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Makorin RING finger protein 3 and central precocious puberty.

ABSTRACT: Makorin RING finger protein 3 (MKRN3) is a key inhibitor of the hypothalamic-pituitary-gonadal axis. Loss-of-function mutations in MKRN3 cause familial and sporadic central precocious puberty (CPP), while polymorphisms are associated with age at menarche. To date, 115 patients with CPP carrying MKRN3 mutations have been described, harboring 48 different genetic variants. The prevalence of MKRN3 mutations in genetically screened populations with CPP is estimated at 9.0%. Girls are more commonly and more seriously affected than boys. MKRN3 is expressed in humans and rodents in the central nervous system. Circulating levels in humans and hypothalamic expression in rodents decrease during pubertal progression. Although some MKRN3 regulators have been identified, the precise mechanism by which MKRN3 inhibits the hypothalamic-pituitary-gonadal axis remains elusive. The role of makorins in developmental physiology and organ differentiation and the role of maternal imprinting are discussed herein.

SUBMITTER: Maione L

PROVIDER: S-EPMC7518508 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Makorin RING finger protein 3 and central precocious puberty.

Maione Luigi L Naulé Lydie L Kaiser Ursula B UB

Current opinion in endocrine and metabolic research 20200826

Makorin RING finger protein 3 (MKRN3) is a key inhibitor of the hypothalamic-pituitary-gonadal axis. Loss-of-function mutations in MKRN3 cause familial and sporadic central precocious puberty (CPP), while polymorphisms are associated with age at menarche. To date, 115 patients with CPP carrying MKRN3 mutations have been described, harboring 48 different genetic variants. The prevalence of MKRN3 mutations in genetically screened populations with CPP is estimated at 9.0%. Girl ...[more]

PMID: 32984644

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Project description:Makorin ring finger proteins (MKRNs) are part the of ubiquitin-proteasome system; a complex system important for cell functions. Ubiquitin fate through proteolytic, non-proteolytic pathways varies, depending on covalent linkage between ubiquitin and protein substrates. Makorin ring finger protein 3 is an integral part of covalent linkage of ubiquitin to protein substrates. Similar to others imprinted genes, MKRN3 also evolve under positive selection; however, which codons are specifically selected in MKRN3 during evolution are needed to be explored. Different maximum-likelihood (ML) codon-based methodologies were used to ascertain positive selection signatures in 22 mammalian sequences of MKRN3 to probe an individual codon for positive selection signatures. By applying the HyPhy software package implemented in the Data Monkey Web Server and CODEML implemented in PAML, evolutionary analysis based on two Ml frameworks were conducted. The analysis was executed by comparing M1a against M2a, M7 against M8, and PAML models and 2∆Lnl (LRT) was resulted by likelihood logs. M1a contributed ω1 (dN/dS) with LRT value (∆Lnl) 12.01, and positive selection was found in M2a with ω3 = 2.23603. To further improve selection test, M8 was compared to M7 with 2∆Lnl (LRT) 30.17, and M8 showed positive selection with ω = 1.55759. The data were fit to M8 than M7, which suggests that M8 was the most significant model of selection. M8 was judged encouraging for this analysis and used to establish a positive selection of MKRN3 proteins. We found Gly312 as a positively selected amino acid in a zinc finger motif/Really Interesting New Gene (RING) finger motif; the former ones' region is involved in RNA binding and the later ones in ubiquitin ligase activity of the protein, vital for protein function. Selection analyses of MKRNs might advance the developments in unique approaches that could lead to genetic progress over the selection of superior individuals with the breeding values higher for certain traits as ancestries to get the next generation.

Project description:BackgroundRecent studies demonstrated that changes in DNA methylation (DNAm) and inactivation of two imprinted genes (MKRN3 and DLK1) alter the onset of female puberty. We aimed to investigate the association of DNAm profiling with the timing of human puberty analyzing the genome-wide DNAm patterns of peripheral blood leukocytes from ten female patients with central precocious puberty (CPP) and 33 healthy girls (15 pre- and 18 post-pubertal). For this purpose, we performed comparisons between the groups: pre- versus post-pubertal, CPP versus pre-pubertal, and CPP versus post-pubertal.ResultsAnalyzing the methylome changes associated with normal puberty, we identified 120 differentially methylated regions (DMRs) when comparing pre- and post-pubertal healthy girls. Most of these DMRs were hypermethylated in the pubertal group (99%) and located on the X chromosome (74%). Only one genomic region, containing the promoter of ZFP57, was hypomethylated in the pubertal group. ZFP57 is a transcriptional repressor required for both methylation and imprinting of multiple genomic loci. ZFP57 expression in the hypothalamus of female rhesus monkeys increased during peripubertal development, suggesting enhanced repression of downstream ZFP57 target genes. Fourteen other zinc finger (ZNF) genes were related to the hypermethylated DMRs at normal puberty. Analyzing the methylome changes associated with CPP, we demonstrated that the patients with CPP exhibited more hypermethylated CpG sites compared to both pre-pubertal (81%) and pubertal (89%) controls. Forty-eight ZNF genes were identified as having hypermethylated CpG sites in CPP.ConclusionMethylome profiling of girls at normal and precocious puberty revealed a widespread pattern of DNA hypermethylation, indicating that the pubertal process in humans is associated with specific changes in epigenetically driven regulatory control. Moreover, changes in methylation of several ZNF genes appear to be a distinct epigenetic modification underlying the initiation of human puberty.

Dataset Information

Makorin RING finger protein 3 and central precocious puberty.

Publications

Makorin RING finger protein 3 and central precocious puberty.

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