Molecular analysis of the neuropeptide Y1 receptor gene in human idiopathic gonadotropin-dependent precocious puberty and isolated hypogonadotropic hypogonadism

Freitas, Karina Cocco Monteiro; Ryan, Ginny L.; Brito, Vinícius Nahime; Tao, Ya-Xiong; Costa, Elaine Maria Frade; Mendonca, Berenice B.; Segaloff, Deborah L.; Latrônico, Ana Claudia

doi:10.1016/j.fertnstert.2006.07.1519

Cited by 20 publications

(14 citation statements)

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“…Mutations in the Y1 subtype receptor for neuropeptide Y ( NPY ) could theoretically cause precocious puberty, as NPY is thought to be an inhibitor of pulsatile GnRH secretion. However, the only currently described mutation has not correlated well with an effect on function or with CPP [16]. Additional studies have investigated genes involved in hypothalamic hamartomas and have identified several with increased expression in patients with CPP [17].…”

Section: Etiologymentioning

confidence: 99%

Central Precocious Puberty: Update on Diagnosis and Treatment

2015

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Central precocious puberty (CPP) is characterized by the same biochemical and physical features as normally timed puberty but occurs at an abnormally early age. Most cases of CPP are seen in girls, in whom it is usually idiopathic. In contrast, ∼50 % of boys with CPP have an identifiable cause. The diagnosis of CPP relies on clinical, biochemical, and radiographic features. Untreated, CPP has the potential to result in early epiphyseal fusion and a significant compromise in adult height. Thus, the main goal of therapy is preservation of height potential. The gold-standard treatment for CPP is go-nadotropin-releasing hormone (GnRH) analogs (GnRHa). Numerous preparations with a range of delivery systems and durations of action are commercially available. While the outcomes of patients treated for CPP have generally been favorable, more research about the psychological aspects, optimal monitoring, and long-term effects of all forms of GnRHa treatment is needed. Several potential therapeutic alternatives to GnRHa exist and await additional investigation.

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Section: Etiologymentioning

confidence: 99%

Central Precocious Puberty: Update on Diagnosis and Treatment

2015

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“…Although these case reports expanded the genotype-phenotype correlations for the kisspeptin pathways, no other CPP cases with gain-of-function mutations in KISS1R or KISS1 have been reported, suggesting that these genetic abnormalities are very rare. Other candidate genes implicated in the regulatory mechanism of GnRH secretion have also been screened (GABRA1 , NPY-Y1R , LIN28B, TAC3 , TACR3, TTF1 and EAP1) , but no pathogenic variants were identified until recently [24,25,26,27,28]. …”

Section: Rare Gain-of-function Mutations In Kiss1 and Kiss1rmentioning

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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“…However, although an increasing number of genes have been implicated in congenital isolated hypogonadotropic hypogonadism and the Kallmann syndrome, 12,13 only a few, rare molecular defects have been identified in patients with central precocious puberty, and no strong association has been proved. 14–18 Only two mutations — one mutation in the gene encoding kiss-peptin-1 ( KISS1 ) and one in the gene encoding its receptor ( KISS1R ) — have been associated with central precocious puberty, despite screening of a relatively large cohort of patients for mutations in these genes, indicating that isolated mutations in KISS1 and KISS1R genes are uncommon causes of central precocious puberty. 19,20 We therefore sought to identify genetic causes of central precocious puberty by performing an exome sequence analysis in 15 families with central precocious puberty.…”

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confidence: 99%

Central Precocious Puberty Caused by Mutations in the Imprinted Gene MKRN3

et al. 2013

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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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Molecular analysis of the neuropeptide Y1 receptor gene in human idiopathic gonadotropin-dependent precocious puberty and isolated hypogonadotropic hypogonadism

Cited by 20 publications

References 38 publications

Central Precocious Puberty: Update on Diagnosis and Treatment

Central Precocious Puberty: Update on Diagnosis and Treatment

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

Central Precocious Puberty Caused by Mutations in the Imprinted Gene MKRN3

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