Mutational analysis of TAC3 and TACR3 genes in patients with idiopathic central pubertal disorders

Tusset, Cíntia; Noel, Sekoni D.; Trarbach, Ericka Barbosa; Silveira, Letícia Ferreira Gontijo; Jorge, Alexander A L; Brito, Vinícius Nahime; Cukier, Priscilla; Seminara, Stephanie B.; Mendonça, Berenice Bilharinho; Kaiser, Ursula B.; Latrônico, Ana Claudia

doi:10.1590/s0004-27302012000900008

Cited by 56 publications

(40 citation statements)

References 33 publications

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“…Moreover, very recent data demonstrated that polymorphisms in the 3′ UTR of KISS1 are associated to CPP and interfere with the conformation of the DNA sequence and potentially the RNA sequence of KISS1, further verifying a role of the KISS1/KISS1R in the abnormal initiation of puberty [29]. Furthermore, in 2012, Tusset et al [30] published a new variant of TAC3 in a girl with CPP, while no mutation in TACR3 was found in their population of 114 patients (107 girls/7 boys) with ICPP.…”

Section: Discussionmentioning

confidence: 99%

Absence of GPR54 and TACR3 Mutations in Sporadic Cases of Idiopathic Central Precocious Puberty

et al. 2014

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Background/Aims: Kisspeptin (KISS1)/GPR54 (KISSR) signaling complex and neurokinin B (NKB)/NKB receptor (TACR3) signaling have been proposed as an integral part of the network coordinating GnRH release. GPR54 (KISS1R) and TACR3 gene mutations have been described in cases of idiopathic hypogonadotrophic hypogonadism, while limited data exist on gain-of-function mutation in GPR54 (KISS1R) gene causing idiopathic central precocious puberty (ICPP). No data on TACR3 mutations in ICPP have been described so far. The aim of this study was to elucidate the possible impact of GPR54 (KISS1R) and TACR3 mutations in ICPP. Methods: PCR-amplified genomic DNA of 38 girls with ICPP was analyzed for GPR54 and TACR3 gene mutations. Results: No GPR54 or TACR3 mutations were found. The A/G coding sequence single nucleotide polymorphism (SNP) on the GPR54 gene (dbSNP ID: rs10407968) was found in 2 patients with ICPP. Conclusion: Our data indicate that GPR54 and TACR3 gene mutations are not a frequent cause of ICPP. The identified A/G synonymous SNP (dbSNP ID: rs10407968) located in exon 1 of the gene is not likely to have a pathogenic role in exon splicing and therefore in the premature initiation of puberty.

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Section: Discussionmentioning

confidence: 99%

Absence of GPR54 and TACR3 Mutations in Sporadic Cases of Idiopathic Central Precocious Puberty

et al. 2014

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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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“…A cohort of patients presenting with congenital hypogonadotrophic hypogonadism has been found to have inactivating mutations affecting the NKB ligand (TAC3) and its receptor (Tusset et al 2012). In a study looking at four such patients, intravenous infusion of kisspeptin-10 resulted in an increase in LH secretion from baseline (P < 0.0001).…”

Section: Kisspeptin In Patients With Nkb Signalling Deficienciesmentioning

confidence: 99%

Kisspeptin across the human lifespan:evidence from animal studies and beyond

Clarke

Dhillo

2016

Journal of Endocrinology

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Since its first description in 1996, the KISS1 gene and its peptide products, kisspeptins, have increasingly become recognised as key regulators of reproductive health. With kisspeptins acting as ligands for the kisspeptin receptor KISS1R (previously known as GPR54 or KPR54), recent work has consistently shown that administration of kisspeptin across a variety of species stimulates gonadotrophin release through influencing gonadotrophin-releasing hormone secretion. Evidence from both animal and human studies supports the finding that kisspeptins are crucial for ensuring healthy development, with knockout animal models, as well as proband genetic testing in human patients affected by abnormal pubertal development, corroborating the notion that a functional kisspeptin receptor is required for appropriate gonadotrophin secretion. Given the large body of evidence that exists surrounding the influence of kisspeptin in a variety of settings, this review summarises our physiological understanding of the role of these important peptides and their receptors, before proceeding to describe the varying role they play across the reproductive lifespan.

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Mutational analysis of TAC3 and TACR3 genes in patients with idiopathic central pubertal disorders

Cited by 56 publications

References 33 publications

Absence of GPR54 and TACR3 Mutations in Sporadic Cases of Idiopathic Central Precocious Puberty

Absence of GPR54 and TACR3 Mutations in Sporadic Cases of Idiopathic Central Precocious Puberty

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

Kisspeptin across the human lifespan:evidence from animal studies and beyond

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