scholarly journals Central Precocious Puberty in a Girl and Early Puberty in Her Brother Caused by a Novel Mutation in the MKRN3 Gene

2014 ◽  
Vol 99 (4) ◽  
pp. E647-E651 ◽  
Author(s):  
Nikolaos Settas ◽  
Catherine Dacou-Voutetakis ◽  
Maria Karantza ◽  
Christina Kanaka-Gantenbein ◽  
George P. Chrousos ◽  
...  
Keyword(s):  
Precocious Puberty ◽  
Novel Mutation ◽  
Structural Alignment ◽  
In Silico Analysis ◽  
Missense Variant ◽  
Central Precocious Puberty ◽  
Dimensional Structure ◽  
Sex Characteristics ◽  
Coding Region ◽  
Early Puberty

Context: Central precocious puberty (CPP), defined as the development of secondary sex characteristics prior to age 8 years in girls and 9 years in boys, results from the premature activation of the hypothalamic-pituitary-gonadal axis. Mutations in the imprinted gene MKRN3 have been recently implicated in familial cases of CPP. Objective: The objective of the study was to uncover the genetic cause of CPP in a family with two affected siblings. Design and participants: The entire coding region of the paternally expressed MKRN3 gene was sequenced in two siblings, a girl with CPP and her brother with early puberty, their parents, and their grandparents. Results: A novel heterozygous missense variant in the MKRN3 gene (p.C340G) was detected in the two affected siblings, their unaffected father, and the paternal grandmother. As expected, the mutated allele followed an imprinted mode of inheritance within the affected family. In silico analysis predicts the mutation as possibly damaging in all five software packages used. Furthermore, structural alignment of the ab initio native and mutant MKRN3 models predicts that the p.C340G mutation leads to significant structural perturbations in the 3-dimensional structure of the C3HC4 really interesting new gene motif of the protein, further emphasizing the functional implications of the novel MKRN3 alteration. Conclusions: We report a novel MKRN3 mutation (p.C340G) in a girl with CPP and her brother with early puberty. MKRN3 alterations should be suspected in all cases with familial CPP or early puberty, especially if male patients are also involved or the precocious puberty trend does not follow the usually observed mother-to-daughter inheritance.

scholarly journals Central Precocious Puberty Caused by a Heterozygous Deletion in the MKRN3 Promoter Region

2018 ◽  
Vol 107 (2) ◽  
pp. 127-132 ◽  
Author(s):  
Delanie B. Macedo ◽  
Monica M. França ◽  
Luciana R. Montenegro ◽  
Marina Cunha-Silva ◽  
Danielle S. Bessa ◽  
...  
Keyword(s):  
Precocious Puberty ◽  
Promoter Region ◽  
Regulatory Region ◽  
In Silico Analysis ◽  
Central Precocious Puberty ◽  
Proximal Promoter ◽  
Loss Of Function ◽  
Wild Type ◽  
Coding Region ◽  
Blood Leukocytes

Context: Loss-of-function mutations in the coding region of MKRN3, a maternally imprinted gene at chromosome 15q11.2, are a common cause of familial central precocious puberty (CPP). Whether MKRN3 alterations in regulatory regions can cause CPP has not been explored to date. We aimed to investigate potential pathogenic variants in the promoter region of MKRN3 in patients with idiopathic CPP. Patients/Methods: A cohort of 110 patients with idiopathic CPP was studied. Family history of precocious sexual development was present in 25%. Mutations in the coding region of MKRN3 were excluded in all patients. Genomic DNA was extracted from peripheral blood leukocytes, and 1,100 nucleotides (nt) of the 5′-regulatory region of MKRN3 were amplified and sequenced. Luciferase assays were performed in GT1–7 cells transiently transfected with plasmids containing mutated and wild-type MKRN3 promoter. Results: We identified a rare heterozygous 4-nt deletion (c.-150_-147delTCAG; –38 to –41 nt upstream to the transcription start site) in the proximal promoter region of MKRN3 in a girl with CPP. In silico analysis predicted that this deletion would lead to the loss of a binding site for a downstream res­ponsive element antagonist modulator (DREAM), a potential transcription factor for MKRN3 and GNRH1 expression. Luciferase assays demonstrated a significant reduction of MKRN3 promoter activity in transfected cells with a c.-150_- 147delTCAG construct plasmid in both homozygous and heterozygous states when compared with cells transfected with the corresponding wild-type MKRN3 promoter region. Conclusion: A rare genetic alteration in the regulatory region of MKRN3 causes CPP.

Genetic factors of idiopathic central precocious puberty and their polygenic risk in early puberty

2021 ◽  
Author(s):  
Wei-De Lin ◽  
Chi-Fung Cheng ◽  
Chung-Hsing Wang ◽  
Wen-Miin Liang ◽  
Chien-Hsiun Chen ◽  
...  
Keyword(s):  
Precocious Puberty ◽  
Pubertal Timing ◽  
Central Precocious Puberty ◽  
P Value ◽  
Validation Group ◽  
Early Puberty ◽  
Genetic Characteristics ◽  
Polygenic Risk ◽  
Idiopathic Central Precocious Puberty ◽  
Group A

Objective: To investigate the genetic characteristics of idiopathic central precocious puberty (ICPP) and validate its polygenic risk for early puberty. Design and methods: A bootstrap subsampling and genome-wide association study was performed on Taiwanese Han Chinese girls comprising 321 ICPP patients and 148 controls. Using previous GWAS data on pubertal timing, a replication study was performed. A validation group was also investigated for the weighted polygenic risk score (wPRS) of the risk of early puberty. Results: A total of 105 SNPs for the risk of ICPP were identified, of which 22 yielded an area under the receiver operating characteristic curve of 0.713 for the risk of early puberty in the validation group. A replication study showed that 33 SNPs from previous GWAS data of pubertal timing were associated with the risk of ICPP (training group: P-value < 0.05). In the validation group, a cumulative effect was observed between the wPRS and the risk of early puberty in a dose-dependent manner [validation group: Cochran-Armitage trend test: P-value < 1.00E-04; wPRS quartile 2 (Q2) (odds ratio [OR] = 5.00, 95% confidence interval [CI]: 1.5516.16), and wPRS Q3 (OR = 11.67, 95% CI: 2.4455.83)]. Conclusions: This study reveals the ICPP genetic characteristics with 22 independent and 33 reported SNPs in the Han Chinese population from Taiwan. This study may contribute to understand the genetic features and underlying biological pathways that control pubertal timing and pathogenesis of ICPP and also to the identify of individuals with a potential genetic risk of early puberty.

scholarly journals Novel mutation in the gonadotropin-releasing hormone receptor (GNRHR) gene in a patient with normosmic isolated hypogonadotropic hypogonadism

2012 ◽  
Vol 56 (8) ◽  
pp. 540-544 ◽  
Author(s):  
Daiane Beneduzzi ◽  
Ericka B. Trarbach ◽  
Ana Claudia Latronico ◽  
Berenice Bilharinho de Mendonca ◽  
Letícia F. G. Silveira
Keyword(s):  
In Silico ◽  
Novel Mutation ◽  
Hypogonadotropic Hypogonadism ◽  
In Silico Analysis ◽  
Control Group ◽  
Coding Region ◽  
Novel Variant ◽  
Gonadotropin Releasing Hormone Receptor ◽  
Inactivating Mutation ◽  
Silico Analysis

We report a novel GNRHR mutation in a male with normosmic isolated hypogonadotropic hypogonadism (nIHH). The coding region of the GNRHR gene was amplified and sequenced. Three variants p.[Asn10Lys;Gln11Lys]; [Tyr283His] were identified in the GNRHR coding region in a male with sporadic complete nIHH. The three variants were absent in the controls (130 normal adults). Familial segregation showed that the previously described p.Asn10Lys and p.Gln11Lys are in the same allele, in compound heterozygozity with the novel variant p.Tyr283His. The p.[Asn10Lys;Gln11Lys] are known inactivating mutations. The p.Tyr283His affects a well-conserved residue, and in silico analysis suggested it is a deleterious variant. We describe a novel GNRHR mutation in a male with nIHH. Absence of the mutation in the control group, conservation among species, in silico analysis, and familial segregation suggest that p.Tyr283His, which was identified in compound heterozygozity with the p.[Asn10Lys;Gln11Lys] variants, is an inactivating mutation. Arq Bras Endocrinol Metab. 2012;56(8):540-4

In silico analysis of a novelMKRN3missense mutation in familial central precocious puberty

2015 ◽  
Vol 84 (1) ◽  
pp. 80-84 ◽  
Author(s):  
Vassos Neocleous ◽  
Christos Shammas ◽  
Marie M. Phelan ◽  
Stella Nicolaou ◽  
Leonidas A. Phylactou ◽  
...  
Keyword(s):  
Precocious Puberty ◽  
In Silico ◽  
In Silico Analysis ◽  
Central Precocious Puberty ◽  
Silico Analysis

scholarly journals Congenital Hyperinsulinism Due to a Novel Activating Glucokinase Mutation: A Case Report and Literature Review

2020 ◽  
Vol 5 (6) ◽  
Keyword(s):  
Case Report ◽  
Novel Mutation ◽  
Gene Mutations ◽  
In Silico Analysis ◽  
Missense Variant ◽  
Laboratory Evaluation ◽  
Congenital Hyperinsulinism ◽  
Hypoglycemic Episode ◽  
Glucokinase Mutation ◽  
Uncertain Significance

Background: Congenital Hyperinsulinism (CHI) constitutes a major cause of persistent and recurrent hypoglycemia, especially in the neonatal period, showing notable phenotypical heterogeneity among affected subjects. Activating mutations of the Glucokinase gene (GCK) are responsible for mild forms of hypoglycemia, due to CHI, usually easily medically managed. Case report: We present a patient at the age of 3.5 years old investigated for persistent hypoglycemia. Laboratory evaluation showed hyperinsulinism during the hypoglycemic episode with a required glucose infusion rate greater than 8-10 mg/kg/min to maintain normoglycemia. Targeted gene panel sequencing revealed an activating missense novel mutation p.Val71Ala in exon 3 of GCK gene, dominantly inherited by his mother. In silico, analysis of this novel missense variant assessed its pathogenicity as being of uncertain significance Conclusions: GCK gene mutations result in varying phenotypic characteristics and responsiveness to diazoxide depending on the type of activating mutation.

Early polycystic ovary-like syndrome in girls with central precocious puberty and exaggerated adrenal response

1995 ◽  
Vol 133 (4) ◽  
pp. 403-406 ◽  
Author(s):  
Liora Lazar ◽  
Rivka Kauli ◽  
Celia Bruchis ◽  
Jardena Nordenberg ◽  
Avinoam Galatzer ◽  
...  
Keyword(s):  
Precocious Puberty ◽  
Polycystic Ovary ◽  
Medical Center ◽  
Hormone Secretion ◽  
Clinical Signs ◽  
Central Precocious Puberty ◽  
Early Puberty ◽  
History Of ◽  
Adrenal Response ◽  
Pco Syndrome

Lazar L, Kauli R, Bruchis C, Nordenberg J, Galatzer A, Pertzelan A. Early polycystic ovary-like syndrome in girls with central precocious puberty and exaggerated adrenal response. Eur J Endocrinol 1995;133:403–6. ISSN 0804–4643 Exaggerated adrenal response (ExAR), i.e. hypersecretion of both 17-hydroxypregnenolone (170HPreg) and 17-hydroxyprogesterone(17OHP) in response to adrenocorticotropic hormone (ACTH) stimulation, is frequently found in women with polycystic ovary (PCO) syndrome who had precocious adrenarche. In an earlier study we found an abnormal adrenal response in girls with idiopathic true central precocious puberty (CPP) at early stages of puberty. On follow-up it was noted that a significant number of girls with CPP develop PCO-like syndrome at a relatively young age. The aim of the present study was to determine if there is an association between ExAR and early PCO in girls with a history of CPP. Included were 49 girls with a history of CPP, 34 of whom were treated with gonadotropin-releasing hormone (GnRH) analog. All 49 were evaluated at full maturity, at ages 12.5–14 years, 0.5–4 years after menarche or resumption of menses. Of the 49 girls, 20 had at least 3/4 clinical signs of PCO (irregular menses, hirsutism, acne and obesity) and were defined as PCOlike+, whereas 29 did not fulfil the criteria and were considered PCO-like -. Girls with a definite enzyme deficiency were excluded from the study. All participants underwent a combined iv ACTHGnRH test at early follicular phase. The PCO-like + girls all revealed ExAR, i.e. an elevated stimulated 17OHPreg of 63.4 ± 9.6 nmol/l (normal 28.6 ± 9.2 nmol/l) and a normal stimulated 17OHPreg/ 17OHP ratio of 7.1 ± 1.8 (normal 6.2 ± 2.7), whereas all the PCO-like – had a normal adrenal response (30.0 ±8.7 and 5.3 ± 2.0 nmol/l, respectively). Compared to the PCO-like – girls, those with PCO-like± had significantly higher levels of testosterone (1.8 ± 0.7 vs 1.0 ± 0.5 nmol/l; p < 0.001), androstenedione (6.6 ±3.2 vs 4.7 ± 1.8 nmol/l; p < 0.02) and dehydroepiandrosterone sulfate (7.8 ± 4.7 vs 4.2 ± 2.5 μmol/l; p < 0.004), and a trend toward inappropriate luteinizing hormone secretion. The prevalence of ExAR (40.8%) in the mature CPP girls (confined to only PCO-like ±) was similar to that previously found by us in another group of girls with CPP at early puberty (44.6%). In conclusion, our findings indicate that the pattern of adrenal response remains unchanged from early puberty to adulthood and is probably inherent. As only the girls with CPP who developed early PCO syndrome showed ExAR, it is suggested that ExAR in early puberty may serve as a predictive marker for the eventual development of PCO. A Pertzelan, Institute of Pediatric and Adolescent Endocrinology, Children's Medical Center of Israel, Beilinson Medical Campus, Kaplan Street, Petah Tiqva 49202, Israel

Association study of DLK1 in girls with idiopathic central precocious puberty

2020 ◽  
Vol 33 (8) ◽  
pp. 1045-1049
Author(s):  
Hae Sang Lee ◽  
Kyung Hee Kim ◽  
Jin Soon Hwang
Keyword(s):  
Precocious Puberty ◽  
In Silico Analysis ◽  
Central Precocious Puberty ◽  
Healthy Controls ◽  
Coding Regions ◽  
Idiopathic Central Precocious Puberty ◽  
Sequence Variations ◽  
Significant Difference ◽  
The Relationship ◽  
Silico Analysis

AbstractObjectiveMutations in the delta-like 1 homolog (DLK1) gene have recently been reported in patients with idiopathic central precocious puberty (CPP). We aimed to investigate DLK1 mutations or polymorphisms in girls with CPP.MethodsA total of 100 girls diagnosed with idiopathic CPP were enrolled. DLK1 coding regions were sequenced in girls with idiopathic CPP and healthy girls (controls). The relationship between identified sequence variations and CPP was evaluated via comparison of allele frequencies between patients with CPP and normal healthy controls.ResultsWe identified five polymorphisms in DLK1. There was no significant difference with regard to allele frequency between patients with CPP and controls. Polymorphism c.549C>T (p.G183G) in DLK1 gene was identified in only one patient with CPP. In silico analysis with human splicing finder suggested that the variant (c.549C>T) leads to splicing defect.ConclusionsThe sequencing of DLK1 gene has uncovered only one potentially meaningful variant. However, our results demonstrate that DLK1 mutations are a relatively rare cause of idiopathic CPP.

scholarly journals Adrenocorticotropin-Dependent Precocious Puberty of Testicular Origin in a Boy with X-Linked Adrenal Hypoplasia Congenita Due to a Novel Mutation in the DAX1 Gene

2001 ◽  
Vol 86 (9) ◽  
pp. 4068-4071 ◽  
Author(s):  
Sorahia Domenice ◽  
Ana Claudia Latronico ◽  
Vinicius Nahime Brito ◽  
Ivo Jorge Prado Arnhold ◽  
Fernando Kok ◽  
...  
Keyword(s):  
Adrenal Insufficiency ◽  
Precocious Puberty ◽  
Stop Codon ◽  
Novel Mutation ◽  
Direct Sequencing ◽  
Receptor Gene ◽  
Premature Stop Codon ◽  
Rare Condition ◽  
Coding Region ◽  
Primary Adrenal Insufficiency

Primary adrenal insufficiency is a rare condition in pediatric age, and its association with precocious sexual development is very uncommon. We report a 2-yr-old Brazilian boy with DAX1 gene mutation whose first clinical manifestation was isosexual gonadotropin-independent precocious puberty. He presented with pubic hair, enlarged penis and testes, and advanced bone age. T levels were elevated, whereas basal and GnRH-stimulated LH levels were compatible with a prepubertal pattern. Chronic GnRH agonist therapy did not reduce T levels, supporting the diagnosis of gonadotropin-independent precocious puberty. Testotoxicosis was ruled out after normal sequencing of exon 11 of the LH receptor gene. At age 3 yr he developed clinical and hormonal features of severe primary adrenal insufficiency. The entire coding region of the DAX1 gene was analyzed through direct sequencing. A nucleotide G insertion between nucleotides 430 and 431 in exon 1, resulting in a novel frameshift mutation and a premature stop codon at position 71 of DAX-1, was identified. Surprisingly, steroid replacement therapy induced a clear decrease in testicular size and T levels to the prepubertal range. These findings suggest that chronic excessive ACTH levels resulting from adrenal insufficiency may stimulate Leydig cells and lead to gonadotropin-independent precocious puberty in some boys with DAX1 gene mutations.

scholarly journals In-silico analysis of non-synonymous-SNPs of STEAP2: To provoke the progression of prostate cancer

2016 ◽  
Vol 11 (1) ◽  
pp. 402-416 ◽  
Author(s):  
Muhammad Naveed ◽  
Sana Tehreem ◽  
Shamsa Mubeen ◽  
Fareeha Nadeem ◽  
Fatima Zafar ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Three Dimensional ◽  
In Silico Analysis ◽  
Genome Project ◽  
Dimensional Structure ◽  
Nucleotide Polymorphisms ◽  
Coding Region ◽  
Computational Tools ◽  
Epithelial Antigens ◽  
Novel Drug

AbstractAs a novel biomarker from the STEAP family, STEAP2 encodes six transmembrane epithelial antigens to prostate cancer. The overexpression of STEAP2 is predicted as the second most common cancer in the world that is responsible for male cancer-related deaths. Nonsynonymous SNPs are important group of SNPs which lead to alternations in encoded polypeptides. Changes in the amino acid sequence of gene products can lead to abnormal tissue function. The present study firstly sorted out those SNPs which exist in the coding region of STEAP2 and evaluated their impact through computational tools. Secondly, the three-dimensional structure of STEAP2 was formed through I-TASSER and validated by different software. Genomic data has been retrieved from the 1000 Genome project and Ensembl and subsequently analysed using computational tools. Out of 177 non-synonymous single nucleotide polymorphisms (nsSNPs) within the coding region, 42 mis-sense SNPs have been predicted as deleterious by all analyses. Our research shows a welldesigned computational methodology to inspect the prostate cancer associated nsSNPs. It can be concluded that these nsSNPs can play their role in the up-regulation of STEAP2 which further leads to progression of prostate cancer. It can benefit scientists in the handling of cancerassociated diseases related to STEAP2 through developing novel drug therapies.

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