Aromatase deficiency caused by mutation of CYP19A1 gene: A case report / 中南大学学报(医学版)

Aromatase deficiency (AD) is a rare autosomal recessive genetic disease caused by loss-of-function mutations in aromatase gene (CYP19A1), leading to congenital estrogen deficiency syndrome. Both mothers of AD patients during pregnancy and female AD fetus show virilization, while male patients are usually diagnosed in adulthood due to continued height increase and metabolic abnormalities. In 2019, a patient with AD was admitted in the Second Xiangya Hospital. The patient was a 37-year-old adult male who continued to grow linearly after adulthood. His estradiol was below the measurable line, the follicle-stimulating hormone (FSH) increased, bone age delayed, epiphysis unfused, and the bone mass reduced. CYP19A1 gene detection showed that c.1093C>T, p.R365W was homozygous mutation. This disease is rare in clinic. Clinicians need to raise awareness of the disease for early diagnosis and treatment to improve the long-term prognosis of patients.

Influence of CYP19A1 gene expression levels in women with breast cancer: a systematic review of the literature

Breast cancer is the most frequently diagnosed malignant neoplasm in women and is considered a multifactorial disease of unknown etiology. One of the major risk factors is genetic alteration. Changes in CYP19A1 gene expression levels have been associated with increased risk and increased aggressiveness of breast cancer. Increased CYP19A1 gene expression and/or aromatase activity are among the major regulatory events for intratumoral production of estrogens in breast malignant tissues. This systematic review aimed to investigate the influence of CYP19A1 gene expression levels in women with breast cancer. The research was carried out using the PubMed, Scopus, and Web of Science databases. Searches were conducted between February 2 and May 15, 2019. Inclusion criteria were studies published between 2009 and 2019, English language publications, and human studies addressing the gene expression of CYP19A1 in breast cancer. A total of 6.068 studies were identified through PubMed (n=773), Scopus (n=2,927), and the Web of Science (n=2,368). After selecting and applying the inclusion and exclusion criteria, six articles were included in this systematic review. This systematic review provides evidence that increased or decreased levels of CYP19A1 gene expression may be related to pathological clinical factors of disease, MFS, OS, DFS, WATi, markers of metabolic function, concentrations of E1, FSH, and in the use of multiple exons 1 of the CYP19A1 gene in breast cancer.

Loss-of-function of sox3 causes follicle development retardation and reduces fecundity in zebrafish

Folliculogenesis is essential for production of female gametes in vertebrates. However, the molecular mechanisms underlying follicle development, particularly apoptosis regulation in ovary, remain elusive. Here, we generated sox3 knockout zebrafish lines using CRISPR/Cas9. sox3 knockout led to follicle development retardation and a reduced fecundity in females. Comparative analysis of transcriptome between sox3 and wild-type ovaries revealed that Sox3 was involved in pathways of ovarian steroidogenesis and apoptosis. Knockout of sox3 promoted follicle apoptosis and obvious apoptosis signals were detected in somatic cells of stages III and IV follicles of sox3 ovaries. Moreover, Sox3 can bind to and activate the promoter of cyp19a1a. Up-regulation of Cyp19a1a expression promoted 17β-estradiol synthesis, which inhibited apoptosis in follicle development. Thus, Sox3 functions as a regulator of Cyp19a1a expression, via 17β-E2 linking apoptosis suppression, which is implicated in improving female fecundity.

Pretentious genomic selection signatures in CYP19A1 gene associated with silent estrous behavior in water buffalo in Pakistan

Background: Poor reproductive efficiency of river buffalos hampers the production capabilities of animals. Buffalos are mainly considered poor breeders owing to the constrained expression of estrus behavior. Failure to display heat signs is an indication of improper functionality of signaling peptides to trigger on a series of behavioral changes, which can be detectable by breeders for timely insemination of females. This might cause an animal to be a repeat breeder. Genomic variations underlying synthesis of signaling peptides can be a useful marker to select superior animals with better reproductive efficiency. In this context, the current study was designed to analyze the CYP19A1 gene in Nili-Ravi buffalo. Results: A total of 97 animals were selected and were divided into two groups on the basis of their heat score. PCR amplification and sequencing of the amplicons were performed using the specific sets of primer, and then, sequences were analyzed for novel variants. A total of 11 polymorphic sites were identified illustrating phenotypic variation in the heat score. Most of the loci were found homologous. Single Nucleotide Polymorphisms (SNPs) were analyzed for association with silent estrus. A three-dimensional protein model was also generated to locate the position of exonic SNPs. Conclusion: This study illustrated that polymorphic sites in the CYP19A1 gene provided potential markers for selection of buffalos with better estrus behavior.

Association of CYP19A1 gene rs7176005 single nucleotide polymorphism with breast cancer risk and clinicopathologic features of tumor / 中华预防医学杂志

Objective@#The aim of this study was to investigate the association of the CYP19A1 rs7176005 single nucleotide polymorphism (SNP) with breast cancer risk and with clinicopathologic features of tumors.@*Methods@#This study was conducted by including 138 patients with breast cancer (cancer group), those who diagnosed as primary breast cancer after operation by pathology. There were 293 cases in the group of benign breast disease which was presented as a solid mass by the color ultrasound and pathologically diagnosed as "fibroadenoma or adenosis" (benign breast disease group), the cases were paired with breast cancer patients by age±5 in the same period, and there were 259 cases in the group of healthy control who received routine physical examination during the same period and were paired with breast cancer patients by age±5 without any detection of breast related diseases (healthy control group) at West China hospital between September 2012 and November 2016. The CYP19A1 rs7176005 SNP was detected by a direct sequencing method. Hardy-Weinberg test was used to analyze the genetic balance of the 3 groups. Chi square test was used to compare the distribution of rs7176005 genotypes between the 3 groups, and the differences of clinicopathological features in breast cancer patients carrying different genotypes.@*Results@#The ages of the breast cancer cases, the benign breast disease group and the healthy control group were (44.69±8.09), (42.33±11.44) and (41.92±9.61) years old, respectively. Hardy-Weinberg equilibrium test identified that the composition ratios of alleles C and T in breast cancer group, benign breast disease group and healthy group were not statistically significant (χ2 values were 0.83, 0.34 and 0.04, respectively, P values were 0.363, 0.561, and 0.852, respectively). All the three groups met the genetic balance, had consistency and could represent the population. Among the 138 cases of breast cancer, the CYP19A1 rs7176005 SNP was significantly associated with the diameter of the tumor (P=0.031). The majority of tumor size was <2 cm in patients who carrying TT and CT genotypes, and the proportion was 75% (12/16) and 58% (40/69), respectively. While those patients with TT genotype were mainly >2 cm and ≤5 cm, and the proportion was 51% (27/53). The distribution of TNM stage among patients with different genotypes was also statistically significant (χ2=11.19, P=0.025). The most common stage was Ⅱ in Patients who carrying CC and CT genotypes, and the proportion was 45.3% (24/53) and 52.2% (36/69), respectively. While those patients with TT genotype was mainly in stage Ⅰ and the proportion was 56.3% (9/16).@*Conclusion@#Though the CYP19A1 rs7176005 SNP is not associated with breast cancer development, breast cancer patients with the C allele exhibit a high tumor growth rate and large diameters.

Effects of Si-Wu Mixture on Ovarian Granulose Cell Treated with Cisplatin through TGF-β3 Protein Pathway / 世界科学技术-中医药现代化

This study was aimed to investigate the effects of Si-Wu mixture on the secretion of E2 and the expression of CYP19al gene in granulosa cells after cell injury.Ovarian granulosa cells of SD rats were treated with cisplatin (CDDP).And the expression levels of E2 and CYP19a1 were determined by different testing methods.The results showed that the level of E2 induced by radioimmunoassay of the Si-Wu group was significantly higher than that of the CDDP group.Meanwhile,the group which added TGF-β3 protein pathway blocker was lower than others.The results of immunohistochemistry and western blotting showed that the expression level of CYP 19a1 of the Si-Wu group was higher than that of the CDDP group.In the western blotting,the group which added blocker was significantly lower than the non-blocking group.It was concluded that the pharmacological serum of Si-Wu mixture can enhance the level of E2 in CDDP cells through TGF-β3 protein pathway.And the effect is accomplished by the intervention of CYP 19a1.

Molecular mechanisms of luteinization

Dynamic changes in steroidogenesis occur in ovarian granulosa cells during ovulation after the LH surge. The ovulatory LH surge induces rapid up-regulation of steroidogenic acute regulatory (StAR) protein and rapid down-regulation of aromatase (Cyp19a1) in granulosa cells undergoing luteinization during ovulation. These rapid changes in StAR and Cyp19a1 gene expression after the LH surge efficiently facilitate progesterone production, which plays a crucial role in ovulation and the following luteinization. Recently, it has become clear that epigenetic regulation such as histone modifications and DNA methylation play a key role in gene expression through the chromatin remodeling of the promoter region. This study reports the in vivo evidence that epigenetic mechanisms including histone modifications, DNA methylation and chromatin remodeling are involved in the rapid changes of StAR and Cyp19a1 gene expression in granulosa cells undergoing luteinization during ovulation.

Mulheres inférteis com endometriose pélvica mínima e leve submetidas à estimulacão ovariana apresentam menor expressão do gene CYP19A1 em células do cumulus / Infertile women with minimal and mild endometriosis submitted tocontrolled ovarian stimulation present lower expression of the gene CYP19A1 in cumulus cells

Objetivo: Menores taxas de gestação em portadoras de endometriose submetidas a técnicas de reprodução assistida podem estar relacionadas à piora da qualidade oocitária. A análise da expressão gênica em células do cumulus (CC) pode fornecer biomarcadores passíveis de predizer a qualidade gamética. O objetivo deste estudo foi comparar os níveis da expressão do gene CYP19A1 em CC de mulheres inférteis com endometriose mínima/leve (I/II) e controles inférteis. Método: Foram selecionadas pacientes com infertilidade por endometriose pélvica inicial e por fator masculino e/ou tubário (grupo controle), submetidas à estimulação ovariana controlada para injeção intracitoplasmática de espermatozoide (ICSI). Imediatamente após a captação oocitária, CC foram isoladas e armazenadas. Foi realizada a quantificação da expressão do gene CYP19A1 nas CC por meio de PCR-Real Time. Resultados: Foram isoladas CC de 23 mulheres inférteis com endometriose I/II e de 41 controles. Observou-se expressão significativamente menor do gene CYP19A1 em CC de mulheres inférteis com endometriose I/II (0,56 ± 0,17) quando comparadas às controles (0,15 ± 0,04) (p = 0,043). Conclusões: A menor expressão do gene CYP19A1 em CC de mulheres inférteis com endometriose pélvica em estágios iniciais pode mediar a piora da qualidade oocitária, abrindo novas perspectivas no entendimento da etiopatogênese da infertilidade relacionada à doença.

Objective: Lower pregnancy rate in women with endometriosis submitted to assisted reproductive techniques might be related to poor oocyte quality. The analysis of the expression of the genes in cumulus cells (CC) might provide biomarkers that can predict gamete quality. The main objective of the present study was to compare the levels of the expression of the gene CYP19A1 in CC of infertile women with minimal and mild (I/II) endometriosis and infertile controls. Method: There were selected patients with infertility caused by initial pelvic endometriosis and by male/tubal factor (control group), submitted to controlled ovarian stimulation to ICSI. Immediately after the oocyte retrieval, CC were isolated and stored. Quantification of the expression of the gene CYP19A1 in CC was performed using PCR-real time.Results: CC were isolated from 23 infertile women with endometriosis I/II and 41 from control. Significant lower expression of the gene CYP19A1 in CC was observed in infertile women with endometriosis I/II (0.56 ± 0.17) when compared to control (0.15 ± 0.04) (p = 0,043). Conclusions: The lower expression of the gene CYP19A1 in CC of infertile women with pelvic endometriosis in initial stages might mediate the poor oocyte quality, opening new perspectives on the understanding of the etiopathogenesis of infertility related to the disease.