respectively identified in 2 nonrelated familial index cases with CPP. Additionally, in a sporadic case with CPP the known frameshift p.Met268ValfsTer23 (p.M268Vfs*23) was found. The imprinted novel MKRN3 mutations identified in this study were also identified as expected in the unaffected fathers following an imprinted mode of inheritance. The pathogenicity of the alterations at the protein level was verified via in silico structural modeling. Age at the onset of puberty was similar among patients with MKRN3 mutations and was earlier compared to those without MKRN3 mutations.

Conclusion: The identification of mutations in the MKRN3 gene in children with a family history of CPP further supports the role of MKRN3 in the onset of pubertal development and supports the fundamental role of this gene in the suppression of the hypothalamic GnRH neurons. Therefore, MKRN3 gene analysis should be considered as an additional critical tool for the diagnosis of familial CPP.

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