scholarly journals GENETICS IN ENDOCRINOLOGY: Genetic etiologies of central precocious puberty and the role of imprinted genes

2020 ◽  
Vol 183 (4) ◽  
pp. R107-R117
Author(s):  
Stephanie A Roberts ◽  
Ursula B Kaiser
Keyword(s):  
Precocious Puberty ◽  
Pubertal Timing ◽  
Association Studies ◽  
Hypogonadotropic Hypogonadism ◽  
Central Precocious Puberty ◽  
Imprinted Genes ◽  
Genome Wide Association Studies ◽  
Early Puberty ◽  
Imprinted Gene

Pubertal timing is regulated by the complex interplay of genetic, environmental, nutritional and epigenetic factors. Criteria for determining normal pubertal timing, and thus the definition of precocious puberty, have evolved based on published population studies. The significance of the genetic influence on pubertal timing is supported by familial pubertal timing and twin studies. In contrast to the many monogenic causes associated with hypogonadotropic hypogonadism, only four monogenic causes of central precocious puberty (CPP) have been described. Loss-of-function mutations in Makorin Ring Finger Protein 3(MKRN3), a maternally imprinted gene on chromosome 15 within the Prader–Willi syndrome locus, are the most common identified genetic cause of CPP. More recently, several mutations in a second maternally imprinted gene, Delta-like noncanonical Notch ligand 1 (DLK1), have also been associated with CPP. Polymorphisms in both genes have also been associated with the age of menarche in genome-wide association studies. Mutations in the genes encoding kisspeptin (KISS1) and its receptor (KISS1R), potent activators of GnRH secretion, have also been described in association with CPP, but remain rare monogenic causes. CPP has both short- and long-term health implications for children, highlighting the importance of understanding the mechanisms contributing to early puberty. Additionally, given the role of mutations in the imprinted genes MKRN3 and DLK1 in pubertal timing, other imprinted candidate genes should be considered for a role in puberty initiation.

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.

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.

MicroRNAs as Biomarker for Breast Cancer

2020 ◽  
Vol 20 (10) ◽  
pp. 1597-1610 ◽  
Author(s):  
Taru Aggarwal ◽  
Ridhima Wadhwa ◽  
Riya Gupta ◽  
Keshav Raj Paudel ◽  
Trudi Collet ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Association Studies ◽  
Large Family ◽  
Breast Cancer Diagnosis ◽  
Cell Multiplication ◽  
Cell Physiology ◽  
Gene Transcript ◽  
Genome Wide Association Studies ◽  
Non Coding Rnas

Regardless of advances in detection and treatment, breast cancer affects about 1.5 million women all over the world. Since the last decade, genome-wide association studies (GWAS) have been extensively conducted for breast cancer to define the role of miRNA as a tool for diagnosis, prognosis and therapeutics. MicroRNAs are small, non-coding RNAs that are associated with the regulation of key cellular processes such as cell multiplication, differentiation, and death. They cause a disturbance in the cell physiology by interfering directly with the translation and stability of a targeted gene transcript. MicroRNAs (miRNAs) constitute a large family of non-coding RNAs, which regulate target gene expression and protein levels that affect several human diseases and are suggested as the novel markers or therapeutic targets, including breast cancer. MicroRNA (miRNA) alterations are not only associated with metastasis, tumor genesis but also used as biomarkers for breast cancer diagnosis or prognosis. These are explained in detail in the following review. This review will also provide an impetus to study the role of microRNAs in breast cancer.

scholarly journals Genetic Determinants of Paget’s Disease of Bone

2021 ◽  
Author(s):  
Navnit S. Makaram ◽  
Stuart H. Ralston
Keyword(s):  
Genetic Factors ◽  
Association Studies ◽  
Paget’S Disease ◽  
Paget's Disease ◽  
Paget’S Disease Of Bone ◽  
Genome Wide Association Studies ◽  
Paget's Disease Of Bone ◽  
Genome Wide ◽  
Family Based

Abstract Purpose of Review To provide an overview of the role of genes and loci that predispose to Paget’s disease of bone and related disorders. Recent Findings Studies over the past ten years have seen major advances in knowledge on the role of genetic factors in Paget’s disease of bone (PDB). Genome wide association studies have identified six loci that predispose to the disease whereas family based studies have identified a further eight genes that cause PDB. This brings the total number of genes and loci implicated in PDB to fourteen. Emerging evidence has shown that a number of these genes also predispose to multisystem proteinopathy syndromes where PDB is accompanied by neurodegeneration and myopathy due to the accumulation of abnormal protein aggregates, emphasising the importance of defects in autophagy in the pathogenesis of PDB. Summary Genetic factors play a key role in the pathogenesis of PDB and the studies in this area have identified several genes previously not suspected to play a role in bone metabolism. Genetic testing coupled to targeted therapeutic intervention is being explored as a way of halting disease progression and improving outcome before irreversible skeletal damage has occurred.

scholarly journals Enteric Viruses and Inflammatory Bowel Disease

Viruses ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 104
Author(s):  
Georges Tarris ◽  
Alexis de Rougemont ◽  
Maëva Charkaoui ◽  
Christophe Michiels ◽  
Laurent Martin ◽  
...  
Keyword(s):  
Association Studies ◽  
Enteric Viruses ◽  
Enteric Virus ◽  
Viral Gastroenteritis ◽  
Blood Group Antigens ◽  
Genome Wide Association Studies ◽  
Virus Infections ◽  
T Helper ◽  
Inflammatory Bowel

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a multifactorial disease in which dietary, genetic, immunological, and microbial factors are at play. The role of enteric viruses in IBD remains only partially explored. To date, epidemiological studies have not fully described the role of enteric viruses in inflammatory flare-ups, especially that of human noroviruses and rotaviruses, which are the main causative agents of viral gastroenteritis. Genome-wide association studies have demonstrated the association between IBD, polymorphisms of the FUT2 and FUT3 genes (which drive the synthesis of histo-blood group antigens), and ligands for norovirus and rotavirus in the intestine. The role of autophagy in defensin-deficient Paneth cells and the perturbations of cytokine secretion in T-helper 1 and T-helper 17 inflammatory pathways following enteric virus infections have been demonstrated as well. Enteric virus interactions with commensal bacteria could play a significant role in the modulation of enteric virus infections in IBD. Based on the currently incomplete knowledge of the complex phenomena underlying IBD pathogenesis, future studies using multi-sampling and data integration combined with new techniques such as human intestinal enteroids could help to decipher the role of enteric viruses in IBD.

Stroke Genetics: Turning Discoveries into Clinical Applications

Stroke ◽  
2021 ◽  
Author(s):  
Martin Dichgans ◽  
Nathalie Beaufort ◽  
Stephanie Debette ◽  
Christopher D. Anderson
Keyword(s):  
Mendelian Randomization ◽  
Association Studies ◽  
Clinical Applications ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Neuroprotective Agents ◽  
Experimental Systems ◽  
Genome Wide ◽  
Rapid Pace

The field of medical and population genetics in stroke is moving at a rapid pace and has led to unanticipated opportunities for discovery and clinical applications. Genome-wide association studies have highlighted the role of specific pathways relevant to etiologically defined subtypes of stroke and to stroke as a whole. They have further offered starting points for the exploration of novel pathways and pharmacological strategies in experimental systems. Mendelian randomization studies continue to provide insights in the causal relationships between exposures and outcomes and have become a useful tool for predicting the efficacy and side effects of drugs. Additional applications that have emerged from recent discoveries include risk prediction based on polygenic risk scores and pharmacogenomics. Among the topics currently moving into focus is the genetics of stroke outcome. While still at its infancy, this field is expected to boost the development of neuroprotective agents. We provide a brief overview on recent progress in these areas.

scholarly journals Current knowledge in hypertension genetics: mosaic theory, candidate genes and genome-wide association studies

2020 ◽  
Vol 26 (5) ◽  
pp. 490-500
Author(s):  
A. O. Konradi
Keyword(s):  
Candidate Genes ◽  
High Performance ◽  
New Technologies ◽  
Current Knowledge ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Modern Approach ◽  
Genome Wide

The article reviews monogenic forms of hypertension, data on the role of heredity of essential hypertension and candidate genes, as well as genome-wide association studies. Modern approach for the role of genetics is driven by implementation of new technologies and their productivity. High performance speed of new technologies like genome-wide association studies provide data for better knowledge of genetic markers of hypertension. The major goal nowadays for research is to reveal molecular pathways of blood pressure regulation, which can help to move from populational to individual level of understanding of pathogenesis and treatment targets.

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.

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