• Ana Paula Abreu, Andrew Dauber, Delanie B Macedo, Sekoni D Noel, Vinicius N Brito, John C Gill, Priscilla Cukier, Iain R Thompson, Victor M Navarro, Priscila C Gagliardi, Tânia Rodrigues, Cristiane Kochi, Carlos Alberto Longui, Dominique Beckers, Francis de Zegher, Luciana R Montenegro, Berenice B Mendonca, Rona S Carroll, Joel N Hirschhorn, Ana Claudia Latronico, and Ursula B Kaiser.
• Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.
• N. Engl. J. Med. 2013 Jun 27; 368 (26): 2467-75.

BackgroundThe onset of puberty is first detected as an increase in pulsatile secretion of gonadotropin-releasing hormone (GnRH). Early activation of the hypothalamic-pituitary-gonadal axis results in central precocious puberty. The timing of pubertal development is driven in part by genetic factors, but only a few, rare molecular defects associated with central precocious puberty have been identified.MethodsWe performed whole-exome sequencing in 40 members of 15 families with central precocious puberty. Candidate variants were confirmed with Sanger sequencing. We also performed quantitative real-time polymerase-chain-reaction assays to determine levels of messenger RNA (mRNA) in the hypothalami of mice at different ages.ResultsWe identified four novel heterozygous mutations in MKRN3, the gene encoding makorin RING-finger protein 3, in 5 of the 15 families; both sexes were affected. The mutations included three frameshift mutations, predicted to encode truncated proteins, and one missense mutation, predicted to disrupt protein function. MKRN3 is a paternally expressed, imprinted gene located in the Prader-Willi syndrome critical region (chromosome 15q11-q13). All affected persons inherited the mutations from their fathers, a finding that indicates perfect segregation with the mode of inheritance expected for an imprinted gene. Levels of Mkrn3 mRNA were high in the arcuate nucleus of prepubertal mice, decreased immediately before puberty, and remained low after puberty.ConclusionsDeficiency of MKRN3 causes central precocious puberty in humans. (Funded by the National Institutes of Health and others.).

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