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

ABSTRACT: 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.).

SUBMITTER: Abreu AP

PROVIDER: S-EPMC3808195 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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

Abreu Ana Paula AP Dauber Andrew A Macedo Delanie B DB Noel Sekoni D SD Brito Vinicius N VN Gill John C JC Cukier Priscilla P Thompson Iain R IR Navarro Victor M VM Gagliardi Priscila C PC Rodrigues Tânia T Kochi Cristiane C Longui Carlos Alberto CA Beckers Dominique D de Zegher Francis F Montenegro Luciana R LR Mendonca Berenice B BB Carroll Rona S RS Hirschhorn Joel N JN Latronico Ana Claudia AC Kaiser Ursula B UB

The New England journal of medicine 20130605 26

<h4>Background</h4>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.<h4>Methods</h4>We performed whole-exome sequencing in 40 members of 15 families with c ...[more]

PMID: 23738509

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Project description:Background: Central Precocious Puberty (CPP) is clinically defined by the development of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys. To date, mutations in the coding region of KISS1, KISS1R, PROKR2, DLK1, and MKRN3 genes have been reported as causative for CPP. This study investigated the presence of causative mutations in both the promoter and the 5'-UTR regions of the MKRN3 gene. Methods: Sanger DNA sequencing was used for screening the proximal promoter and 5'-UTR region of the MKRN3 gene in a group of 73 index girls with CPP. Mutations identified were cloned in luciferase reporter gene vectors and transiently transfected in GN11 cells in order to check for changes in the activity of the MKRN3 promoter. GN11 cells were previously checked for Mkrn3 expression using lentivirus mediated knock-down. In silico analysis was implemented for the detection of changes in the mRNA secondary structure of the mutated MKRN3 5'-UTR. Results: Three novel heterozygous mutations (-166, -865, -886 nt upstream to the transcription start site) located in the proximal promoter region of the MKRN3 gene were identified in six non-related girls with CPP. Four of these girls shared the -865 mutation, one the -166, and another one the -886. A 5'-UTR (+13 nt downstream to the transcription start site) novel mutation was also identified in a girl with similar clinical phenotype. Gene reporter assay evaluated the identified promoter mutations and demonstrated a significant reduction of MKRN3 promoter activity in transfected GN11 cells. In silico analysis for the mutated 5'-UTR predicted a significant change of the mRNA secondary structure. The minimum free energy (MFE) of the mutated 5'-UTR was higher when compared to the corresponding wild-type indicating less stable RNA secondary structure. Conclusion: Our findings demonstrated novel genetic alterations in the promoter and 5'-UTR regulatory regions of the MKRN3 gene. These changes add to another region to check for the etiology of CPP.

Dataset Information

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

Publications

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

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