What controls the timing of puberty? An update on progress from genetic investigation

Gajdos, Zofia K. Z.; Hirschhorn, Joel N.; Palmert, Mark R.

doi:10.1097/med.0b013e328320253c

Cited by 83 publications

(45 citation statements)

References 93 publications

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“…It is also possible that the heterozygous mutations in GNRH1 do not contribute to the pathogenesis of nIHH and that only the homozygous frameshift mutation is causal. However, there is clear precedent for association of nIHH/KS with heterozygous mutations in FGF8 and PROK2, which also encode secreted ligands (9,10,14,15). Another possibility is that heterozygous GNRH1 mutations act in conjunction with mutations in other genes to cause nIHH, a mechanism that has been observed for several other nIHH/KS genes (15,(38)(39)(40).…”

Section: Discussionmentioning

confidence: 99%

GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism

Chan

Guillebon

Lang‐Muritano

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

180

138

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Idiopathic hypogonadotropic hypogonadism (IHH) is a condition characterized by failure to undergo puberty in the setting of low sex steroids and low gonadotropins. IHH is due to abnormal secretion or action of the master reproductive hormone gonadotropin-releasing hormone (GnRH). Several genes have been found to be mutated in patients with IHH, yet to date no mutations have been identified in the most obvious candidate gene, GNRH1 itself, which encodes the preprohormone that is ultimately processed to produce GnRH. We screened DNA from 310 patients with normosmic IHH (nIHH) and 192 healthy control subjects for sequence changes in GNRH1. In 1 patient with severe congenital nIHH (with micropenis, bilateral cryptorchidism, and absent puberty), a homozygous frameshift mutation that is predicted to disrupt the 3 C-terminal amino acids of the GnRH decapeptide and to produce a premature stop codon was identified. Heterozygous variants not seen in controls were identified in 4 patients with nIHH: 1 nonsynonymous missense mutation in the eighth amino acid of the GnRH decapeptide, 1 nonsense mutation that causes premature termination within the GnRH-associated peptide (GAP), which lies C-terminal to the GnRH decapeptide within the GnRH precursor, and 2 sequence variants that cause nonsynonymous amino-acid substitutions in the signal peptide and in GnRH-associated peptide. Our results establish mutations in GNRH1 as a genetic cause of nIHH.GnRH ͉ luteinizing hormone-releasing hormone ͉ LHRH

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Section: Discussionmentioning

confidence: 99%

GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism

Chan

Guillebon

Lang‐Muritano

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

180

138

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“…Pubertal timing is influenced by complex interactions of genetic, nutritional, environmental and socioeconomic factors [2,3]. Compelling evidence supporting genetic effects on pubertal timing has mainly been provided by population-based studies [4].…”

Section: Introductionmentioning

confidence: 99%

New Causes of Central Precocious Puberty: The Role of Genetic Factors

2014

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A pivotal event in the onset of puberty in humans is the reemergence of the pulsatile release of the gonadotropin-releasing hormone (GnRH) from hypothalamic neurons. Pathways governing GnRH ontogeny and physiology have been discovered by studying animal models and humans with reproductive disorders. Recent human studies implicated the activation of kisspeptin and its cognate receptor (KISS1/KISS1R) and the inactivation of MKRN3 in the premature reactivation of GnRH secretion, causing central precocious puberty (CPP). MKRN3, an imprinted gene located on the long arm of chromosome 15, encodes makorin ring finger protein 3, which is involved in ubiquitination and cell signaling. The MKRN3 protein is derived only from RNA transcribed from the paternally inherited copy of the gene due to maternal imprinting. Currently, MKRN3 defects represent the most frequent known genetic cause of familial CPP. In this review, we explored the clinical, hormonal and genetic aspects of children with sporadic or familial CPP caused by mutations in the kisspeptin and MKRN3 systems, essential genetic factors for pubertal timing.

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“…With this approach only genes that were known to be associated with height could be tested. Studies aimed at detecting genes associated with age at menarche have not yielded positive results so far [9]. …”

Section: Hypothetical Pathophysiology Of Issmentioning

confidence: 99%

Definition and Subcategorization of Idiopathic Short Stature: Between Consensus and Controversy

Wit¹

2011

Horm Res Paediatr

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Although various expert and consensus meetings have been held, there remains uncertainty about the definition of idiopathic short stature (ISS) and its subgroups. In this short review, the hypothetical pathophysiology, diagnosis and subcategorization of ISS are discussed. ISS in childhood may be the result of a combination of variants of three groups of genes: (1) single genes (or combinations of a few single genes) of which mutations, deletions or duplications are associated with a relatively large negative effect on height; (2) genes of which relatively frequently occurring polymorphisms are associated with a small negative effect on height; and (3) genes associated with delayed maturation of the epiphyseal plate. Differentiation between ISS and short children born small for gestational age and those with dysmorphic syndromes, systemic diseases or growth hormone deficiency and resistance can be difficult. Subcategorization based on distance to target height and onset of puberty is arbitrary, but useful.

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What controls the timing of puberty? An update on progress from genetic investigation

Abstract: This review provides an update of the genes implicated in disorders of puberty, discusses genes and pathways that may be involved in the timing of normal puberty, and suggests additional avenues of investigation to identify genetic regulators of puberty in the general population.

Cited by 83 publications

References 93 publications

GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism

GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism

New Causes of Central Precocious Puberty: The Role of Genetic Factors

Definition and Subcategorization of Idiopathic Short Stature: Between Consensus and Controversy

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