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

Leka-Emiri, Sofia; Louizou, Eirini; Kambouris, Marios; Chrousos, George P.; Roux, Nicolas de; Kanaka‐Gantenbein, Christina

doi:10.1159/000356913

Cited by 15 publications

(12 citation statements)

References 37 publications

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“…These findings are consistent with the data published by other groups [25,26,36,37,38,39]. Nonetheless, as we have sequenced the 4,813 OMIM genes, we are developing a further analysis to find any other genes implicated in the neuroregulation of puberty.…”

Section: Discussionsupporting

confidence: 91%

Clinical Exome Sequencing Reveals MKRN3 Pathogenic Variants in Familial and Nonfamilial Idiopathic Central Precocious Puberty

Ortiz-Cabrera¹,

Riveiro-Álvarez²,

López-Martínez³

et al. 2016

Horm Res Paediatr

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Background/Aims: Idiopathic central precocious puberty (ICPP) is the premature activation of the hypothalamic-pituitary-gonadal axis in the absence of organic disease. Up to now, just gain-of-function mutations of KISS1/KISS1R and loss-of-function mutations of the maternally imprinted gene MKRN3 are the known genetic causes of ICPP. Our intention is to evaluate variants present in genes related to the pubertal onset pathway that could act as disease-causing or predisposing variants. Methods: We studied the clinical exome of 20 patients diagnosed with ICPP using the Illumina platform. The bioinformatics analysis was performed using 2 different programs, and the variants were filtered according to a list of genes related to the gonadotropin-releasing hormone pathway. Results: In a “sporadic case,” we found a missense variant in MKRN3 NM_005664.3: c.203G>A, causing the protein change NP_005655.1:p.Arg68His, predicted as pathogenic by 2 informatics tools. The proband carrying this variant was diagnosed with ICPP at 7.75 years of age. We did not find any pathogenic variants in KISS1, KISS1R, LIN28, GNRH, GNRHR, TACR3, and TAC3. Conclusion:MKRN3 is the most frequent genetic cause of familial ICPP, so it is wise to screen for MKRN3 mutations in all patients with familial ICPP and in patients with an unclear paternal pubertal history.

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Section: Discussionsupporting

confidence: 91%

Clinical Exome Sequencing Reveals MKRN3 Pathogenic Variants in Familial and Nonfamilial Idiopathic Central Precocious Puberty

Ortiz-Cabrera¹,

Riveiro-Álvarez²,

López-Martínez³

et al. 2016

Horm Res Paediatr

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“…Many of the other identified loci are associated with BMI or energy homeostasis (Elks et al, 2010). While GPR54 (Teles et al, 2008;Leka-Emiri et al, 2014), TACR3 (Leka-Emiri et al, 2014) and LIN28B (SilveiraNeto et al, 2012) mutations seem to be very uncommon or absent in patients with precocious puberty (PP), inactivating mutations in the makorin ring finger protein 3 (MKRN3) gene, have been recently identified in 2-3% of sporadic PP and even more frequently in familial PP (Abreu et al, 2013;Macedo et al, 2014;Schreiner et al, 2014) and result in invalidation of a so far unidentified inhibitory neuroendocrine mechanism.…”

Section: Genetic Regulation Of Pubertal Timing and Environmental Intementioning

confidence: 99%

Developmental variations in environmental influences including endocrine disruptors on pubertal timing and neuroendocrine control: Revision of human observations and mechanistic insight from rodents

Parent

Franssen

Fudvoye

et al. 2015

Frontiers in Neuroendocrinology

160

140

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Puberty presents remarkable individual differences in timing reaching over 5 years in humans. We put emphasis on the two edges of the age distribution of pubertal signs in humans and point to an extended distribution towards earliness for initial pubertal stages and towards lateness for final pubertal stages. Such distortion of distribution is a recent phenomenon. This suggests changing environmental influences including the possible role of nutrition, stress and endocrine disruptors. Our ability to assess neuroendocrine effects and mechanisms is very limited in humans. Using the rodent as a model, we examine the impact of environmental factors on the individual variations in pubertal timing and the possible underlying mechanisms. The capacity of environmental factors to shape functioning of the neuroendocrine system is thought to be maximal during fetal and early postnatal life and possibly less important when approaching the time of onset of puberty.

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“…Mutations or SNPs associated with CPP were initially described in KISS1 and KISS1R (7,8,9), but mutations of these genes are very rare in sporadic cases of iCPP (10). A recent whole-exome sequencing study identified mutations in the makorin RING finger 3 (MKRN3) gene in 15 individuals with iCPP (11).…”

Section: Introductionmentioning

confidence: 99%

Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty

Simon

Mekhail

et al. 2016

European Journal of Endocrinology

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Context and objective: Idiopathic central precocious puberty (iCPP) is defined as early activation of the hypothalamicpituitary-gonadal axis in the absence of identifiable central lesions. Mutations of the makorin RING finger 3 (MKRN3) gene are associated with iCPP. We aimed to assess the frequency of MKRN3 mutations in iCPP and to compare the phenotypes of patients with and without MKRN3 mutations. Design: An observational study was carried out on patients recruited at pediatric hospitals in France and Italy. Forty-six index CPP cases were screened for mutations in the MKRN3 coding sequence: 28 index cases of familial cases and 18 cases did not report any familial history of CPP. The endocrine phenotype was compared between MKRN3 mutated and non-mutated patients. Results: MKRN3 mutations were identified in one sporadic and 13 familial cases. We identified five new heterozygous missense mutations predicted to be deleterious for protein function and two frameshift mutations, one new and the other recurrent, predicted to result in truncated proteins. Age at puberty onset varied very little among patients with MKRN3 mutations and puberty occurred earlier in these patients than in those without MKRN3 mutations (6.0 years (5.4-6.0) vs 7.0 years (6.0-7.0), PZ0.01). Conclusions: MKRN3 mutations are common in familial iCPP. MKRN3 is one of the gatekeepers of the postnatal activation of the gonadotropic axis.

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

Cited by 15 publications

References 37 publications

Clinical Exome Sequencing Reveals <b><i>MKRN3</i></b> Pathogenic Variants in Familial and Nonfamilial Idiopathic Central Precocious Puberty

Clinical Exome Sequencing Reveals <b><i>MKRN3</i></b> Pathogenic Variants in Familial and Nonfamilial Idiopathic Central Precocious Puberty

Developmental variations in environmental influences including endocrine disruptors on pubertal timing and neuroendocrine control: Revision of human observations and mechanistic insight from rodents

Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty

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