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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
Tomohiro Ishii, Ryuji Fukuzawa, Takeshi Sato, Koji Muroya, Masanori Adachi, Kenji Ihara, Junko Igaki, Yukihiro Hasegawa, Seiji Sato, Toshikatsu Mitsui, Tomonobu Hasegawa
OBJECTIVE: Congenital lipoid adrenal hyperplasia (lipoid CAH) results in impairment of adrenal and gonadal steroidogenesis caused by STAR mutations. Our previous study revealed upregulation of genes associated with inflammatory or immune response and macrophage infiltration in the adrenal cortex of Star-knockout mice. This study aimed at investigating macrophage infiltration in the gonads from human patients with lipoid CAH. DESIGN: This study includes seven patients with lipoid CAH who underwent gonadectomy: two XX women (age, 22 and 40 years) and five XY boys (1 year)...
August 2016: European Journal of Endocrinology
Inas Mazen, Mohamed Abdel-Hamid, Mona Mekkawy, Joëlle Bignon-Topalovic, Radia Boudjenah, Mona El Gammal, Mona Essawi, Anu Bashamboo, Ken McElreavey
The phenotypic spectrum of patients carrying NR5A1 mutations ranges from 46,XY gonadal dysgenesis to male infertility. Phenotypic variability could be due to digenic or oligogenic inheritance of pathogenic variants in other testis-determining genes. Here, exome sequencing identified 2 pathogenic de novo NR5A1 mutations in 2 patients with 46,XY gonadal dysgenesis, p.Q206Tfs*20 and p.Arg313Cys. The latter patient also carried a missense mutation in MAP3K1. Our data extend the number of NR5A1 gene mutations associated with gonadal dysgenesis...
2016: Sexual Development: Genetics, Molecular Biology, Evolution, Endocrinology, Embryology, and Pathology of Sex Determination and Differentiation
H Tuhan, A Anik, G Catli, H Onay, A Aykut, A Abaci, E Bober
Steroidogenic factor-1 (SF-1), also known as nuclear receptor subfamily 5 group A member 1 (NR5A1), is a member of orphan receptor subfamily and located on chromosome 9 (9q33). In 46, XY individuals with mutation of SF-1 gene, adrenal failure, testis dysgenesis, androgen synthesis defects, hypospadias and anorchia with microphallus, infertility can occur from severe to mild. We report a case of a 20-day-old male who is admitted to our clinic due to ambiguous genitalia. In this report, we describe a novel heterozygous c...
May 2, 2016: Andrologia
J Boberg, M Axelstad, T Svingen, K Mandrup, S Christiansen, A M Vinggaard, U Hass
Parabens comprise a group of preservatives commonly added to cosmetics, lotions, and other consumer products. Butylparaben has estrogenic and antiandrogenic properties and is known to reduce sperm counts in rats following perinatal exposure. Whether butylparaben exposure can affect other endocrine sensitive endpoints, however, remains largely unknown. In this study, time-mated Wistar rats (n = 18) were orally exposed to 0, 10, 100, or 500 mg/kg bw/d of butylparaben from gestation day 7 to pup day 22. Several endocrine-sensitive endpoints were adversely affected...
July 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
Mohamed M A Hussein, Haytham A Ali, Islam M Saadeldin, Mona M Ahmed
Zinc oxide nanopartciles (ZnONPs) involved in advanced technologies, and their wide-scale use in consumer market makes human beings more prone to the exposure to ZnONPs. The present study was undertaken to evaluate amelioration of ZnONP-induced toxicities with querectin in male albino rats. ZnONPs-treated rats showed a significant decrease in sperm cell count, sperm motility, live and normal sperms, as well as serum testosterone level. Severe histopathological damage with a significant increase in lipid peroxidation and a decrease in antioxidant enzymes activity and the GSH level were observed in the affected testis...
April 25, 2016: Journal of Biochemical and Molecular Toxicology
Fumie Kubota-Nakayama, Yasuhiro Nakamura, Sachiko Konosu-Fukaya, Abdullah Azmahani, Kazue Ise, Yuto Yamazaki, Yuko Kitawaki, Saulo J A Felizola, Yoshikiyo Ono, Kei Omata, Ryo Morimoto, Noriyuki Iwama, Fumitoshi Satoh, Hironobu Sasano
Adrenal Cushing syndrome (CS) is caused by the overproduction of cortisol in adrenocortical tumors including adrenal cortisol-producing adenoma (CPA). In CS, steroidogenic enzymes such as 17α-hydroxylase/17, 20-lase (CYP17A1), 3β-hydroxysteroid dehydrogenase (HSD3B), and 11β-hydroxylase (CYP11B1) are abundantly expressed in tumor cells. In addition, several transcriptional factors have been reported to play pivotal roles in the regulation of these enzymes in CPA, but their correlations with those enzymes above have still remained largely unknown...
August 2016: Human Pathology
Qing-Ping Xie, Xue He, Yi-Ning Sui, Li-Li Chen, Li-Na Sun, De-Shou Wang
Steroidogenic factor-1 (Sf-1) (officially designated nuclear receptor subfamily 5 group A member 1 [NR5A1]) is a master regulator of steroidogenesis and reproduction in mammals. However, its function remains unclear in nonmammalian vertebrates. In the present study, we used immunohistochemistry to detect expression of Sf-1 in the steroidogenic cells, the interstitial, granulosa, and theca cells of the ovary, and the Leydig cells of the testis, in Nile tilapia. Clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 (Cas9) cleavage of sf-1 resulted in a high mutation rate in the F0 generation and a phenotype of gonadal dysgenesis and reduced steroidogenic cells in XX and XY fish...
June 2016: Endocrinology
Nan Miao, Xin Wang, Yue Hou, Yanping Feng, Yanzhang Gong
Several studies indicate that sexual dimorphic microRNAs (miRNAs) in chicken gonads are likely to have important roles in sexual development, but a more global understanding of the roles of miRNAs in sexual differentiation is still needed. To this end, we performed miRNA expression profiling in chicken gonads at embryonic day 5.5 (E5.5). Among the sex-biased miRNAs validated by qRT-PCR, twelve male-biased and six female-biased miRNAs were consistent with the sequencing results. Bioinformatics analysis revealed that some sex-biased miRNAs were potentially involved in gonadal development...
July 5, 2016: Molecular and Cellular Endocrinology
Ralf Werner, Isabel Mönig, Julia August, Clemens Freiberg, Ralf Lünstedt, Benedikt Reiz, Lutz Wünsch, Paul-Martin Holterhus, Alexandra Kulle, Ulla Döhnert, Stefan A Wudy, Annette Richter-Unruh, Christoph Thorns, Olaf Hiort
The differential diagnosis of 46,XY disorders of sex development (DSD) is based on the distinction between forms of gonadal dysgenesis and disorders of androgen biosynthesis and action. However, clinical and endocrine evaluations are often not conclusive. Here, we describe an adolescent female with hirsutism and hyperandrogenization at puberty. Her karyotype was 46,XY, and clinical investigation demonstrated clitoromegaly, but no uterine remnants were detected. Histology of the gonads revealed a testicular structure with a Sertoli-cell-only pattern...
2015: Sexual Development: Genetics, Molecular Biology, Evolution, Endocrinology, Embryology, and Pathology of Sex Determination and Differentiation
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