scholarly journals Heterozygous Deletions in MKRN3 Cause Central Precocious Puberty Without Prader-Willi Syndrome

2020 ◽  
Vol 105 (8) ◽  
pp. 2732-2739
Author(s):  
Brooke N Meader ◽  
Alessandro Albano ◽  
Hilal Sekizkardes ◽  
Angela Delaney
Keyword(s):  
Precocious Puberty ◽  
Copy Number ◽  
Genetic Diagnosis ◽  
Central Precocious Puberty ◽  
Chromosomal Microarray ◽  
Imprinted Genes ◽  
Prader Willi Syndrome ◽  
Loss Of Function ◽  
Gene Deletions ◽  
Pubertal Onset

Abstract Context Loss-of-function mutations in the imprinted genes MKRN3 and DLK1 cause central precocious puberty (CPP) but whole gene deletions have not been reported. Larger deletions of the chromosome 15q11-13 imprinted locus, including MKRN3, cause Prader-Willi syndrome (PWS). CPP has been reported in PWS but is not common, and the role of MKRN3 in PWS has not been fully elucidated. Objective To identify copy number variants in puberty-related, imprinted genes to determine their role in CPP. Methods Probands with idiopathic CPP had chromosomal microarray (CMA) and targeted deletion/duplication testing for MKRN3 and DLK1. Results Sixteen female probands without MKRN3 or DLK1 variants identified by Sanger sequencing were studied. Whole gene deletions of MKRN3 were identified in 2 subjects (13%): a complete deletion of MKRN3 in Patient A (pubertal onset at 7 years) and a larger deletion involving MAGEL2, MKRN3, and NDN in Patient B (pubertal onset 5.5 years). Both were paternally inherited. Patient B had no typical features of PWS, other than obesity, which was also present in her unaffected family. Conclusions We identified 2 cases of whole gene deletions of MKRN3 causing isolated CPP without PWS. This is the first report of complete deletions of MKRN3 in patients with CPP, emphasizing the importance of including copy number variant analysis for MKRN3 mutation testing when a genetic diagnosis is suspected. We speculate that there is a critical region of the PWS locus beyond MKRN3, MAGEL2, and NDN that is responsible for the PWS phenotype.

scholarly journals Central Precocious Puberty That Appears to Be Sporadic Caused by Paternally Inherited Mutations in the Imprinted Gene Makorin Ring Finger 3

2014 ◽  
Vol 99 (6) ◽  
pp. E1097-E1103 ◽  
Author(s):  
Delanie B. Macedo ◽  
Ana Paula Abreu ◽  
Ana Claudia S. Reis ◽  
Luciana R. Montenegro ◽  
Andrew Dauber ◽  
...  
Keyword(s):  
Precocious Puberty ◽  
Copy Number ◽  
Age Of Onset ◽  
Ring Finger ◽  
In Silico Analysis ◽  
Central Precocious Puberty ◽  
Paternal Allele ◽  
Chromosome 15 ◽  
Loss Of Function ◽  
Imprinted Gene

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.

scholarly journals Exploring the Potential Role of DLK1 in Pubertal Initiation

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A667-A667
Author(s):  
Youn Hee Jee ◽  
Angela Delaney ◽  
Melissa Jennings ◽  
Jack Adam Yanovski ◽  
Jeffrey Baron
Keyword(s):  
Precocious Puberty ◽  
Preoptic Area ◽  
Transmembrane Protein ◽  
Previous History ◽  
Tanner Stage ◽  
Central Precocious Puberty ◽  
Male Rats ◽  
Soluble Form ◽  
Loss Of Function ◽  
Pubertal Onset

Abstract The mechanisms that orchestrate the initiation of puberty are not well understood. DLK1 encodes a transmembrane protein that interacts with NOTCH1 receptor to negatively regulate NOTCH signaling. Loss-of-function mutations in DLK1 cause central precocious puberty, suggesting that DLK1 normally inhibits the reproductive axis centrally. The soluble form of DLK1, which is generated by proteolytic cleavage of the DLK1 extracellular domain, is measurable in human serum. We hypothesized that serum soluble DLK1 concentrations decline with age and that the decline, either in circulating levels or in tissue expression, contributes to the physiological mechanisms triggering pubertal initiation. Serum DLK1 was measured by immunoassay in 102 healthy subjects (age newborn - 26 yrs, 54 male). DLK1 concentrations did not differ by sex, BMI SDS, height, or status of fasting. DLK1 concentrations declined overall with age (R2=0.04, P<0.001). However, there was not a substantial decline in the peripubertal period (mean± SEM, at Tanner stage 1, 2, 3, 4, 5: 14.8 ± 1.9, 16.4 ± 1.2, 17.0 ± 5, 13.6 ± 3, 9.7 ± 0.9 ng/mL). Serum DLK1, measured in 12 subjects (2 male) with a previous history of idiopathic central precocious puberty, did not differ from healthy controls. We next hypothesized that declining expression of Dlk1 or increasing expression of competing canonical NOTCH ligands in hypothalamus contributes to pubertal onset. The preoptic area (POA) was microdissected from rat brains (age 4 d, 2 w, 6 w, and 8-16 w, n=5 each) and expression was measured by RT-PCR. Dlk1 expression increased with age in both female and male rats (P<0.001). Notch1 expression did not change with age. Expression of two ligands, Jag1 and Dll4, showed a peak at age 6 w, around the time of puberty, but only in males, and none of the other ligands (Jag1, Dll1, and Dll3) showed increasing expression at the age of puberty. In conclusion, we did not find evidence that declining serum soluble DLK1 concentrations in humans, declining DLK1 expression in rat preoptic area, or increasing NOTCH ligand expression in rat preoptic area contribute to pubertal onset.

AMH levels at central precocious puberty and premature thelarche: is it a parameter?

2015 ◽  
Vol 28 (11-12) ◽  
Author(s):  
Nursel Muratoglu Sahin ◽  
Sibel Tulgar Kinik ◽  
Mustafa Agah Tekindal ◽  
Nilufer Bayraktar
Keyword(s):  
Precocious Puberty ◽  
Central Precocious Puberty ◽  
Breast Development ◽  
Premature Thelarche ◽  
Pubertal Onset ◽  
Antimullerian Hormone ◽  
The Mean ◽  
Antimüllerian Hormone

AbstractThe possible difference of antimüllerian hormone (AMH) levels at central precocious puberty (CPP) and premature thelarche (PT) has not been properly evaluated.By evaluating AMH levels in girls with diagnosed CPP and PT, we aim to show the change of AMH levels at the pubertal onset.Sixty-five girls who have breast development before the age of 8 years and 25 healthy girls were enrolled in the study.The subjects were divided into two groups as CPP and PT, according to results of GnRH test. AMH levels were determined in the two groups.The mean AMH levels of the CPP group were significantly lower than those in the PT group (13.57±9.85 pmol/L and 58.42±12.78 pmol/L, respectively, p=0.022).These results suggest that the AMH levels decrease in the duration of the hypothalamus-pituitary-ovarian axis activation. We thought that AMH might/may be a marker for distinguishing between CPP and PT.

scholarly journals Genotype-phenotype correlations in central precocious puberty caused by MKRN3 mutations

2020 ◽  
Author(s):  
Carlos Eduardo Seraphim ◽  
Ana Pinheiro Machado Canton ◽  
Luciana Montenegro ◽  
Maiara Ribeiro Piovesan ◽  
Delanie B Macedo ◽  
...  
Keyword(s):  
Precocious Puberty ◽  
Genetic Defect ◽  
Ring Finger ◽  
Central Precocious Puberty ◽  
Bone Age ◽  
Control Group ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Reproductive Axis ◽  
Time Of Presentation

Abstract Context Loss-of-function mutations of makorin RING finger protein 3 (MKRN3) are the most common monogenic cause of familial central precocious puberty (CPP). Objective To describe the clinical and hormonal features of a large cohort of patients with CPP due to MKRN3 mutations and compare the characteristics of different types of genetic defects. Patients/methods Multiethnic cohort of 716 patients with familial or idiopathic CPP screened for MKRN3 mutations using Sanger sequencing. A group of 156 Brazilian girls with idiopathic CPP (ICPP) was used as control group. Results Seventy-one patients (45 girls and 26 boys from 36 families) had 18 different loss-of-function MKRN3 mutations. Eight mutations were classified as severe (70% of patients). Among the 71 patients, first pubertal signs occurred at 6.2 ± 1.2 years in girls and 7.1 ± 1.5 years in boys. Girls with MKRN3 mutations had a shorter delay between puberty onset and first evaluation and higher FSH levels compared to ICPP. Patients with severe MKRN3 mutations had a greater bone age advancement compared to patients with missense mutations (2·3 ± 1·6 vs. 1·6 ± 1·4 years, p = 0.048), and had higher basal LH levels (2·2 ± 1·8 vs. 1·1 ± 1·1 UI/L, p=0.018) at the time of presentation. Computational protein modeling revealed that 60% of the missense mutations were predicted to cause protein destabilization. Conclusions Inherited premature activation of the reproductive axis caused by loss-of-function mutations of MKRN3 is clinically indistinct from ICPP. However, the type of genetic defect may affect bone age maturation and gonadotropin levels.

scholarly journals A Novel Loss-of-Function MKRN3 Variant in a Chinese Patient With Familial Precocious Puberty: A Case Report and Functional Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Xueling Yin ◽  
Junqi Wang ◽  
Tianting Han ◽  
Zhang Tingting ◽  
Yuhong Li ◽  
...  
Keyword(s):  
Case Report ◽  
Precocious Puberty ◽  
Transcriptional Activity ◽  
Central Precocious Puberty ◽  
Chinese Patient ◽  
Functional Study ◽  
Loss Of Function ◽  
Pediatric Endocrinology ◽  
Functional Studies ◽  
Clinical Pediatric

Background: Central precocious puberty (CPP) is one of the most common and complex problems in clinical pediatric endocrinology practice. Mutation of the MKRN3 gene can cause familial CPP.Methods and Results: Here we reported a Chinese patient bearing a novel MKRN3 mutation (c.G277A/p.Gly93Ser) and showing the CPP phenotype. Functional studies found that this mutation of MKRN3 attenuated its autoubiquitination, degradation, and inhibition on the transcriptional activity of GNRH1, KISS1, and TAC3 promoters.Conclusion: MKRN3 (Gly93Ser) is a loss-of-function mutation, which attenuates the inhibition on GnRH1-related signaling, suggesting that this mutant can lead to central precocious puberty.

scholarly journals CENTRAL PRECOCIOUS PUBERTY IN TWO BOYS WITH PRADER-WILLI SYNDROME ON GROWTH HORMONE TREATMENT

2019 ◽  
Vol 5 (6) ◽  
pp. e352-e356 ◽  
Author(s):  
Elena Monai ◽  
Anders Johansen ◽  
Erik Clasen-Linde ◽  
Ewa Rajpert-De Meyts ◽  
Niels Erik Skakkebæk ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Precocious Puberty ◽  
Growth Hormone Treatment ◽  
Pubertal Timing ◽  
Pubertal Development ◽  
Central Precocious Puberty ◽  
Hormone Treatment ◽  
Prader Willi Syndrome ◽  
Gnrh Analog ◽  
Premature Adrenarche

Objective: Prader-Willi syndrome (PWS) is a rare genetic neuroendocrine disorder characterized by hypotonia, obesity, short stature, and mental retardation. Incomplete or delayed pubertal development as well as premature adrenarche are usually found in PWS, whereas central precocious puberty is rarely seen. Methods: This study reports the clinical, biochemical, and histologic findings in 2 boys with PWS who developed central precocious puberty. Results: Both boys were started on growth hormone therapy during the first years of life according to the PWS indication. They had both bilateral cryptorchidism at birth and had orchidopexy in early childhood. Retrospective histologic analysis of testicular biopsies demonstrated largely normal tissue architecture and germ cell maturation, but severely decreased number of prespermatogonia in one of the patients. Both boys had premature adrenarche around the age of 6. Precocious puberty was diagnosed in both boys with enlargement of testicular volume (>3 mL), signs of virilization and a pubertal response to a gonadotropin-releasing hormone (GnRH) test and they were both treated with GnRH analog. Conclusion: The cases described here displayed typical characteristics for PWS, a considerable heterogeneity of the hypothalamic-pituitary function, as well as testicular histology. Central precocious puberty is extremely rare in PWS boys, but growth hormone treatment may play a role in the pubertal timing.

Central precocious puberty and growth hormone deficiency in a boy with Prader-Willi syndrome

2008 ◽  
Vol 167 (12) ◽  
pp. 1455-1458 ◽  
Author(s):  
Antonino Crinò ◽  
Girolamo Di Giorgio ◽  
Riccardo Schiaffini ◽  
Alessandra Fierabracci ◽  
Sabrina Spera ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Deficiency ◽  
Precocious Puberty ◽  
Central Precocious Puberty ◽  
Hormone Deficiency ◽  
Prader Willi Syndrome

scholarly journals Mosaic duplication of 8q24.1q24.3 detected by chromosomal microarray but not karyotyping in two unrelated fetuses with cardiac defects

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Shaobin Lin ◽  
Shufang Huang ◽  
Xueling Ou ◽  
Heng Gu ◽  
Yonghua Wang ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Copy Number ◽  
Genetic Disorders ◽  
Genetic Diagnosis ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Cardiac Defects ◽  
Prenatal Genetic Diagnosis ◽  
Tumor Tissues ◽  
Number Variation

Abstract Background Discordance between traditional cytogenetic and molecular cytogenetic tests is rare but not uncommon. The explanation of discordance between two genetic methods is difficult but especially important for genetic counseling, particularly for prenatal genetic diagnosis. Case presentation Two unrelated fetuses were diagnosed with cardiac defects by prenatal ultrasound examination, and invasive cordocentesis was performed to obtain cord blood samples for prenatal genetic diagnosis. For both fetuses, chromosomal microarray analysis (CMA) detected a novel approximately 27-Mb mosaic duplication with a high copy number of approximately six to seven copies on chromosome 8q24.1q24.3 that was not identified by karyotyping. To exclude artificial errors and validate laboratory detection results, multiple procedures including copy number variation sequencing, fluorescence in situ hybridization, and short tandem repeat and single-nucleotide polymorphism genotype comparison were performed, confirming the discordant results between CMA and karyotyping. The potential causes of discordance between CMA and karyotyping using fetal blood lymphocytes are discussed; we suggest that extrachromosomal DNA or cell-free DNA fragmentation originating from certain tumor tissues with 8q24.1q24.3 duplication might deserve further investigation. Conclusions This study may be helpful for prenatal evaluation and genetic counseling for subsequent patients with similar mosaic 8q24.1q24.3 duplications. Additionally, more cases and further research are needed to understand whether mosaic 8q24.1q24.3 duplication is associated with certain genetic disorders and to investigate the causes of discordance between molecular and morphological methods.

scholarly journals Molecular screening of PROKR2 gene in girls with idiopathic central precocious puberty

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Francesca Aiello ◽  
Grazia Cirillo ◽  
Alessandra Cassio ◽  
Raffaella Di Mase ◽  
Gianluca Tornese ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Precocious Puberty ◽  
Rare Variants ◽  
Hypogonadotropic Hypogonadism ◽  
Central Precocious Puberty ◽  
Fisher Exact Test ◽  
Loss Of Function ◽  
Molecular Screening ◽  
Exact Test ◽  
First Case

Abstract Background Prokineticin receptor 2 (PROKR2) loss of function mutations have been described as cause of hypogonadotropic hypogonadism. In 2017, a first case of central precocious puberty (CPP) caused by PROKR2 heterozygous gain of function mutation was described in a 3.5 years-old girl. No other cases have been reported yet. This study performs a molecular screening in girls with early onset CPP (breast budding before 6 years of age) to identify possible alterations in PROKR2. Methods We analysed DNA of 31 girls with idiopathic CPP diagnosed via basal LH levels > 0.3 IU/L or peak-LH > 5 IU/L after stimulation, without any MKRN3 mutations. The Fisher exact test was used to compare polymorphism allele frequency to corresponding ones in genome aggregation database (gnomAD). Results No rare variants were identified. Five polymorphisms were found (rs6076809, rs8116897, rS3746684, rs3746682, rs3746683). All except one (i.e. rs3746682) had a minor allele frequency (MAF) similar to that reported in literature. rs3746682 presented a MAF higher than that described in the gnomAD (0.84 in our cohort vs 0.25 from gnomAD). Conclusions As for other G protein-coupled receptors (i.e. GPR54), mutations in PROKR2 do not seem to be a frequent cause of CPP in girls.

Sign in / Sign up

Export Citation Format

Share Document