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

Simon, Dominique; Ba, Ibrahima; Mekhail, Nancy; Écosse, Emmanuel; Paulsen, Anne; Zénaty, Delphine; Houang, Muriel; Perelroizen, M. Jesuran; Filippo, Gianpaolo De; Salerno, Mariacarolina; Simonin, G.; Reynaud, Rachel; Carel, Jean‐Claude; Léger, Juliane; Roux, Nicolas de

doi:10.1530/eje-15-0488

Cited by 95 publications

(111 citation statements)

References 19 publications

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“…On the other hand, expression of excitatory genes such as KiSS1, Tac are elevated and initiate sexual maturation [23]. Abreu et al [24-26]. reported that a loss-of-function mutation of makorin ring finger protein 3 (MKRN3) is a common cause of familial central precocious puberty; this implicates that MKRN3 as a key repressor of puberty control as well as a new pathway of puberty regulation.…”

Section: Discussionmentioning

confidence: 99%

Enhanced at Puberty-1 (Eap1) Expression Critically Regulates the Onset of Puberty Independent of Hypothalamic Kiss1 Expression

Пин

2017

Cell Physiol Biochem

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Background/Aims: Enhance at puberty-1 (Eap1) is an intronless gene that regulates the onset of puberty through a network of hypothalamic genes. However, precise mechanistic events essential for Eap1-regulation of puberty have not been fully elucidated. Eap1 is thought to promote the initiation of puberty through regulation of the hypothalamic metastasis-suppressor KiSS1. We aim to investigate this hypothesis by genetically perturbing Eap1 through RNA interference in vivo. Methods: We first engineered and optimized four sets of shRNAs that target rat Eap1 mRNA as well as one negative control shRNA. After generating lentiviral (LV) particles, we examined the suppression of Eap1 in NRK-54E cell line to select the most efficient one. Sequencelly, LV-Eap1-shRNA or controls including LV-eGFP and saline were intraventricular microinjected into 21-day-old rats. Rats were raised in appropriate conditions and we examined the time of vaginal opening, ovary physiology as well as hypothalamic puberty-regulatory genes at three developmental stages: juvenile (postnatal day PND25), early puberty (PND35), adult (PND42). Results: Hypothalamic suppression of Eap1 delayed the onset of rat vaginal opening. Hematoxylin and eosin (H&E) staining revealed a significant reduction of corpus luteum (CL) at PND35, but at PND42 CL levels were normal relative to control. In conjunction with differences in phenotype and ovary morphology, GnRH expression and transcripts were also reduced at PND25 and PND35, while their levels were similar to control at PND42. KiSS1 mRNA and protein levels were not significantly different at all three developmental stages. Conclusion: Eap1 expression critically regulates puberty as well as GnRH expression. However, Eap1-regulation of puberty may not necessitate KiSS1/GPR54 signaling.

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Section: Discussionmentioning

confidence: 99%

Enhanced at Puberty-1 (Eap1) Expression Critically Regulates the Onset of Puberty Independent of Hypothalamic Kiss1 Expression

Пин

2017

Cell Physiol Biochem

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“…Other cases of central precocious puberty are associated with mutations in the imprinted MKRN3 gene encoding the makorin ring finger protein 3, a gene located in the imprinted Prader Willi syndrome region (Settas et al, 2014;Simon et al, 2015;Fig. 4).…”

Section: Genetic Factors Associated With Precocious Puberty In Humansmentioning

confidence: 99%

“…4). Data from Human cases and animal models suggests that MKRN3 plays an inhibitory role in the reproductive axis and may represent a new pathway in pubertal regulation (Ong et al, 2009;Simon et al, 2015). MKNR3 is expressed ubiquitously.…”

Section: Genetic Factors Associated With Precocious Puberty In Humansmentioning

confidence: 99%

The timing of puberty (oocyte quality and management)

Duittoz¹,

Tillet²,

Bourhis³

et al. 2016

Anim Reprod

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This review aims at giving an overview on the physiological events leading to puberty onset in mammals and more specifically in cattle. Puberty is an important developmental milestone in mammals involving numerous changes in various physiological regulations and behaviors. It is a physiological unique event integrating several important central regulations at the crossroad of adaptation to environment: reproductive axis, feeding behavior and nutritional controls, growth, seasonal rhythm and stress. Puberty onset is also an important economic parameter in replacement heifer program and in genomic selection (genomic bulls). The quest for advanced puberty onset should be carefully balanced by its impact on physiological parameters of the animal and its offspring. Thus one has to carefully consider each step leading to puberty onset and set up a strategy that will lead to early puberty without being detrimental in the long term. In this review, major contributions in the understanding of puberty process obtained in rodents, primates and farm animals such as sheep and cattle are discussed. In the first part we will detail the endocrine events leading to puberty onset with a special focus on the regulation of GnRH secretion. In the second part we will describe the neural mechanisms involved in silencing and reactivating the GnRH neuronal network. These central mechanisms are at the crossroad of the integration of environmental factors such as the nutritional status, the stress and the photoperiod that will be discussed in the third part. In the fourth part, we will discuss the genetic determinants of puberty onset and more particularly in humans, where several pathologies are associated with puberty delay or advance and in cattle where several groups have now identified genomic regions or gene networks associated with puberty traits. Last but not least, in the last part we will focus on the embryologist point of view, how to get good oocytes for in vitro fertilization and embryo development from younger animals.

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“…Among those idiopathic cases, de Vries et al [15] described 27.5% familial cases, suggesting an autosomal dominant pattern with incomplete penetrance. So far, variants in 3 genes have been related with the etiology of ICPP, i.e., KISS1 [16] , KISS1R [17], and MKRN3 [2,10,18,19,20,21,22,23,24]. In KISS1 and KISS1R , the pathologic variants are gaining function.…”

Section: Introductionmentioning

confidence: 99%

“…In MKRN3 , there are loss-of-function mutations, and it is also important to point out that this gene is maternally imprinted, which means that the pathogenic variant is inherited from the father. Mutations in MKRN3 have been described in Brazilian [2,10], American [2,10], Korean [6], and European [10,18,19,20,21,22,23,24] populations. …”

Section: Introductionmentioning

confidence: 99%

Clinical Exome Sequencing Reveals <b><i>MKRN3</i></b> 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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Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty

Cited by 95 publications

References 19 publications

Enhanced at Puberty-1 (Eap1) Expression Critically Regulates the Onset of Puberty Independent of Hypothalamic Kiss1 Expression

Enhanced at Puberty-1 (Eap1) Expression Critically Regulates the Onset of Puberty Independent of Hypothalamic Kiss1 Expression

The timing of puberty (oocyte quality and management)

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

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