ESPE Abstracts (2016) 86 RFC12.5

a1st Pediatric, Faculty of Health Sciences, Medical Department, Aristotle University, Thessaloniki, Greece; bSt George’s University of London, Medical School at the University of Nicosia, Nicosia, Cyprus; cDepartment of Molecular Genetics, Function & Therapy, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus; dNMR Centre for Structural Biology, Institute of Integrative Biology, University of Liverpool, Liverpool, UK

Background: The onset of puberty is influenced by the interplay of stimulating and restraining factors, many of which have a genetic origin. Premature activation of the GnRH secretion in central precocious puberty (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: Explore the genetic causes responsible for CPP and the potential role of the RING-finger protein 3 (MKRN3) gene.

Method: We investigated potential sequence variations in the intronless MKRN3 gene by Sanger sequencing of the entire 507 amino acid coding region of exon 1 in a Greek family with four girls three of them affected and which presented with CPP at the age of 3 and 5 and 6 years respectively.

Results: A novel heterozygous p.Glu298Ter (p.E298*) nonsense mutation in the MKRN3 gene was identified in all four siblings with the younger ones being identical twins. This nonsense variant is predicted to lead to premature termination of translation thus is a damaging and pathogenic alteration causing CPP. The imprinted MKRN3 missense mutation was also identified as expected in the unaffected father and followed an imprinted mode of inheritance. The pathogenicity of the alteration at the protein level via an in silico structural model and a functional assay is also explored.

Conclusion: A novel mutation in the MKRN3 gene in four sisters with CPP was identified, supporting the fundamental role of this gene in the suppression of the hypothalamic GnRH neurons and also the ethnic diversity with this condition.

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