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Cited by 140Hypothalamic control of reproductive hormonesGenetic Syndromes and ImprintingGenetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities

Central precocious puberty that appears to be sporadic caused by paternally inherited mutations in the imprinted gene makorin ring finger 3

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Macedo, Delanie B., Abreu, Ana Paula, Reis, Ana Claudia S., Montenegro, Luciana R., Dauber, Andrew, Beneduzzi, Daiane, Cukier, Priscilla, Silveira, Leticia F. G. +15 more·2014·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2013-3126PMC PMC4037732
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Abstract

CONTEXT: Loss-of-function mutations in makorin ring finger 3 (MKRN3), an imprinted gene located on the long arm of chromosome 15, have been recognized recently as a cause of familial central precocious puberty (CPP) in humans. MKRN3 has a potential inhibitory effect on GnRH secretion. OBJECTIVES: The objective of the study was to investigate potential MKRN3 sequence variations as well as copy number and methylation abnormalities of the 15q11 locus in patients with apparently sporadic CPP. SETTING AND PARTICIPANTS: We studied 215 unrelated children (207 girls and eight boys) from three university medical centers with a diagnosis of CPP. All but two of these patients (213 cases) reported no family history of premature sexual development. First-degree relatives of patients with identified MKRN3 variants were included for genetic analysis. MAIN OUTCOME MEASURES: All 215 CPP patients were screened for MKRN3 mutations by automatic sequencing. Multiplex ligation-dependent probe amplification was performed in a partially overlapping cohort of 52 patients. RESULTS: We identified five novel heterozygous mutations in MKRN3 in eight unrelated girls with CPP. Four were frame shift mutations predicted to encode truncated proteins and one was a missense mutation, which was suggested to be deleterious by in silico analysis. All patients with MKRN3 mutations had classical features of CPP with a median age of onset at 6 years. Copy number and methylation abnormalities at the 15q11 locus were not detected in the patients tested for these abnormalities. Segregation analysis was possible in five of the eight girls with MKRN3 mutations; in all cases, the mutation was inherited on the paternal allele. CONCLUSIONS: We have identified novel inherited MKRN3 defects in children with apparently sporadic CPP, supporting a fundamental role of this peptide in the suppression of the reproductive axis.

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Crossref · 10.1210/jc.2013-3126

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  • 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 [74]

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Authors
Macedo, D. B., Abreu, A. P., Reis, A. C. S., Montenegro, L. R., Dauber, A., Beneduzzi, D., Cukier, P., Silveira, L. F. G., Teles, M. G., Carroll, R. S., Junior, G. G., Filho, G. G., Gucev, Z., Arnhold, I. J. P., de Castro, M., Moreira, A. C., Martinelli, C. E., Hirschhorn, J. N., Mendonca, B. B., Brito, V. N., Antonini, S. R., Kaiser, U. B., & Latronico, A. C.
Affiliations
  • Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (BR)
  • Universidade de São Paulo (BR)
  • Broad Institute (US)
  • Unidade de Endocrinologia do Desenvolvimento e Laboratório de Hormônios e Genética Molecular/LIM42, Disciplina de Endocrinologia (D.B.M., A.P.A., L.R.M., D.B., P.C., L.F.G.S., M.G.T., I.J.P.A., B.B.M., V.N.B., A.C.L.), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil, 05403-900;
  • Division of Endocrinology, Diabetes, and Hypertension (A.P.A., R.S.C., U.B.K.),Cambridge, Massachusetts 02142;
  • Unidade de Endocrinologia Pediátrica (G.G.J., G.G.F.), Universidade de Campinas, SP, Brasil, 13084-970;
  • Ss. Cyril and Methodius University in Skopje (MK)
  • Departamento de Puericultura e Pediatria (A.C.S.R., M.C., A.C.M., C.E.M., S.R.A.), Faculdade de Medicina de Ribeirão Preto, da Universidade de São Paulo, Ribeirão Preto, SP, Brasil, 14049900;
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2014-06-01
Volume
99
Issue
6
Pages
E1097-E1103
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jc.2013-3126
PMC
PMC4037732
OpenAlex
W2154616573
Cited by
140
References
37
Citations by year
2026: 5 · 2025: 3 · 2024: 6 · 2023: 10 · 2022: 10 · 2021: 11 · 2020: 16 · 2019: 17 · 2018: 15 · 2017: 8 · 2016: 21 · 2015: 15 · 2014: 2 · 2013: 1
FWCI
18.62
Type
journal article
Language
en
Open access
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
Eunice Kennedy Shriver National Institute of Child Health and Human Development (F05HD072773, K23HD073351, P50HD028138, R21HD066495, P30HD018655, U54HD028138, R01HD082314)
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, paternally inherited mutation, novel mutations, GnRH secretion, copy number abnormalities, DNA methylation
MeSH terms
Child, DNA Mutational Analysis, Fathers, Female, Humans, Male, Mutation, Pedigree, Puberty, Precocious, Ribonucleoproteins, Cohort Studies, Genomic Imprinting, Inheritance Patterns, Ubiquitin-Protein Ligases

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