Scientific Publications

Central Precocious Puberty Caused by Mutations in the Imprinted Gene MKRN3.

Publication TypeJournal Article
AuthorsAbreu, AP, Dauber A., Macedo DB, Noel SD, Brito VN, Gill JC, Cukier P., Thompson IR, Navarro VM, Gagliardi PC, Rodrigues T., Kochi C., Longui CA, Beckers D., de Zegher F., Montenegro LR, Mendonca BB, Carroll RS, Hirschhorn JN, Latronico AC, and Kaiser UB
AbstractBackground 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.).
Year of Publication2013
JournalThe New England journal of medicine
Volume368
Issue26
Pages2467-2475
Date Published (YYYY/MM/DD)2013/06/27
ISSN Number0028-4793
DOI10.1056/NEJMoa1302160
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/23738509?dopt=Abstract