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Amany Abdel-Rahman Mohamed, Wafaa A M Mohamed, Safaa I Khater
This study aimed to evaluate the adverse effects of the insecticide imidacloprid (IMI) on male spermatogenesis, steroidogenesis, and DNA damage in sexually mature and immature rats. Forty male rats (mature and immature) were equally divided into four groups: two mature and two immature groups. IMI groups of both ages were orally administered IMI in corn oil at a concentration of 1 mg/mL for kg BW/day, whereas their respective controls were orally administered corn oil only (1 mL/kg of body weight) daily for 65 days...
November 30, 2016: Environmental Pollution
Raja Brauner, Flavia Picard-Dieval, Henri Lottmann, Sébastien Rouget, Joelle Bignon-Topalovic, Anu Bashamboo, Ken McElreavey
BACKGROUND: Families with 46,XY Disorders of Sex Development (DSD) have been reported, but they are considered to be exceptionally rare, with the exception of the familial forms of disorders affecting androgen synthesis or action. The families of some patients with anorchia may include individuals with 46,XY gonadal dysgenesis. We therefore analysed a large series of patients with 46,XY DSD or anorchia for the occurrence in their family of one of these phenotypes and/or ovarian insufficiency and/or infertility and/or cryptorchidism...
November 29, 2016: BMC Pediatrics
Anu Bashamboo, Caroline Eozenou, Sandra Rojo, Ken McElreavey
Human sex-determination (SD) involves complex mutually antagonistic genetic interactions of testis- and ovary-determining pathways. For many years both male and female sex-determination was considered to be regulated by a linear cascade of pro-male and pro-female genes respectively, however it has become clear that male and female development is achieved through the repression of the alternative state. A gene determining the formation of a testis may function by repressing the female state and vice-versa. Uniquely in development, SD is achieved by suppression of the alternate fate and maintained in adulthood by a mutually antagonistic double-repressive pathway...
November 28, 2016: Clinical Genetics
Pierre B Cattenoz, Claude Delaporte, Wael Bazzi, Angela Giangrande
NR5A1 is essential for the development and for the function of steroid producing glands of the reproductive system. Moreover, its misregulation is associated with endometriosis, which is the first cause of infertility in women. Hr39, the Drosophila ortholog of NR5A1, is expressed and required in the secretory cells of the spermatheca, the female exocrine gland that ensures fertility by secreting substances that attract and capacitate the spermatozoids. We here identify a direct regulator of Hr39 in the spermatheca: the Gcm transcription factor...
November 25, 2016: Scientific Reports
Jonathan M Swartz, Ryan Ciarlo, Michael H Guo, Aser Abrha, Benjamin Weaver, David A Diamond, Yee-Ming Chan, Joel N Hirschhorn
BACKGROUND: A variant in steroidogenic factor-1 (SF-1, encoded by the gene NR5A1), p.Arg92Trp, has recently been reported in multiple families with 46,XX ovotesticular or testicular disorders of sex development (DSD). This amino acid change impacts the DNA-binding domain and perturbs gonadal differentiation pathways. METHODS: Whole-exome sequencing was performed on a 46,XX subject with ovotesticular DSD. RESULTS: Exome results identified a heterozygous NR5A1 variant, p...
November 18, 2016: Hormone Research in Pædiatrics
Mami Miyado, Masafumi Inui, Maki Igarashi, Yuko Katoh-Fukui, Kei Takasawa, Akiko Hakoda, Junko Kanno, Kenichi Kashimada, Kenji Miyado, Moe Tamano, Tsutomu Ogata, Shuji Takada, Maki Fukami
NR5A1 is the key regulator of adrenal and gonadal development in both humans and mice. Recently, a missense substitution in human NR5A1, p.R92W, was shown to underlie gonadal dysgenesis in genetic males and testicular formation in genetic females. Here, we investigated the phenotypic effects of the p.R92W mutation on murine development. Mice carrying the p.R92W mutation manifested a similar but milder phenotype than that of the previously described Nr5a1 knockout mice. Importantly, mutation-positive XX mice showed no signs of masculinization...
2016: Biology of Sex Differences
Sunita M C De Sousa, Karin S Kassahn, Liam C McIntyre, Chan-Eng Chong, Hamish S Scott, David J Torpy
BACKGROUND: The 46,XY female is characterised by a male karyotype and female phenotype arising due to any interruption in the sexual development pathways in utero. The cause is usually genetic and various genes are implicated. CASE PRESENTATION: Herein we describe a 46,XY woman who was first diagnosed with androgen insensitivity syndrome (testicular feminisation) at 18 years; however, this was later questioned due to the presence of intact Müllerian structures...
November 8, 2016: BMC Endocrine Disorders
Dorien Baetens, Bérénice B Mendonça, Hannah Verdin, Martine Cools, Elfride De Baere
Genetic studies in Disorders of Sex Development (DSD), representing a wide spectrum of developmental or functional conditions of the gonad, have mainly been oriented towards the coding genome. Application of genomic technologies, such as whole exome sequencing, result in a molecular genetic diagnosis in ~50% of cases with DSD. Many of the genes mutated in DSD encode transcription factors such as SRY, SOX9, NR5A1, and FOXL2, characterized by a strictly regulated spatiotemporal expression. Hence, it can be hypothesized that at least part of the missing genetic variation in DSD can be explained by non-coding mutations in regulatory elements that alter gene expression, either by reduced, mis- or overexpression of their target genes...
November 1, 2016: Clinical Genetics
Jessica Kremen, Yee-Ming Chan, Jonathan M Swartz
PURPOSE OF REVIEW: Disorders of sex development (DSD) are a diverse group of conditions affecting gonadal development, sexual differentiation, or chromosomal sex. In this review, we will discuss recent literature on the genetic causes of DSD, with a focus on novel genetic sequencing technologies, new phenotypes associated with known DSD genes, and increasing recognition of the role of genetic regulatory elements in DSD. RECENT FINDINGS: We performed a comprehensive search of PubMed through August 2016 to identify important peer-reviewed publications from 2015 to 2016 on the topic of DSD genetics...
January 2017: Current Opinion in Urology
V Chauhan, V P Jyotsna, V Jain, R Khadgawat, R Dada
46,XY gonadal dysgenesis (GD) constitutes a rare group of disorders characterized by the presence of dysfunctional testes in genotypic males. The molecular etiology is not known in about 2 thirds of instances. The aim of this study was to identify the genetic cause in patients with 46,XY gonadal dysgenesis. Based on clinical, cytogenetic, and biochemical screening, 10 patients with 46,XY GD were recruited. Direct sequencing of SRY, NR5A1, SOX9, DAX1, DHH, DMRT1 genes was carried out for molecular analysis. Among 10 patients, 5 were diagnosed with complete gonadal dysgenesis (CGD), 3 with partial gonadal dysgenesis (PGD), and 3 with testicular agenesis...
October 6, 2016: Hormone and Metabolic Research, Hormon- und Stoffwechselforschung, Hormones et Métabolisme
Maki Igarashi, Kei Takasawa, Akiko Hakoda, Junko Kanno, Shuji Takada, Mami Miyado, Takashi Baba, Ken-Ichirou Morohashi, Toshihiro Tajima, Kenichiro Hata, Kazuhiko Nakabayashi, Yoichi Matsubara, Ryohei Sekido, Tsutomu Ogata, Kenichi Kashimada, Maki Fukami
The role of monogenic mutations in the development of 46,XX testicular/ovotesticular disorders of sex development (DSD) remains speculative. Although mutations in NR5A1 are known to cause 46,XY gonadal dysgenesis and 46,XX ovarian insufficiency, such mutations have not been implicated in testicular development of 46,XX gonads. Here, we identified identical NR5A1 mutations in two unrelated Japanese patients with 46,XX testicular/ovotesticular DSD. The p.Arg92Trp mutation was absent from the clinically normal mothers and from 200 unaffected Japanese individuals...
September 9, 2016: Human Mutation
Mabrouka Doghman-Bouguerra, Enzo Lalli
Adrenocortical carcinomas (ACC) are rare malignant tumors of the adrenal cortex whose prognosis remains ominous. Considerable progress has been made during the last few years in the identification of the molecular mechanisms implicated in their pathogenesis. Overexpression of the transcription factor Steroidogenic Factor-1 (SF-1/NR5A1), a pivotal regulator of adrenocortical development and steroidogenic function, has a stage-independent negative prognostic value in patients with ACC. (1) Studies in cell lines and animal models have shown that an increased SF-1 dosage is able to increase adrenocortical cell proliferation and triggers tumorigenesis...
August 11, 2016: Cell Cycle
Jonathan M Swartz, Ryan Ciarlo, Michael H Guo, Aser Abrha, David A Diamond, Yee-Ming Chan, Joel N Hirschhorn
BACKGROUND: Undervirilized 46,XY males with bifid scrotum often pose a diagnostic challenge, and the majority of cases typically do not receive a genetic diagnosis. NR5A1 mutations can be seen in 10-20% of the cases and are a relatively common cause of undervirilization. METHODS: Whole-exome sequencing was utilized to study 10 undervirilized 46,XY subjects with bifid scrotum. RESULTS: Exome sequencing identified novel NR5A1 variants, both affecting exon 7, in 2 of the 10 subjects with bifid scrotum...
August 24, 2016: Hormone Research in Pædiatrics
Dorien Baetens, Hans Stoop, Frank Peelman, Anne-Laure Todeschini, Toon Rosseel, Frauke Coppieters, Reiner A Veitia, Leendert H J Looijenga, Elfride De Baere, Martine Cools
PURPOSE: We aimed to identify the genetic cause in a cohort of 11 unrelated cases and two sisters with 46,XX SRY-negative (ovo)testicular disorders of sex development (DSD). METHODS: Whole-exome sequencing (n = 9), targeted resequencing (n = 4), and haplotyping were performed. Immunohistochemistry of sex-specific markers was performed on patients' gonads. The consequences of mutation were investigated using luciferase assays, localization studies, and RNA-seq. RESULTS: We identified a novel heterozygous NR5A1 mutation, c...
August 4, 2016: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Yao Wang, Maree Bilandzic, Guck T Ooi, Jock K Findlay, Kaye L Stenvers
This study tested the hypothesis that inhibins act in an autocrine manner on Leydig cells using a pre-pubertal Leydig cell line, TM3, as a model of immature Leydig cells. The expression of Inha, Inhba, and Inhbb in TM3 cells was determined by RT-PCR and the production of the inhibin-alpha subunit was confirmed by western blot. Knockdown of Inha expression resulted in significant decreases in the expression of Leydig cell markers Cyp17a1, Cyp11a1, Nr5a1, and Insl3. Western blot showed that activin A, TGFβ1 and TGFβ2 activated SMAD2, and that knockdown of Inha expression in TM3 cells enhanced both activin A- and TGFβ-induced SMAD2 activation...
November 15, 2016: Molecular and Cellular Endocrinology
Helena C Fabbri, Juliana G Ribeiro de Andrade, Andréa T Maciel-Guerra, Gil Guerra-Júnior, Maricilda P de Mello
Mutations in the NR5A1 gene, which encodes the steroidogenic factor 1 (SF1), are responsible for different phenotypes of disorders of sex development (DSD), such as bilateral anorchia and hypospadias. Furthermore, they can be associated with primary amenorrhea, premature ovarian failure, male infertility, adrenal tumors, and endometriosis. Direct sequencing of the 7 NR5A1 exons including ∼1,000 bp of the 5'-upstream and 3'-downstream regions and all intron-exon boundaries was performed in patients with DSD...
2016: Sexual Development: Genetics, Molecular Biology, Evolution, Endocrinology, Embryology, and Pathology of Sex Determination and Differentiation
Megumi Hatano, Toshiro Migita, Tomokazu Ohishi, Yuichi Shima, Yoshihiro Ogawa, Ken-Ichirou Morohashi, Yukihiro Hasegawa, Futoshi Shibasaki
Genetic mutations of steroidogenic factor 1 (also known as Ad4BP or Nr5a1) have increasingly been reported in patients with 46,XY disorders of sex development (46,XY disorders of sex development). However, because the phenotype of 46,XY disorders of sex development with a steroidogenic factor 1 mutation is wide-ranging, its precise diagnosis remains a clinical problem. We previously reported the frequent occurrence of lipid accumulation in Leydig cells among patients with 46,XY disorders of sex development with a steroidogenic factor 1 mutation, an observation also reported by other authors...
July 25, 2016: Endocrine
Tanja Spanic, Neza Grgurevic, Gregor Majdic
Steroidogenic factor 1 (SF-1), officially designated NR5A1, is essential for gonadal and adrenal development and for the normal structure of the ventromedial hypothalamus (VMH), as demonstrated by SF-1 knockout mice (SF-1 KO), but much less is known about the possible effects of haploinsufficiency of the SF-1 gene. In the present study, maternal behavior in SF-1 KO heterozygous mice was evaluated. Behavioral tests revealed that SF-1 KO heterozygous females have impaired maternal behavior. In comparison to wild-type (WT) females, SF-1 KO heterozygous females retrieved significantly fewer pups into their nests, latency to retrieve and crouch over the pups was longer, and their nests were lower quality...
2016: Frontiers in Behavioral Neuroscience
Xu Shen, Xue Bai, Jin Xu, Min Zhou, Haipin Xu, Qinghua Nie, Xuemei Lu, Xiquan Zhang
Transition from laying to incubation behavior in chicken is an interesting topic in reproductive biology. The decline of incubation behavior in chicken population has led to considerable phenotypic differences in reproductive traits between breeds. However, the exact genetic mechanism of the reproductive phase transition still largely unknown and little is known about the gene expression changes that contribute to the phenotypic differences. We performed mRNA sequencing to investigate the molecular mechanism underlying the transition from laying to brooding and to detect difference in gene regulation underlying the phenotypic diversification using two chicken breeds...
September 2016: Molecular Biology Reports
Anu Bashamboo, Patricia A Donohoue, Eric Vilain, Sandra Rojo, Pierre Calvel, Sumudu N Seneviratne, Federica Buonocore, Hayk Barseghyan, Nathan Bingham, Jill A Rosenfeld, Surya Narayan Mulukutla, Mahim Jain, Lindsay Burrage, Shweta Dhar, Ashok Balasubramanyam, Brendan Lee, Caroline Eozenou, Jenifer P Suntharalingham, Ksh de Silva, Lin Lin, Joelle Bignon-Topalovic, Francis Poulat, Carlos F Lagos, Ken McElreavey, John C Achermann
Cell lineages of the early human gonad commit to one of the two mutually antagonistic organogenetic fates, the testis or the ovary. Some individuals with a 46,XX karyotype develop testes or ovotestes (testicular or ovotesticular disorder of sex development; TDSD/OTDSD), due to the presence of the testis-determining gene, SRY Other rare complex syndromic forms of TDSD/OTDSD are associated with mutations in pro-ovarian genes that repress testis development (e.g. WNT4); however, the genetic cause of the more common non-syndromic forms is unknown...
July 4, 2016: Human Molecular Genetics
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