A missense mutation in MKRN3 in a Danish girl with central precocious puberty and her brother with early puberty

Känsäkoski, Johanna; Raivio, Taneli; Juul, Anders; Tommiska, Johanna

doi:10.1038/pr.2015.159

Cited by 36 publications

(24 citation statements)

References 15 publications

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“…Several studies have indicated that the reactivation of GnRH secretion with pubertal initiation may be associated with downregulation of the Makorin ring finger 3 gene ( MKRN3 )[2, 3, 6–8]. Kisspeptin, a GnRH agonist encoded by the KISS1 gene, also plays an essential role in regulating the timing of puberty[9–11].…”

Section: Introductionmentioning

confidence: 99%

DNA Methylation Patterns in the Hypothalamus of Female Pubertal Goats

Yang

et al. 2016

PLoS ONE

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Female pubertal development is tightly controlled by complex mechanisms, including neuroendocrine and epigenetic regulatory pathways. Specific gene expression patterns can be influenced by DNA methylation changes in the hypothalamus, which can in turn regulate timing of puberty onset. In order to understand the relationship between DNA methylation changes and gene expression patterns in the hypothalamus of pubertal goats, whole-genome bisulfite sequencing and RNA-sequencing analyses were carried out. There was a decline in DNA methylation levels in the hypothalamus during puberty and 268 differentially methylated regions (DMR) in the genome, with differential patterns in different gene regions. There were 1049 genes identified with distinct expression patterns. High levels of DNA methylation were detected in promoters, introns and 3′-untranslated regions (UTRs). Levels of methylation decreased gradually from promoters to 5′-UTRs and increased from 5′-UTRs to introns. Methylation density analysis demonstrated that methylation level variation was consistent with the density in the promoter, exon, intron, 5′-UTRs and 3′-UTRs. Analyses of CpG island (CGI) sites showed that the enriched gene contents were gene bodies, intergenic regions and introns, and these CGI sites were hypermethylated. Our study demonstrated that DNA methylation changes may influence gene expression profiles in the hypothalamus of goats during the onset of puberty, which may provide new insights into the mechanisms involved in pubertal onset.

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Section: Introductionmentioning

confidence: 99%

DNA Methylation Patterns in the Hypothalamus of Female Pubertal Goats

Yang

et al. 2016

PLoS ONE

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“…Currently, MKRN3 mutations represent the most frequent genetic cause of iCPP since being identified in 2013 [2]. To the best of our knowledge, our comprehensive review revealed that 23 different loss-of-function mutations (12 frameshift and 11 missense mutations) of MKRN3 have been described in 58 patients (48 females, 10 males) with iCPP from 35 different families (Table 2) [9 ,16,17,19,20,21,22,23]. Mutations in MKRN3 were identified as the cause of premature sexual development in one-third of familial iCPP cases [9].…”

Section: Discussionmentioning

confidence: 99%

Two Frameshift Mutations in MKRN3 in Turkish Patients with Familial Central Precocious Puberty

et al. 2016

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Background: Little is known about the genetic causes responsible for idiopathic central precocious puberty (iCPP). More recently, described loss-of-function mutations in the makorin ring finger protein 3 (MKRN3) gene have been demonstrated to be involved in the pathogenesis of familial iCPP. Aim: The objective of this study was to investigate the potential role of MKRN3 in patients with familial iCPP. Methods: We investigated potential sequence variations in the maternal imprinted MKRN3 gene using Next Generation Sequencing (NGS) analysis in 31 participants from 2 families (6 participants were diagnosed with familial iCPP on the basis of clinical and hormonal findings). Six patients diagnosed with familial iCPP and their unaffected first- and second-degree relatives, including their grandparents, were screened for MKRN3 gene variants. Results: Two heterozygous frameshift mutations (c.441_441delG, p.H148Tfs*23 and c803_803delAT, p.M268Vfs*23) were described in the MKRN3 gene in 2 probands with familial iCPP and in some of their family members. These frameshift mutations create a premature stop codon and result in a truncated protein. Conclusions: Our report further expands the MKRN3 gene mutation spectrum in patients with familial iCPP. Screening for potential MKRN3 variants should be performed in patients with familial iCPP as well as in patients with sporadic iCPP.

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“…This variant is located in a cytosine homopolymer between nucleotides 476 and 482 and is a potential hotspot [10,18]. There has been some evidence that girls with MKRN3 mutations begin puberty earlier than boys [18,20,34], but in the majority of the published series, the age of presentation of the male patients was absent or recorded as the age of diagnosis. Therefore, this could be a bias of data recollection, and more studies of phenotype/genotype correlations are needed.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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A missense mutation in MKRN3 in a Danish girl with central precocious puberty and her brother with early puberty

Cited by 36 publications

References 15 publications

DNA Methylation Patterns in the Hypothalamus of Female Pubertal Goats

DNA Methylation Patterns in the Hypothalamus of Female Pubertal Goats

Two Frameshift Mutations in MKRN3 in Turkish Patients with Familial Central Precocious Puberty

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

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