Accelerated passage of gene-modified monkeys by hormone-induced precocious puberty.
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ABSTRACT:
SUBMITTER: Liu Z
PROVIDER: S-EPMC8310752 | biostudies-literature | 2021 Jul
REPOSITORIES: biostudies-literature
Publications
Accelerated passage of gene-modified monkeys by hormone-induced precocious puberty.
Liu Zhen Z Li Kui K Cai Yijun Y Liu Qiming Q Zhang Tikui T Lu Yong Y Nie Yanhong Y Wang Yan Y Yan Zhiguang Z Qu Yinwei Y Li Yuzhuo Y Wang Zhanyang Z Xiong Zhi-Qi ZQ Sun Qiang Q
National science review 20210504 7
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Project description:To evaluate the epigenetic status in sperm from the precocious monkeys, whole genome and single-base resolution maps of 5- methylcytosine (mC) analysis was performed by bisulfite-sequencing (BS-Seq) at an average depth of 15.4-fold per strand in DNA sample from the sperm of a naturally-matured monkey (#2) and 13.6-fold from a sexual precocious monkey (#49). Around 70% of all cytosine in genome were covered at least five times in each sample. We analyzed the average methylation levels and density of cytosinein two samples and found that there was no significant difference between the hormone-treated group and control group.
2021-03-02 | GSE167929 | GEO
Project description:Accelerated passage of gene-modified monkeys by hormone-induced precocious puberty
| PRJNA705598 | ENA
Project description:Central precocious puberty (CPP) is associated with adverse health outcomes in females; however, CPP pathogenesis remains unclear. In this study, we investigated the association of 20 single nucleotide polymorphisms (SNPs) in eight genes with CPP risk and hormone levels. A case-control study on 247 and 243 girls with and without CPP, respectively, was conducted at Kunming Children's Hospital, China, from September 2019 to August 2020. The genotype of the SNPs and their haplotypes were identified. Additionally, the effects of the polymorphisms on hormone levels were investigated. Three variants (rs10159082, rs7538038, and rs5780218) in KISS1 and two variants (rs7895833 and rs3758391) in SIRT1 were related to an increased CPP risk (odds ratio (OR) = 1.524, 1.507, 1.409, 1.348, and 1.737; 95% confidence interval (CI) = 1.176-1.974, 1.152-1.970, 1.089-1.824, 1.023-1.777, and 1.242-2.430, respectively). Rs3740051in SIRT1 and rs1544410 in VDR reduced CPP risk (OR = 0.689, 0.464; 95% CI, 0.511-0.928, 0.232-0.925, respectively). Rs1544410, rs7975232, and rs731236 in VDR were negatively correlated with peak follicle-stimulating hormone (FSH; β = -2.181; P=0.045), basal FSH (β = -0.391; P=0.010), and insulin-like growth factor (β = -50.360; P=0.041) levels, respectively. KISS1, SIRT1, and VDR variants were associated with CPP susceptibility, and VDR SNPs influenced hormonal levels in Chinese females with CPP. In particular, VDR polymorphism rs1544410 was associated with both CPP risk and GnRH-stimulated peak FSH levels. Further functional research and large-scale genetic studies of these loci and genes are required to confirm our findings.
| S-EPMC9420594 | biostudies-literature
Project description:BackgroundMakorin ring finger protein 3 gene (MKRN3) gene mutation is the most common genetic cause of central precocious puberty (CPP) in children. Due to the lack of ideal MKRN3-modified animal model (MKRN3-modified mice enter puberty only 4-5 days earlier than normal mice), the related research is limited.MethodsTherefore, the MKRN3-modified rabbit was developed using CRISPR (clustered regularly interspaced short palindromic repeats) gene editing technology. The genotype identification and phenotype evaluation of MKRN3-modified rabbits were carried out.ResultsThe first estrus of MKRN3-modified female rabbits was observed ~27 days earlier than that of wild-type female rabbits, with a typical CPP phenotype. This study found increased gonadotropin releasing hormone (GnRH) and decreased gonadotropin inhibiting hormone (GnIH) in the hypothalamus of the CPP rabbit model with MKRN3 gene mutation. Although this study failed to fully clarify the pathogenesis of CPP caused by MKRN3 mutation, it found some differentially expressed genes and potential pathways through transcriptome sequencing.ConclusionsThis study established a novel CPP model: paternal MKRN3 gene-modified rabbit. It is hoped that the establishment of this model will help researchers better understand, treat, and prevent CPP in the future.
| S-EPMC11904109 | biostudies-literature
Project description:PurposePrecocious puberty refers to the development of secondary sex characteristics before ages 8 and 9 years in girls and boys, respectively. Central precocious puberty (CPP) is caused by premature activation of the hypothalamus-pituitary-gonadal (HPG) axis and causes thelarche in girls before the age of 8. A gonadotropin-releasing hormone (GnRH) stimulation test is the standard diagnostic modality for diagnosing CPP. However, the test cannot always be used for screening because it is expensive and time-consuming. This study aimed to find alternative reliable screening parameters to identify HPG axis activation in girls <8 years old (CPP) and for girls 8-9 years old (early puberty, EP).MethodsFrom January 2013 to June 2015, medical records from 196 girls younger than 9 years old with onset of breast development were reviewed, including 126 girls who had a bone age (BA) 1 year above their chronological age. All patients underwent a GnRH stimulation test, and 117 underwent pelvic sonography. The girls were divided into 4 groups based on age and whether the GnRH stimulation test showed evidence of central puberty. Subanalyses were also conducted within each group based on peak luteinizing hormone (LH) level quartiles.ResultsBasal serum LH level was the most sensitive marker for screening CPP and EP. The cutoff values were 0.245 IU/L for CPP under 8 years old (P=0.049, area under the curve [AUC]=0.764, 88% sensitivity, 48% specificity) and 0.275 IU/L for EP between 8-9 years old (P=0.005, AUC=0.813, 79% sensitivity, 77% specificity). Peak LH level decreased as BMI z-score among subgroups increased when there was no difference in BA; however, higher BA eliminated this effect.ConclusionBasal serum LH level is a useful screening parameter for diagnosing CPP and EP in girls. Peak LH levels were lower with increasing BMI z-score, although older BA eliminated this effect.
| S-EPMC6790867 | biostudies-literature
Project description:Pubertal onset is known to result from reactivation of the hypothalamic-pituitary-gonadal (HPG) axis, which is controlled by complex interactions of genetic and nongenetic factors. Most cases of precocious puberty (PP) are diagnosed as central PP (CPP), defined as premature activation of the HPG axis. The cause of CPP in most girls is not identifiable and, thus, referred to as idiopathic CPP (ICPP), whereas boys are more likely to have an organic lesion in the brain. ICPP has a genetic background, as supported by studies showing that maternal age at menarche is associated with pubertal timing in their offspring. A gain of expression in the kisspeptin gene (KISS1), gain-of-function mutation in the kisspeptin receptor gene (KISS1R), loss-of-function mutation in makorin ring finger protein 3 (MKRN3), and loss-of-function mutations in the delta-like homolog 1 gene (DLK1) have been associated with ICPP. Other genes, such as gamma-aminobutyric acid receptor subunit alpha-1 (GABRA1), lin-28 homolog B (LIN28B), neuropeptide Y (NPYR), tachykinin 3 (TAC3), and tachykinin receptor 3 (TACR3), have been implicated in the progression of ICPP, although their relationships require elucidation. Environmental and socioeconomic factors may also be correlated with ICPP. In the progression of CPP, epigenetic factors such as DNA methylation, histone posttranslational modifications, and noncoding ribonucleic acids may mediate the relationship between genetic and environmental factors. CPP is correlated with short- and long-term adverse health outcomes, which forms the rationale for research focusing on understanding its genetic and nongenetic factors.
| S-EPMC8990949 | biostudies-literature
Project description:ObjectiveGonadotropin-releasing hormone agonist (GnRHa) treatment improves the potential for gaining height in patients with central precocious puberty (CPP). However, most studies have focused on girls because CPP in boys is relatively rare. Therefore, we aimed to determine the effect of GnRHa treatment on auxological outcomes in boys with CPP.MethodsEighty-five boys with CPP were treated with leuprolide or triptorelin acetate 3.75 mg over 2 years. Anthropometry, bone age, sexual maturity rating, and predicted adult height (PAH) were assessed every 6 months. Furthermore, 20 boys were followed up after treatment discontinuation until achievement of the final adult height (FAH).ResultsThe mean chronological age (CA) and bone age (BA) of the patients with CPP at treatment initiation were 9.5 ± 0.5 years and 11.7 ± 0.9 years, respectively. The mean duration of treatment was 2.87 ± 0.63 years. The PAH at treatment initiation was 172.1 cm (-0.23 ± 1.05 PAH standard deviation score). The PAH at treatment discontinuation (176.2 ± 6.6 cm) was significantly higher than the pretreatment PAH. In addition, the mean final adult height in the 20 boys who were followed up after discontinuation of treatment was 173.4 ± 5.8 cm, which was significantly higher than the initial PAH (170.1 ± 4.5 cm; p = 0.006). In multivariate analysis, the height gain (the difference between the FAH and PAH at treatment initiation) significantly correlated with the target height.ConclusionLong-term GnRHa treatment significantly improved the growth potential and FAH in boys with CPP.
| S-EPMC7728242 | biostudies-literature
Project description:BackgroundThe 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.MethodsWe 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.ResultsWe 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.ConclusionsDeficiency of MKRN3 causes central precocious puberty in humans. (Funded by the National Institutes of Health and others.).
| S-EPMC3808195 | biostudies-literature
Project description:BackgroundPuberty can be considered the end point of a maturation process which is defined by the dynamic interactions of genes and environmental factors during prenatal and postnatal development. Kisspeptin/G protein-coupled receptor-54, is as an essential gatekeeper and regulator of GnRH neurons, and a key factor in initiation of puberty. Loss and gain of functional mutations in the GPR54 gene are associated with hypogonadotropic hypogonadism and precocious puberty, respectively. This study was designed to evaluate variations of GPR54 in familial precocious puberty.MethodsGenomic DNA was extracted from peripheral whole blood of 25 subjects with familial precocious puberty. Coding exons 1-5 of the GPR54 gene were amplified by polymerase chain reaction (PCR) and the PCR products were purified and sequenced. DNA sequences were compared to the human GenBank GPR54 sequence using Sequencher sequence alignment software.ResultsWe detected three different Single Nucleotide Polymorphisms (SNPs) in GPR54: rs10407968 (24A > T) in 13 subjects (52%); rs3050132 (1091 T > A) in 16 subjects (64%), and a novel polymorphism (492C > G) in one subject (4%), while three subjects (12%) had no SNPs. No mutations were found in the GPR54 gene.ConclusionsRegarding the presence of SNPs in 88% of the subjects in this study, it is likely a relationship exists between the SNPs of the GPR54 gene and familial precocious puberty. Further research is needed to investigate this possibility, and potential functional effects of these polymorphisms.
| S-EPMC6329138 | biostudies-literature
Project description:OBJECTIVE:Gonadotropin-releasing hormone agonists (GnRHa) are the treatment of choice for central precocious puberty (CPP) and have been widely used for several decades. We determined the effect of GnRHa treatment on the auxological outcomes of girls with idiopathic CPP. METHODS:This study included 84 girls treated monthly with depot leuprolide acetate who had reached adult height. We compared their final adult height (FAH) with their initial predicted adult height (PAH). We performed a multivariate analysis of the factors associated with FAH on all girls diagnosed with CPP. RESULTS:We performed the final evaluations at a mean age of 14.1 ± 0.8 years after a mean treatment duration of 2.98 ± 0.73 years (ranging from 1.5-4.8 years). Menarche had occurred at 12.6 ± 0.6 years of age, which was 16.5 ± 6.1 months after discontinuation of GnRHa therapy. Mean FAH was 160.1 ± 5.0 cm, which was significantly higher than the initial PAH (156.1 ± 5.7 cm; P < 0.001). To investigate whether growth outcomes were influenced by the age at initial treatment, we divided all patients into two groups, those treated between 6 and 8 years (n = 23) and those treated after 8 years (n = 61); no significant differences were observed in FAH between the two groups. FAH was significantly and positively correlated with the height standard deviation score (SDS) at the end of treatment and with the target height, whereas the difference between bone age and chronological age at the start and end of treatment was negatively correlated with FAH. CONCLUSION:FAH was significantly higher than the initial PAH in girls with CPP who were treated with GnRHa. Also, GnRHa treatment was still effective even after 8 years of age in girls with CPP.
| S-EPMC6104939 | biostudies-literature