Makorin RING finger protein 3 and central precocious puberty.
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ABSTRACT:
SUBMITTER: Maione L
PROVIDER: S-EPMC7518508 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:CONTEXT:Loss-of-function mutations in makorin ring finger 3 (MKRN3), an imprinted gene located on the long arm of chromosome 15, have been recognized recently as a cause of familial central precocious puberty (CPP) in humans. MKRN3 has a potential inhibitory effect on GnRH secretion. OBJECTIVES:The objective of the study was to investigate potential MKRN3 sequence variations as well as copy number and methylation abnormalities of the 15q11 locus in patients with apparently sporadic CPP. SETTING AND PARTICIPANTS:We studied 215 unrelated children (207 girls and eight boys) from three university medical centers with a diagnosis of CPP. All but two of these patients (213 cases) reported no family history of premature sexual development. First-degree relatives of patients with identified MKRN3 variants were included for genetic analysis. MAIN OUTCOME MEASURES:All 215 CPP patients were screened for MKRN3 mutations by automatic sequencing. Multiplex ligation-dependent probe amplification was performed in a partially overlapping cohort of 52 patients. RESULTS:We identified five novel heterozygous mutations in MKRN3 in eight unrelated girls with CPP. Four were frame shift mutations predicted to encode truncated proteins and one was a missense mutation, which was suggested to be deleterious by in silico analysis. All patients with MKRN3 mutations had classical features of CPP with a median age of onset at 6 years. Copy number and methylation abnormalities at the 15q11 locus were not detected in the patients tested for these abnormalities. Segregation analysis was possible in five of the eight girls with MKRN3 mutations; in all cases, the mutation was inherited on the paternal allele. CONCLUSIONS:We have identified novel inherited MKRN3 defects in children with apparently sporadic CPP, supporting a fundamental role of this peptide in the suppression of the reproductive axis.
| S-EPMC4037732 | biostudies-literature
Project description:Makorin ring finger protein 3 (MKRN3) is an important neuroendocrine player in the control of pubertal timing and upstream inhibitor of gonadotropin-releasing hormone secretion. In mice, expression of Mkrn3 in the hypothalamic arcuate and anteroventral periventricular nucleus is high early in life and declines before the onset of puberty. Therefore, we aimed to explore if the persistence of hypothalamic Mkrn3 expression peripubertally would result in delayed puberty. Female mice that received neonatal bilateral intracerebroventricular injections of a recombinant adeno-associated virus expressing Mkrn3 had delayed vaginal opening and first estrus compared with animals injected with control virus. Subsequent estrous cycles and fertility were normal. Interestingly, male mice treated similarly did not exhibit delayed puberty onset. Kiss1, Tac2, and Pdyn mRNA levels were increased in the mediobasal hypothalamus in females at postnatal day 28, whereas kisspeptin and neurokinin B protein levels in the arcuate nucleus were decreased, following Mkrn3 overexpression, compared to controls. Cumulatively, these data suggest that Mkrn3 may directly or indirectly target neuropeptides of Kiss1 neurons to degradation pathways. This mouse model suggests that MKRN3 may be a potential contributor to delayed onset of puberty, in addition to its well-established roles in central precocious puberty and the timing of menarche.
| S-EPMC10233297 | biostudies-literature
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.
| S-EPMC6472170 | biostudies-literature
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.
| S-EPMC6251202 | biostudies-literature
Project description:Metachromatic leucodystrophy (MLD) is a rare inherited lysosomal disorder caused by reduced activity of the enzyme arylsulfatase A with accumulation of sulfatides in the nervous system. We report a female child affected by MLD who developed central precocious puberty (CPP). This association has not been described so far. The proposita, after normal growth and psychomotor development, at age of 30 months presented with a rapidly progressive gait disturbance with frequent falls and with loss of acquired language skills. Magnetic resonance imaging showed leukoencephalopathy. Biochemical blood essays showed a 91% reduction in the arylsulfatase A activity and genetic analysis revealed compound heterozygous mutations of the Arylsulfatase A gene, enabling diagnosis of MLD. Subsequently, the patient had further rapid deterioration of motor and cognitive functions and developed drug-resistant epilepsy. At 4 years and 7 months of age bilateral thelarche occurred. Magnetic resonance imaging showed a small pituitary gland, extensive signal changes of the brain white matter, increased choline, decreased N-acetyl-aspartate and presence of lactate on 1HMR spectroscopy. Pelvic ultrasound demonstrated a slightly augmented uterine longitudinal diameter (42 mm). The gonadotropin-releasing hormone stimulation test revealed a pubertal LH peak of 12.9 UI/l. A diagnosis of CPP was made and treatment with gonadotropin-releasing hormone agonists was initiated, with good response. In conclusion, a CPP may occur in MLD as in other metabolic diseases with white matter involvement. We hypothesize that brain accumulation of sulfatides could have interfered with the complex network regulating with the hypothalamic-pituitary axis and thus triggering CPP in our patient.
| S-EPMC6117375 | biostudies-literature
Project description:PURPOSE:Single-nucleotide polymorphism (SNP) markers within LIN28B have been reported to be related to the timing of pubertal growth. However, no study has investigated the frequency of genetic markers in girls with precocious puberty (PP) or early puberty (EP). This study aimed to determine the frequency of putative genetic markers in girls with PP or EP. METHODS:Genomic DNAs were obtained from 77 and 109 girls that fulfilled the criteria for PP and EP, respectively. The controls in this study were 144 healthy volunteers between 20 and 30 years of age. The haplotypes were reconstructed using 11 SNPs of LIN28B, and haplotype association analysis was performed. The haplotype frequencies were compared. Differences in the clinical and laboratory parameters were analyzed according to the haplotype dosage. RESULTS:Eleven SNPs in LIN28B were all located in a block that was in linkage disequilibrium. The haplotype could be reconstructed using 2 representative SNPs, rs4946651 and rs369065. The AC haplotype was less frequently observed in the PP group than in the controls (0.069 vs. 0.144, P=0.010). The trend that girls with non-AC haplotypes tended to have earlier puberty onset (P=0.037) was illustrated even in the EP+PP patient group by Kaplan-Meier analysis. CONCLUSION:The results of the present study showed that non-AC haplotypes of LIN28B had a significant association with PP in girls.
| S-EPMC3488615 | biostudies-literature
Project description:A critical body weight is necessary for pubertal development, an effect mediated in part by leptin. The potential regulation by leptin of Makorin Ring Finger Protein 3 (MKRN3), in which loss-of-function mutations are the most common genetic cause of central precocious puberty, has not been previously explored. In mice, expression of Mkrn3 in the hypothalamic arcuate nucleus is high early in life and declines before the onset of puberty. Therefore, we aimed to explore if leptin contributes to the decrease in hypothalamic Mkrn3 mRNA levels observed in mice during pubertal development. We first used a leptin-deficient (ob/ob) mouse model. Mkrn3 mRNA levels in the mediobasal hypothalamus (MBH), which includes the arcuate nucleus, and in the preoptic area (POA), both showed a significant decrease with age from postnatal day (PND) 12 to PND30 in ob/ob mice in both males and females, similar to that observed in wild-type mice. To further explore the effects of leptin on Mkrn3 expression, we exposed prepubertal wild-type mice to high levels of leptin from age PND9-12, which did not result in any significant difference in Mkrn3 expression levels in either the MBH or POA. In summary, regulation of Mkrn3 expression by leptin was not observed in either the MBH or the POA, 2 hypothalamic sites important for pubertal maturation. These data suggest that the decline in Mkrn3 at the onset of puberty may occur independently of leptin and support our hypothesis that MKRN3 is a bona fide controller of puberty initiation.
| S-EPMC7304661 | biostudies-literature
Project description:The poly(A)-binding protein (PABP), a key component of different ribonucleoprotein complexes, plays a crucial role in the control of mRNA translation rates, stability, and subcellular targeting. In this study we identify RING zinc finger protein Makorin 1 (MKRN1), a bona fide RNA-binding protein, as a binding partner of PABP that interacts with PABP in an RNA-independent manner. In rat brain, a so far uncharacterized short MKRN1 isoform, MKRN1-short, predominates and is detected in forebrain nerve cells. In neuronal dendrites, MKRN1-short co-localizes with PABP in granule-like structures, which are morphological correlates of sites of mRNA metabolism. Moreover, in primary rat neurons MKRN1-short associates with dendritically localized mRNAs. When tethered to a reporter mRNA, MKRN1-short significantly enhances reporter protein synthesis. Furthermore, after induction of synaptic plasticity via electrical stimulation of the perforant path in vivo, MKRN1-short specifically accumulates in the activated dendritic lamina, the middle molecular layer of the hippocampal dentate gyrus. Collectively, these data indicate that in mammalian neurons MKRN1-short interacts with PABP to locally control the translation of dendritic mRNAs at synapses.
| S-EPMC3256852 | biostudies-literature
Project description:BackgroundPubertal timing is a strongly heritable trait, but no single puberty gene has been identified. Thus, the genetic background of idiopathic central precocious puberty (ICPP) is poorly understood. Overall, the genetic modulation of pubertal onset most likely arises from the additive effect of multiple genes, but also monogenic causes of ICPP probably exist, as cases of familial ICPP have been reported. Mutations in KISS1 and KISSR, coding for kisspeptin and its receptor, involved in GnRH secretion and puberty onset, have been suggested causative for monogenic ICPP. Variation in LIN28B was associated with timing of puberty in genome-wide association (GWA) studies. LIN28B is a human ortholog of the gene that controls, through microRNAs, developmental timing in C. elegans. In addition, Lin28a transgenic mice manifest the puberty phenotypes identified in the human GWAS. Thus, both LIN28B and LIN28A may have a role in pubertal development and are good candidate genes for monogenic ICPP.MethodsThirty girls with ICPP were included in the study. ICPP was defined by pubertal onset before 8 yrs of age, and a pubertal LH response to GnRH testing. The coding regions of LIN28B, LIN28A, KISS1, and KISS1R were sequenced. The missense change in LIN28B was also screened in 132 control subjects.ResultsNo rare variants were detected in KISS1 or KISS1R in the 30 subjects with ICPP. In LIN28B, one missense change, His199Arg, was found in one subject with ICPP. However, this variant was also detected in one of the 132 controls. No variation in LIN28A was found.ConclusionsWe did not find any evidence that mutations in LIN28B or LIN28A would underlie ICPP. In addition, we confirmed that mutations in KISS1 and KISS1R are not a common cause for ICPP.
| S-EPMC3184284 | biostudies-literature
Project description:BACKGROUND:The onset of puberty is first detected as an increase in pulsatile secretion of gonadotropin-releasing hormone (GnRH). Early activation of the hypothalamic-pituitary-gonadal axis results in central precocious puberty. The timing of pubertal development is driven in part by genetic factors, but only a few, rare molecular defects associated with central precocious puberty have been identified. METHODS:We performed whole-exome sequencing in 40 members of 15 families with central precocious puberty. Candidate variants were confirmed with Sanger sequencing. We also performed quantitative real-time polymerase-chain-reaction assays to determine levels of messenger RNA (mRNA) in the hypothalami of mice at different ages. RESULTS:We identified four novel heterozygous mutations in MKRN3, the gene encoding makorin RING-finger protein 3, in 5 of the 15 families; both sexes were affected. The mutations included three frameshift mutations, predicted to encode truncated proteins, and one missense mutation, predicted to disrupt protein function. MKRN3 is a paternally expressed, imprinted gene located in the Prader-Willi syndrome critical region (chromosome 15q11-q13). All affected persons inherited the mutations from their fathers, a finding that indicates perfect segregation with the mode of inheritance expected for an imprinted gene. Levels of Mkrn3 mRNA were high in the arcuate nucleus of prepubertal mice, decreased immediately before puberty, and remained low after puberty. CONCLUSIONS:Deficiency of MKRN3 causes central precocious puberty in humans. (Funded by the National Institutes of Health and others.).
| S-EPMC3808195 | biostudies-literature