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N Engl J Med DOI:10.1056/NEJMoa1302160

Central precocious puberty caused by mutations in the imprinted gene MKRN3.

Publication TypeJournal Article
Year of Publication2013
AuthorsAbreu, APaula, Dauber, A, Macedo, DB, Noel, SD, Brito, VN, Gill, JC, Cukier, P, Thompson, IR, Navarro, VM, Gagliardi, PC, Rodrigues, T, Kochi, C, Longui, CAlberto, Beckers, D, de Zegher, F, Montenegro, LR, Mendonca, BB, Carroll, RS, Hirschhorn, JN, Latronico, AClaudia, Kaiser, UB
JournalN Engl J Med
Date Published2013 Jun 27
KeywordsAnimals, Arcuate Nucleus of Hypothalamus, Child, Child, Preschool, Exome, Female, Frameshift Mutation, Genetic Association Studies, Heterozygote, Humans, Hypothalamus, Male, Mice, Mutation, Missense, Pedigree, Puberty, Precocious, Ribonucleoproteins, RNA, Messenger, Sequence Analysis, DNA

BACKGROUND: The 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.

METHODS: We 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.

RESULTS: We 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.

CONCLUSIONS: Deficiency of MKRN3 causes central precocious puberty in humans. (Funded by the National Institutes of Health and others.).


Alternate JournalN. Engl. J. Med.
PubMed ID23738509
PubMed Central IDPMC3808195
Grant ListK99 HD071970 / HD / NICHD NIH HHS / United States
K23 HD073351 / HD / NICHD NIH HHS / United States
R21HD066495 / HD / NICHD NIH HHS / United States
R21 HD066495 / HD / NICHD NIH HHS / United States
P30 HD018655 / HD / NICHD NIH HHS / United States
U54HD28138 / HD / NICHD NIH HHS / United States
T32 DK007529 / DK / NIDDK NIH HHS / United States
1K23HD073351 / HD / NICHD NIH HHS / United States
U54 HD028138 / HD / NICHD NIH HHS / United States
F05 HD072773 / HD / NICHD NIH HHS / United States
1F05HD072773-01 / HD / NICHD NIH HHS / United States