A GPR54-activating mutation in a patient with central precocious puberty.
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ABSTRACT:
SUBMITTER: Teles MG
PROVIDER: S-EPMC2859966 | biostudies-literature | 2008 Feb
REPOSITORIES: biostudies-literature
Publications
A GPR54-activating mutation in a patient with central precocious puberty.
Teles Milena Gurgel MG Bianco Suzy D C SD Brito Vinicius Nahime VN Trarbach Ericka B EB Kuohung Wendy W Xu Shuyun S Seminara Stephanie B SB Mendonca Berenice B BB Kaiser Ursula B UB Latronico Ana Claudia AC
The New England journal of medicine 20080201 7
Gonadotropin-dependent, or central, precocious puberty is caused by early maturation of the hypothalamic-pituitary-gonadal axis. In girls, this condition is most often idiopathic. Recently, a G protein-coupled receptor, GPR54, and its ligand, kisspeptin, were described as an excitatory neuroregulator system for the secretion of gonadotropin-releasing hormone (GnRH). In this study, we have identified an autosomal dominant GPR54 mutation--the substitution of proline for arginine at codon 386 (Arg3 ...[more]
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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:MKRN3, located on chromosome 15q11.2, encodes makorin ring-finger 3, which is an upstream suppressor of the hypothalamic-pituitary-gonadal axis. Mutation of this gene induces central precocious puberty (CPP). As MKRN3 is maternally imprinted, only the paternal allele is expressed. This is the first report of an 8-year-old Japanese girl with CPP caused by a novel frameshift mutation in MKRN3 (p.Glu229Argfs*3).
| S-EPMC5435957 | biostudies-literature
Project description:BackgroundIdiopathic central precocious puberty (ICPP) is supposed to be non-existent in a context of testicular destruction that is typically present in Klinefelter syndrome (KS). Herein, we describe a rare case of ICPP in a Klinefelter patient (47,XXY) with 2 maternal X chromosomes. Moreover, we highlight the differences in gonadotropin levels in comparison to males with ICPP and a normal karyotype.Case presentationAn 8 years old boy with a history of cryptorchidism was evaluated for precocious puberty (Tanner staging: P2/G3). Both testes measured 25x35mm. His hormonal profile confirmed a central origin of precocious puberty with high serum testosterone (4.3 ng/ml), luteinizing hormone [LH (3.5 UI/l)] and follicle stimulating hormone [FSH (7.7 UI/l)] levels. Luteinizing hormone-releasing hormone (LHRH) test amplified LH and FSH secretion to 24 and 14 UI/l respectively. Brain magnetic resonance imaging (MRI) was normal. No MKRN3 mutation was detected. He was treated for ICPP for two years. During puberty, he suffered from hypergonadotropic hypogonadism leading to the diagnosis of KS (47,XXY karyotype). Chromosomal analysis by fluorescent multiplex polymerase chain reaction (PCR) using X chromosome microsatellite markers identified 2 maternal X chromosomes. Analysing 8 cases of KS developing ICPP (our reported case and 7 other published cases) revealed that these KS patients with ICPP have higher LH and FSH levels during ICPP episode than in ICPP patients with a normal karyotype (ICPP with KS vs ICPP with a normal karyotype: LH levels 9.4 ± 12 vs 1.1 ± 0.6 UI/l; FSH levels 23.1 ± 38.5 vs 2.7 ± 1.5 UI/l). Furthermore, their response to gonadotropin-releasing hormone (GnRH) stimulation is characterized by excessive LH and FSH secretion (LH levels post-GnRH: 58 ± 48 vs 15.5 ± 0.8 UI/l; FSH levels post-GnRH: 49.1 ± 62.1 vs 5.7 ± 3.9 UI/l).ConclusionsICPP in boys is extremely rare. The pathophysiology of ICPP in KS is unknown. However, maternal X supplementary chromosome and early testicular destruction may play a significant role in the initiation of ICPP, in part explaining the relative "overrepresentation of ICPP in KS. Thus, karyotype analysis could be considered for boys suffering from ICPP, especially if testicular size is smaller or gonadotropins are significantly elevated.
| S-EPMC7724694 | biostudies-literature
Project description:The purpose of this study was to explore the effect of the traditional Chinese medicine Fuyou formula on precocious puberty (PP). The Fy formula may exert an effect in female rats with PP and GT-7 cells through the GPR54/GnRH signaling pathway. To confirm the effect of the Fy formula on PP through the GPR54/GnRH signaling pathway, we first treated GT1-7 cells with the Fy formula and observed changes in the expression of related genes and proteins and in GnRH secretion. Then, we randomly divided young female Sprague-Dawley rats into the control group, model group, leuprorelin group and the Fy formula group. A PP model was established by injection of danazol on postnatal day 5, and the Fy formula was administered on PND15. The time of vaginal opening, the wet weights of the ovary and uterus, serum hormone levels and the expression of hypothalamic-related genes were observed. We found that the Fy formula delayed vaginal opening, decreased the wet weights and coefficients of the ovary and uterus, decreased the levels of serum hormones (E2, follicle-stimulating hormone and luteinizing hormone) and the cellular GnRH level, and downregulated the gene expression of Kiss1, GPR54 and GnRH in the hypothalamus and the gene and protein expression of GPR54 and GnRH in GT1-7 cells. In conclusion, the Fy formula may alleviate PP via the GPR54/GnRH signaling pathway.
| S-EPMC7859969 | 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: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.
| S-EPMC7518508 | 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: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:Familial male-limited precocious puberty (FMPP) is a rare form of gonadotropin-independent precocious puberty that is caused by an activating mutation of the LHCGR gene. Herein, we report a case of FMPP with a mutation of the LHCGR gene in a Korean boy with familial history of precocious puberty through 3 generations. A 16-month-old boy presented with signs of precocious puberty, including pubic hair, acne, and increased growth velocity. The patient's grandfather and father had a history of precocious puberty and profound short stature. On physical examination, the patient had prepubertal testes with pubic hair development appropriate for Tanner stage II. The stretched penile length was 7 cm (>2 standard deviation score), and observed bone age was that of a 4-year-old boy. Laboratory findings showed high serum testosterone (5.74 ng/mL [appropriate for Tanner IV-V]; normal range, <0.05 ng/mL) with suppressed luteinizing hormone (<0.07 mIU/mL) and normal serum level of follicular stimulating hormone (0.56 mIU/mL; normal range, 0.38-1.11 mIU/mL). Genetic testing revealed a pathogenic variant of LHCGR (c.1730 C>T (p.Thr577Ileu)), confirming FMPP. Bicalutamide and anastrozole were administered, and pubertal progression was sufficiently suppressed without any specific side effects. To our knowledge, this is the first case of genetically confirmed FMPP in Korea.
| S-EPMC10925783 | biostudies-literature