A novel stopgain mutation c.G992A (p.W331X) in <i>TACR3</i> gene was identified in nonobstructive azoospermia by targeted next‐generation sequencing

Epigenetics & Chromatin

Wang

et al. 2023

Background Sex determination and differentiation are complex and delicate processes. In female chickens, the process of sex differentiation is sensitive and prone to be affected by the administration of aromatase inhibitors, which result in chicken sex reversal and infertility. However, the molecular mechanisms underlying sex differentiation and infertility in chicken sex reversal remain unclear. Therefore, we established a sex-reversed chicken flock by injecting an aromatase inhibitor, fadrozole, and constructed relatively high-resolution profiles of the gene expression and chromatin accessibility of embryonic gonads. Results We revealed that fadrozole affected the transcriptional activities of several genes, such as DMRT1, SOX9, FOXL2, and CYP19A1, related to sex determination and differentiation, and the expression of a set of gonadal development-related genes, such as FGFR3 and TOX3, by regulating nearby open chromatin regions in sex-reversed chicken embryos. After sexual maturity, the sex-reversed chickens were confirmed to be infertile, and the possible causes of this infertility were further investigated. We found that the structure of the gonads and sperm were greatly deformed, and we identified several promising genes related to spermatogenesis and infertility, such as SPEF2, DNAI1, and TACR3, through RNA-seq. Conclusions This study provides clear insights into the exploration of potential molecular basis underlying sex differentiation and infertility in sex-reversed chickens and lays a foundation for further research into the sex development of birds.

Section: Discussionmentioning

confidence: 99%

ATAC-seq and RNA-seq analysis unravel the mechanism of sex differentiation and infertility in sex reversal chicken

Epigenetics & Chromatin

Wang

et al. 2023

“…Mutation screening of genes associated with spermatogenesis was carried out by targeted exome sequencing as described previously . Genomic DNA was isolated from peripheral blood samples of all patients and subjected to exome capture using the in‐house targeted genes panel (Peking Medriv Academy of Genetics and Reproduction, Peking).…”

Section: Methodsmentioning

confidence: 99%

Identification of KISS1R gene mutations in disorders of non‐obstructive azoospermia in the northeast population of China

Geng

Clinical Laboratory Analysis

Liu

et al. 2019

Self Cite

Background: Non-obstructive azoospermia (NOA), a serious phenotype of male spermatogenesis failure, is a multifactorial disease which is regulated by genetic, epigenetic, and environmental factors. Some gene structural variants have been demonstrated to be related to NOA. Loss-of-function mutations of KISS1R cause normosmic idiopathic hypogonadotropic hypogonadism (IHH) which result in azoospermia at the pre-testicular level. The objective of this research was to investigate genetic variants of KISS1R in NOA patients. Methods:The entire coding region of 52 spermatogenesis-associated genes (KISS1R included) was sequenced from 200 NOA patients. Mutation screening was performed to identify genetic variations of these genes by targeted exome sequencing. Sequencing data analysis was carried out by a series of bioinformatics tools.Candidate variants confirmation was performed by Sanger sequencing. Functional analysis of candidate variants was evaluated using SIFT and PolyPhen-2.Results: Three heterozygous missense variants in KISS1R were identified in three patients, respectively. No deleterious variations in other candidate genes were found in the three patients. Two of these three variants, p.A211T and p.G186E, had been reported in the ExAC and dbSNP database, respectively, while the other variant p.A301D was novel. These variants were all predicted to be likely pathogenic by in silico analysis. Conclusion:Our study revealed three heterozygous missense variants in KISS1R which expanded the mutation spectrum of KISS1R in infertile men with NOA in the northeast of China.

“…Because of its role in growth, development, and reproduction, Tacr3 /NK3R is associated with many diseases such as hypogonadotropic hypogonadism, , idiopathic central precocious puberty, − and nonobstructive azoospermia . In addition, in the rat model of developmental hypothyroidism, Tacr3 in the hippocampal CA1 region shows a sustained increase in Tacr3- expressing cells until adult age, suggesting that Tacr3 /NK3R is also involved in some growth-related endocrine diseases.…”

Section: Functions Of Tacr3/nk3rmentioning

confidence: 99%

Tacr3/NK3R: Beyond Their Roles in Reproduction

Wang

Chu

2020

ACS Chem. Neurosci.

The Tacr3 gene encodes tachykinin receptor 3 (NK3R), which belongs to the tachykinin receptor family. This family of proteins includes typical G protein-coupled receptors and belongs to the rhodopsin subfamily. NK3R functions by binding to its high-affinity ligand, neurokinin B(NKB). The role of Tacr3/NK3R in growth and reproduction has been extensively studied, but Tacr3/NK3R is also widely expressed in the nervous system from the spinal cord to the brain and is involved in both physiological and pathological processes in the nervous system, including mood disorders, chronic pain, learning and memory deficiencies, Alzheimer's disease, Parkinson's disease, addiction-related processes, hypoxicischemic encephalopathy, body fluid management, neural development, and schizophrenia. Here, we summarize the structure of NK3R/NKB and its cellular signaling as well as the expression of Tacr3/NK3R in the nervous system, and we provide a comprehensive summary of the role of Tacr3/NK3R in neurological diseases, including reproduction-related disorders and other neurological diseases. At the end of this review, we propose the hypothesis that Tacr3/NK3R mediates a variety of brain functions by affecting the excitability of different neurons with specific functions. On the basis of this "excited or not" hypothesis, more studies related to Tacr3 should be carried out in other nervous system diseases in order to better understand the biological roles of Tacr3.