Central Precocious Puberty Caused by Mutations in the Imprinted Gene MKRN3
Open accessAbstract
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.).
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The first gene with an inhibitory effect on GnRH secretion with mutations identified in human beings was MKRN3.
“The first gene with an inhibitory effect on GnRH secretion with mutations identified in human beings was MKRN3 (table, figure 2).”
From Pubertal development and regulation (2016) · cites this paper as [52]
The identification of MKRN3 arose from whole-exome sequencing analysis of families with central precocious puberty.
“The identification of this novel factor in the GnRH network arose from whole-exome sequencing analysis of families with central precocious puberty.52”
From Pubertal development and regulation (2016) · cites this paper as [52]
MKRN3 is the most common genetic defect associated with central precocious puberty so far; families with central precocious puberty from several different ethnic groups harbour mutations in this gene.
“MKRN3 is the most common genetic defect associated with central precocious puberty so far; families with central precocious puberty from several different ethnic groups harbour mutations in this gene.52,71–76”
From Pubertal development and regulation (2016) · cites this paper as [52]
MKRN3 expression in the arcuate nucleus of mice is high prepubertally and decreases before puberty initiation, reaching very low levels in adult life.
“MKRN3 expression in the arcuate nucleus of mice is high prepubertally and decreases before puberty initiation, reaching very low levels in adult life.52”
From Pubertal development and regulation (2016) · cites this paper as [52]
All MKRN3 mutations identified in patients with central precocious puberty were inherited from their fathers.
“Following this inheritance pattern, all MKRN3 mutations identified in patients with central precocious puberty were inherited from their fathers.52”
From Pubertal development and regulation (2016) · cites this paper as [52]
Genetic studies have led to the identification of the most common known genetic cause of central precocious puberty, MKRN3.
“More recently, genetic studies have led to the identification of the most common known genetic cause of central precocious puberty, MKRN3.52”
From Pubertal development and regulation (2016) · cites this paper as [52]
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- Authors
- Abreu, A. P., Dauber, A., Macedo, D. B., Noel, S. D., Brito, V. N., Gill, J. C., Cukier, P., Thompson, I. R., Navarro, V. M., Gagliardi, P. C., Rodrigues, T., Kochi, C., Longui, C. A., Beckers, D., de Zegher, F., Montenegro, L. R., Mendonca, B. B., Carroll, R. S., Hirschhorn, J. N., Latronico, A. C., & Kaiser, U. B.
- Affiliations
- Brigham and Women's Hospital (US)
- Broad Institute (US)
- Universidade de São Paulo (BR)
- Nemours Children’s Clinic (US)
- Hospital das Clínicas da Universidade Federal de Minas Gerais (BR)
- Faculdade de Ciências Médicas da Santa Casa de São Paulo (BR)
- Universitair Ziekenhuis Leuven (BE)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2013-06-27
- Volume
- 368
- Issue
- 26
- Pages
- 2467-2475
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC3808195
- OpenAlex
- W1981122661
- Cited by
- 534
- References
- 38
- Citations by year
- 2026: 30 · 2025: 31 · 2024: 33 · 2023: 36 · 2022: 42 · 2021: 43 · 2020: 56 · 2019: 41 · 2018: 45 · 2017: 35 · 2016: 46 · 2015: 54 · 2014: 36 · 2013: 5
- FWCI
- 56.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- Digital Access to Libraries (Université catholique de Louvain (UCL), l'Université de Namur (UNamur) and the Université Saint-Louis (USL-B)) (submittedVersion)
- UNIFESP Institutional Repository (Universidade Federal de São Paulo) (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007529)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (F05HD072773, R00HD071970, K12HD051959, K23HD073351, K99HD071970, R21HD066495, P30HD018655, U54HD028138)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Keywords
- central precocious puberty, MKRN3, genomic imprinting, chromosome 15q11-q13, paternally expressed genes, frameshift mutation, missense mutations, hypothalamic-pituitary-gonadal axis, GnRH pulsatility, arcuate nucleus
- MeSH terms
- Animals, Arcuate Nucleus of Hypothalamus, Child, Child, Preschool, Female, Heterozygote, Humans, Hypothalamus, Male, Pedigree, Puberty, Precocious, Ribonucleoproteins, RNA, Messenger, Frameshift Mutation, Sequence Analysis, DNA, Mutation, Missense, Ubiquitin-Protein Ligases, Mice, Genetic Association Studies, Exome
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