scholarly journals Clinical and molecular genetic features of 3 family cases of the central precocious puberty, due to MKRN3 gene defects

2021 ◽  
Vol 67 (3) ◽  
pp. 55-61
Author(s):  
N. A. Zubkova ◽  
A. A. Kolodkina ◽  
N. A. Makretskaya ◽  
P. L. Okorokov ◽  
T. V. Pogoda ◽  
...  
Keyword(s):  
Precocious Puberty ◽  
Molecular Genetic ◽  
Ring Finger ◽  
Central Precocious Puberty ◽  
Loss Of Function ◽  
Genetic Features ◽  
Sporadic Cases ◽  
The Russian Federation ◽  
Gene Defects ◽  
Gonadotropic Hormones

Gonadotropin-dependent precocious puberty (central) is a condition resulting from the early (up to 8 years in girls and 9 years in boys) reactivation of the hypothalamic-pituitary-gonadal axis. An increase in the secretion of sex steroids by the gonads in this form is a consequence of the stimulation of the sex glands by gonadotropic hormones of the pituitary gland. In the absence of central nervous system abnormalities, CPP is classified as idiopathic and as familial in some cases, emphasizing the genetic origin of this disorder. Loss-of-function mutations in Makorin Ring Finger Protein 3 (MKRN3) are the most common identified genetic cause of central precocious puberty compared to sporadic cases. In the present study we performed the first descrition of 3 family cases of central precocious puberty duo to novel MKRN3 gene mutation detected by NGS in the Russian Federation.

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 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.

Serum level of NPTX1 is independent of serum MKRN3 in central precocious puberty

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Hwal Rim Jeong ◽  
Jong Seo Yoon ◽  
Hye Jin Lee ◽  
Yeong Suk Shim ◽  
Min Jae Kang ◽  
...  
Keyword(s):  
Serum Level ◽  
Precocious Puberty ◽  
Standard Deviation Score ◽  
Ring Finger ◽  
Central Precocious Puberty ◽  
Serum Levels ◽  
Enzyme Linked Immunosorbent Assay ◽  
Loss Of Function ◽  
Early Puberty ◽  
Significant Difference

AbstractBackgroundMakorin ring finger protein 3 (MKRN3) is associated with the initiation of puberty, and loss of function mutation of MKRN3 is the most common genetic cause of central precocious puberty (CPP). A recent study reported that MKRN3 interacts with and suppresses neural pentraxin-1 precursor (NPTX1) activity via polyubiquitination during early puberty in the mouse hypothalamus.ObjectiveThis study investigated the correlation between serum NPTX1 and MKRN3 in CPP girls and predicted the potential role of NPTX1 in pubertal progression.MethodsIn this case–control study, we examined 34 girls diagnosed with CPP and 34 healthy prepubertal girls. Anthropometric and hormonal parameters were measured and serum levels of NPTX1 and MKRN3 were evaluated with commercial enzyme-linked immunosorbent assay kits.ResultsSerum MKRN3 level decreased significantly in CPP patients compared to controls (344.48 ± 333.77 and 1295.21 ± 780.80 pg/mL, respectively, p<0.001). Serum MKRN3 tended to decrease as Tanner breast stage increased. However, no significant difference was observed in serum NPTX1 levels between patients and controls (20.14 ± 31.75 ng/mL and 12.93 ± 8.28 ng/mL, respectively, p=0.248). The serum level of NPTX1 did not change significantly with the Tanner breast stage. Serum NPTX1 was correlated with the height standard deviation score (r=0.255; p<0.05), but was not correlated with serum MKRN3 level or the others. Conclusion: Although serum NPTX1 level was independent of serum MKRN3 level, the possibility they might be involved in the progression of puberty or CPP remains. Further research is needed to determine their role in the hypothalamus.

scholarly journals SUN-725 Clinical and Genetic Features of Families with Maternally Inherited Central Precocious Puberty

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Flávia Rezende Tinano ◽  
Ana Pinheiro Machado Canton ◽  
Luciana Ribeiro Montenegro ◽  
Andrea de Castro Leal ◽  
Carolina Ramos ◽  
...  
Keyword(s):  
Precocious Puberty ◽  
Association Studies ◽  
Brain Mri ◽  
Family Members ◽  
Central Precocious Puberty ◽  
Breast Development ◽  
Female Group ◽  
Genome Wide Association Studies ◽  
Abnormal Gait ◽  
Genetic Features

Abstract Context: The clinical recognition of familial central precocious puberty (CPP) has significantly increased in the last years. This fact can be related to the recent descriptions of genetic causes associated with this pediatric condition, such as loss-of-function mutations of two imprinted genes (MKRN3 and DLK1). Inherited defects in both genes cause paternally inherited CPP. However, no genetic abnormality has been described in families with maternally inherited CPP so far. Objectives: To characterize the clinical and genetic features of several families with maternally inherited CPP. Setting and Participants: We analyzed clinical and genetic features of children with familial CPP. No brain MRI alterations were detected in the selected patients with CPP. MKRN3 and DLK1 pathogenic mutations were excluded. Whole-exome sequencing was performed in selected cases. Results: We studied 177 children from 141 families with familial CPP. Paternal inheritance was evidenced in 44 families (31%), whereas 58 (41%) had maternally inheritance. Indeterminate inheritance was detected in the remaining families. Maternally inherited CPP affected mainly female patients (69 girls and two boys). Thelarche occurred at mean age of 6.1 ± 1.9 years in this female group. Most of girls had Tanner 3 (41%) and Tanner 4 (35%) breast development at first evaluation. One boy had additional syndromic features (macrosomia, autism, bilateral eyelid ptosis, high arcade palate, irregular teeth and abnormal gait). The pedigree analysis of patients with maternally inherited CPP revealed the following affected family members: 42 mothers, 10 grandmothers, 11 sisters, 12 aunts, and 11 female cousins. Most of the families (41) had two affected consecutive generations, while eight families had three affected generations. No consanguinity was referred. Ongoing molecular analysis revealed two rare heterozygous variants in the boy with syndromic CPP and three affected family members with precocious menarche (mother, maternally half-sister, and maternally aunt): a frameshift deletion (p.F144fs) in MKKS; and a missense variant (p.P267L) in UGT2B4, which encodes a protein involved in estrogen hydroxylation and it was related to menarche timing in genome-wide association studies. Conclusions: Maternally inherited CPP was diagnosed mainly in girls, who had thelarche at mean age of 6 years old. Dominant pattern of inheritance was more prevalent, with direct maternal transmission in 72% of the studied families. New candidate genes might be implicated with maternally inherited CPP.

MKRN3 Levels in Girls with Central Precocious Puberty during GnRHa Treatment: A Longitudinal Study

2018 ◽  
Vol 90 (3) ◽  
pp. 190-195 ◽  
Author(s):  
Anna Grandone ◽  
Grazia Cirillo ◽  
Marcella Sasso ◽  
Gianluca Tornese ◽  
Caterina Luongo ◽  
...  
Keyword(s):  
Precocious Puberty ◽  
Ring Finger ◽  
Central Precocious Puberty ◽  
Serum Levels ◽  
Breast Development ◽  
Control Group ◽  
Ring Finger Protein ◽  
Finger Protein ◽  
17Β Estradiol ◽  
Puberty Onset

Background: Recently, mutations of makorin RING finger protein 3 (MKRN3) have been identified in familial central precocious puberty (CPP). Serum levels of this protein decline before the pubertal onset in healthy girls and boys and are lower in patients with CPP compared to prepubertal matched pairs. The aim of our study was to investigate longitudinal changes in circulating MKRN3 levels in patients with CPP before and during GnRH analogs (GnRHa) treatment. Methods: We performed a longitudinal prospective study. We enrolled 15 patients with CPP aged 7.2 years (range: 2–8) with age at breast development onset < 8 years and 12 control girls matched for the time from puberty onset (mean age 11.8 ± 1.2 years). Serum values of MKRN3, gonadotropins, and 17β-estradiol were evaluated before and during treatment with GnRHa (at 6 and 12 months). The MKRN3 gene was genotyped in CPP patients. In the girls from the control group, only basal levels were analyzed. Results: No MKRN3 mutations were found among CPP patients. MKRN3 levels declined significantly from baseline to 6 months of GnRHa treatment (p = 0.0007) and from 6 to 12 months of treatment (p = 0.003); MKRN3 levels at 6 months were significantly lower than in the control girls (p < 0.0001). Conclusions: We showed that girls with CPP had a decline in peripheral levels of MKRN3 during GnRHa treatment. Our data suggest a suppression of MKRN3 by continuous pharmacological administration of GnRHa.

scholarly journals Evolutionary Conservation of MKRN3 and Other Makorins and Their Roles in Puberty Initiation and Endocrine Functions

2019 ◽  
Vol 37 (04) ◽  
pp. 166-173 ◽  
Author(s):  
Lydie Naulé ◽  
Ursula B. Kaiser
Keyword(s):  
Wide Spectrum ◽  
Pubertal Timing ◽  
Pubertal Development ◽  
Protein Structures ◽  
Ring Finger ◽  
Central Precocious Puberty ◽  
Evolutionary Conservation ◽  
Loss Of Function ◽  
Underlying Mechanisms

AbstractPuberty is a critical period of development regulated by genetic, nutritional, and environmental factors. The role of makorin ring finger protein 3 (MKRN3) in the regulation of pubertal timing was revealed when loss-of-function mutations were identified in patients with central precocious puberty (CPP). To date, MKRN3 mutations are the most common known genetic cause of CPP. MKRN3 is a member of the makorin family of ubiquitin ligases, together with MKRN1 and MKRN2. The Mkrn genes have been identified in both vertebrates and invertebrates and show high evolutionary conservation of their gene and protein structures. While the existence of Mkrn orthologues in a wide spectrum of species suggests a vital cellular role of the makorins, their role in puberty initiation and endocrine functions is just beginning to be investigated. In this review, we discuss recent studies that have shown the involvement of Mkrn3 and other makorins in the regulation of pubertal development and other endocrine functions, including metabolism and fertility, as well as their underlying mechanisms of action.

scholarly journals The Peripubertal Decline in Makorin Ring Finger Protein 3 Expression is Independent of Leptin Action

2020 ◽  
Vol 4 (7) ◽  
Author(s):  
Stephanie A Roberts ◽  
Ana Paula Abreu ◽  
Victor M Navarro ◽  
Joy N Liang ◽  
Caroline A Maguire ◽  
...  
Keyword(s):  
Arcuate Nucleus ◽  
Pubertal Development ◽  
Ring Finger ◽  
Central Precocious Puberty ◽  
Mrna Levels ◽  
Ring Finger Protein ◽  
Loss Of Function ◽  
Wild Type ◽  
Finger Protein ◽  
Significant Difference

Abstract 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.

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.

Molecular Screening of MKRN3, DLK1, and KCNK9 Genes in Girls with Idiopathic Central Precocious Puberty

2017 ◽  
Vol 88 (3-4) ◽  
pp. 194-200 ◽  
Author(s):  
Anna Grandone ◽  
Carlo Capristo ◽  
Grazia Cirillo ◽  
Marcella Sasso ◽  
Giuseppina Rosaria Umano ◽  
...  
Keyword(s):  
Precocious Puberty ◽  
Rare Variants ◽  
Point Mutations ◽  
Central Precocious Puberty ◽  
Sporadic Case ◽  
Age At Menarche ◽  
Nucleotide Polymorphisms ◽  
Familial Cases ◽  
Idiopathic Central Precocious Puberty ◽  
Sporadic Cases

Background: Mutations in the imprinted gene MKRN3 have been described as a common genetic cause of idiopathic central precocious puberty (CPP), in particular in familial cases. However, the exact prevalence of mutations is unknown. Single nucleotide polymorphisms in 2 other imprinted genes, DLK1 and KCNK9, have been associated with age at menarche. We investigated the prevalence of mutations in MKRN3, DLK1, and KCNK9 genes in a cohort of girls with idiopathic CPP. Methods: MKRN3, DLK1, and KCNK9 coding regions were sequenced in 60 girls with idiopathic CPP (familial in 23 cases). Results: Three mutations, including a new one, in MKRN3 were found in 2 familial cases (c.1229G>A; p.Cys410Ter and c.477_485del; p.Pro160Cysfs*14) (8.7%) and in 1 sporadic case (c.982C>T; p.Arg328Cys) (2.8%). We did not find rare variants in DLK1 and KCNK9 genes. Conclusions: (1) The prevalence of MKRN3 mutations in our cohort was similar to that reported in the literature in sporadic cases but lower than previously described in familial ones. This could be due to different inheritance patterns of families studied; (2) we expanded the phenotype of MKRN3 defects describing 3 more patients with MKRN3 mutations; and (3) point mutations in DLK1 and KCNK9 at least do not seem to be a common cause of CPP in girls.

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