Central precocious puberty in a girl and early puberty in her brother caused by a novel mutation in the MKRN3 gene

Settas, Nikolaos; Dacou-Voutetakis, Catherine; Karantza, Maria; Kanaka-Gantenbein, Christina; Chrousos, George P.; Voutetakis, Antonis

doi:10.1210/jc.2013-4084

Cited by 80Hypothalamic control of reproductive hormonesGenetic Syndromes and ImprintingGenetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities

Central precocious puberty in a girl and early puberty in her brother caused by a novel mutation in the MKRN3 gene

Settas, Nikolaos, Dacou-Voutetakis, Catherine, Karantza, Maria, Kanaka-Gantenbein, Christina, Chrousos, George P., Voutetakis, Antonis·2014·The Journal of Clinical Endocrinology & Metabolism

DOI 10.1210/jc.2013-4084

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Abstract

CONTEXT: Central precocious puberty (CPP), defined as the development of secondary sex characteristics prior to age 8 years in girls and 9 years in boys, results from the premature activation of the hypothalamic-pituitary-gonadal axis. Mutations in the imprinted gene MKRN3 have been recently implicated in familial cases of CPP. OBJECTIVE: The objective of the study was to uncover the genetic cause of CPP in a family with two affected siblings. DESIGN AND PARTICIPANTS: The entire coding region of the paternally expressed MKRN3 gene was sequenced in two siblings, a girl with CPP and her brother with early puberty, their parents, and their grandparents. RESULTS: A novel heterozygous missense variant in the MKRN3 gene (p.C340G) was detected in the two affected siblings, their unaffected father, and the paternal grandmother. As expected, the mutated allele followed an imprinted mode of inheritance within the affected family. In silico analysis predicts the mutation as possibly damaging in all five software packages used. Furthermore, structural alignment of the ab initio native and mutant MKRN3 models predicts that the p.C340G mutation leads to significant structural perturbations in the 3-dimensional structure of the C3HC4 really interesting new gene motif of the protein, further emphasizing the functional implications of the novel MKRN3 alteration. CONCLUSIONS: We report a novel MKRN3 mutation (p.C340G) in a girl with CPP and her brother with early puberty. MKRN3 alterations should be suspected in all cases with familial CPP or early puberty, especially if male patients are also involved or the precocious puberty trend does not follow the usually observed mother-to-daughter inheritance.

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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 [76]

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Authors: Settas, N., Dacou-Voutetakis, C., Karantza, M., Kanaka-Gantenbein, C., Chrousos, G. P., & Voutetakis, A.
Affiliations: National and Kapodistrian University of Athens (GR)
Division of Endocrinology, Metabolism, and Diabetes, First Department of Pediatrics, Medical School, National and Kapodistrian University of Athens, “Aghia Sophia” Children's Hospital, GR-11527 Athens, Greece
Corresponding author: Voutetakis, Antonis
ORCID: Settas, Nikolaos
Chrousos, George P.
Voutetakis, Antonis
Venue: The Journal of Clinical Endocrinology & Metabolism
Publisher: The Endocrine Society
Published: 2014-04-01
Volume: 99
Issue: 4
Pages: E647-E651
ISSN: 0021-972X (ISSN-L)
1945-7197
DOI: 10.1210/jc.2013-4084
OpenAlex: W2082739380
Cited by: 80
References: 20
Citations by year: 2026: 1 · 2025: 2 · 2024: 1 · 2023: 4 · 2022: 5 · 2021: 5 · 2020: 5 · 2019: 8 · 2018: 9 · 2017: 10 · 2016: 17 · 2015: 10 · 2014: 3
FWCI: 16.15
Type: journal article
Language: en
Open access: closed
Locations: The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
PubMed (publishedVersion)
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, precocious puberty, paternal imprinting, imprinted genes, novel missense mutation, hypothalamic-pituitary-gonadal axis
MeSH terms: Child, Female, Humans, Male, Models, Molecular, Puberty, Precocious, Ribonucleoproteins, Protein Structure, Secondary, Mutation, Missense, Polymorphism, Single Nucleotide, Siblings, Ubiquitin-Protein Ligases

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Central precocious puberty in a girl and early puberty in her brother caused by a novel mutation in the MKRN3 gene

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