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Yasuhiro Nakamura - One of the best experts on this subject based on the ideXlab platform.
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Expression of steroidogenic enzymes and their transcription factors in cortisol-producing adrenocortical adenomas: immunohistochemical analysis and quantitative real-time polymerase chain reaction studies
Human Pathology, 2016Co-Authors: Fumie Kubota-nakayama, Sachiko Konosu-fukaya, Abdullah Azmahani, Yuko Kitawaki, Saulo J.a. Felizola, Yuto Yamazaki, Yasuhiro Nakamura, Kei OmataAbstract:Summary 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 17 α -hydroxylase/17, 20-lase (CYP17A1), 3 β -hydroxysteroid dehydrogenase (HSD3B), and 11 β -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. Therefore, in this study, we examined the status of steroidogenic enzymes and their transcriptional factors in 78 and 15 CPA cases by using immunohistochemistry and quantitative real-time polymerase chain reaction (qPCR), respectively. Immunoreactivity of HSD3B2, CYP11B1, CYP17A1, steroidogenic factor-1 (SF1[NR5A1]), GATA6, and nerve growth factor induced–B (NGFIB[NR4A1]) was detected in tumor cells. Results of qPCR analysis revealed that expression of HSD3B2 mRNA was significantly higher than that of HSD3B1, and CYP11B1 mRNA was significantly higher than CYP11B2. In addition, the expression of CYP11B1 mRNA was positively correlated with those of NR5A1, GATA6, and NR4A1. These results all indicated that HSD3B2 but not HSD3B1 was mainly involved in cortisol overproduction in CPA. In addition, NR5A1, GATA6, and NR4A1 were all considered to play important roles in cortisol overproduction through regulating CYP11B1 gene transcription.
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3β-hydroxysteroid dehydrogenase isoforms in human aldosterone-producing adenoma
Molecular and Cellular Endocrinology, 2014Co-Authors: Sachiko Konosu-fukaya, Saulo J.a. Felizola, Fumitoshi Satoh, Ryo Morimoto, Yasuhiro Nakamura, Takashi Maekawa, K. Takeda, Koshin KatsuAbstract:Abstract It has become important to evaluate the possible involvement of 3β-hydroxysteroid dehydrogenase type 1 (HSD3B1) and 2 (HSD3B2) isoforms in aldosterone-producing adenoma (APA). In this study, we studied 67 and 100 APA cases using real-time quantitative PCR (qPCR) and immunohistochemistry, respectively. Results of qPCR analysis demonstrated that HSD3B2 mRNA was significantly more abundant than HSD3B1 mRNA (P
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3β-Hydroxysteroid dehydrogenase isoforms in human aldosterone-producing adenoma.
Molecular and cellular endocrinology, 2014Co-Authors: Sachiko Konosu-fukaya, Saulo J.a. Felizola, Fumitoshi Satoh, Ryo Morimoto, Yasuhiro Nakamura, Takashi Maekawa, K. Takeda, Yoshikiyo Ono, Kazue Ise, Koshin KatsuAbstract:Abstract It has become important to evaluate the possible involvement of 3β-hydroxysteroid dehydrogenase type 1 (HSD3B1) and 2 (HSD3B2) isoforms in aldosterone-producing adenoma (APA). In this study, we studied 67 and 100 APA cases using real-time quantitative PCR (qPCR) and immunohistochemistry, respectively. Results of qPCR analysis demonstrated that HSD3B2 mRNA was significantly more abundant than HSD3B1 mRNA ( P HSD3B1 mRNA significantly correlated with CYP11B2 (aldosterone synthase) mRNA ( P 0.0001) and plasma aldosterone concentration (PAC) of the patients ( P 0.0001). Results of immunohistochemistry subsequently revealed that HSD3B2 immunoreactivity was detected in the great majority of APA but a significant correlation was also detected between HSD3B1 and CYP11B2 ( P 0.0001). In KCNJ5 mutated APA, CYP11B2 mRNA ( P 0.0001) and HSD3B1 mRNA ( P = 0.011) were significantly higher than those of wild type APA. These results suggest that HSD3B1 is involved in aldosterone production, despite its lower levels of expression compared with HSD3B2, and also possibly associated with KCNJ5 mutation in APA.
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Abstract 008: Novel Pathological Diagnosis Between Aldosterone Producing Adenoma And Idiopathic Hyperaldosteronism
Hypertension, 2014Co-Authors: Fumitoshi Satoh, Kei Omata, Masataka Kudo, Yoshitsugu Iwakura, Ryo Morimoto, Kazumasa Seiji, Kei Takase, Yasuhiro NakamuraAbstract:The expressions of steroidogenic enzymes to produce aldosterone like CYP11B1, CYP11B2, 3BHSD1 and 3BHSD2 remain to be clarified to confirm pathological subclassification between aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA). Furthermore, we examined the correlation between APA tumor size and the status of intratumoral steroidogenic enzymes involved in aldosterone biosynthesis using immunohistochemistry. Surgically proven forty APA patients and ten IHA patients were retrospectively studied. Multi-detector computed tomography, AVS, and laparoscopic adrenalectomy were performed in all of the patients studied. The tumor area of APA at the maximum diameter of the sections was precisely measured by ImageJ software. The status of steroidogenic enzymes was immunohistochemically analyzed using monoclonal antibodies for CYP11B1, CYP11B2, 3BHSD1 and 3BHSD2, and the findings were evaluated according to the H-score system, based on both the number of immunopositive cells and relative immunointensity. Adrenal masses were not detected by computed tomography in 20 APA patients.In all of 10 IHA patients, hyperplastic zona glomerulosa was accompanied by an expression of HSD3B1. In contrast, tumor cells in all 40 APA patients were not immunopositive to HSD3B1, but strongly and dominanty expressed HSD3B2. Perhaps, due to compensatory responses to excess aldosterone, APA had an adjacent zona glomerulosa whose immunoreactivities to HSD3B1 and HSD3B2 were profoundly reduced in all 40 APA patients. Maximum tumor area obtained in the specimens was significantly correlated with preoperative plasma aldosterone concentration, urinary aldosterone excretion, the H-score of CYP11B1, and was inversely correlated with the H-score of CYP11B2. These results demonstrated that small adenomas could produce sufficient aldosterone to cause clinically overt primary aldosteronism because of the significantly higher CYP11B2 expression per tumor area. Monoclonal antibodies against HSD3B1 and HSD3B2 could be useful for immunohistochemical differentiation between APA and IHA. In addition, the relatively higher CYP11B2 expression per area in smaller APA could clinically cause PA despite their CT-undetectable tumor size.
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isoform specific monoclonal antibodies against 3β hydroxysteroid dehydrogenase isomerase family provide markers for subclassification of human primary aldosteronism
The Journal of Clinical Endocrinology and Metabolism, 2014Co-Authors: Masao Doi, Motomi Tainaka, Yunhong Hotta, Yukari Takahashi, Jean-michel Fustin, Fumitoshi Satoh, Ryo Morimoto, Yasuhiro Nakamura, Takashi Maekawa, Kei TakaseAbstract:Context: Therapeutic management of primary aldosteronism requires accurate differentiation between aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA). However, little is known about the molecular features that delineate the difference between APA and IHA. Two different isoforms of 3β-hydroxysteroid dehydrogenase (HSD3B1 and HSD3B2) are thought to be expressed in the human adrenal gland, but the lack of isoform-specific antibody has so far hampered mapping of these isoforms in APA and IHA. Objectives: The aim of our study is to develop and characterize isoform-specific monoclonal antibodies against HSD3B1 and HSD3B2. Using these antibodies, we determined for the first time the immunolocalization of HSD3B1 and HSD3B2 in normal human adrenal cortex as well as in adrenal specimens from APA and IHA. Results: Immunohistochemical analysis with isoform-specific antibodies revealed zone-specific expression of HSD3B1 and HSD3B2 in the adrenal cortex. HSD3B1 immunoreactivities were essential...
William E. Rainey - One of the best experts on this subject based on the ideXlab platform.
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Development of monoclonal antibodies against the human 3β-hydroxysteroid dehydrogenase/isomerase isozymes
Steroids, 2017Co-Authors: Celso E. Gomez-sanchez, Kazutaka Nanba, Mark Lewis, Maniselvan Kuppusamy, William E. Rainey, Elise P. Gomez-sanchezAbstract:Abstract The human 3β-hydroxysteroid dehydrogenase/isomerase (HSD3B) enzymes catalyze the conversion of 3β-hydroxy Δ5-6 steroids into 3-keto Δ4-5 steroids, which is required for the synthesis of the mature steroid hormones secreted by the adrenal and gonads. The human has 2 isozymes, the HSD3B1 that is traditionally located in placenta and extra-adrenal tissues and the HSD3B2 that is expressed in the adrenal and gonads. Mice with both cryptochrome 1 and 2 genes deletion were recently found to have salt-sensitive hypertension and hyperaldosteronism. These deletions were also associated with overexpression of the Hsd3b6 enzyme, the homolog of the human HSD3B1, in the zona glomerulosa which was believed to explain the hyperaldosteronism. A report using antibodies against human HSD3B1 suggested that it was expressed in the zona glomerulosa of normal human adrenals and in patients with idiopathic hyperaldosteronism and the HSD3B2 expressed in both the zona fasciculata and glomerulosa. We have developed specific monoclonal antibodies against the human HSD3B1 and HSD3B2 isozymes and found that the main enzyme expressed in the zona glomerulosa was the HSD3B2. Faint staining of the adrenal was also obtained using the anti-HSD3B1antibody only at high concentrations of antibody. This study fails to confirm that HSD3B1 expression in the human zona glomerulosa and double immunofluorescence clearly shows that the HSD3B2 is expressed in the zona glomerulosa and fasciculata and in the zona glomerulosa HSD3B2 is co-expressed with aldosterone synthase (CYP11B2).
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Human adrenal cells that express both 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2) and cytochrome b5 (CYB5A) contribute to adrenal androstenedione production.
The Journal of steroid biochemistry and molecular biology, 2010Co-Authors: Yasuhiro Nakamura, Hironobu Sasano, Yewei Xing, Xiao-gang Hui, Yumi Kurotaki, Katsuhiko Ono, Tony Cohen, William E. RaineyAbstract:Androstenedione is one of several weak androgens produced in the human adrenal gland. 3β-Hydroxysteroid dehydrogenase type 2 (HSD3B2) and cytochrome b5 (CYB5A) are both required for androstenedione production. However, previous studies demonstrated the expression of HSD3B2 within the zona glomerulosa (ZG) and fasciculata (ZF) but low levels in the zona reticularis. In contrast, CYB5A expression increases in the zona reticularis (ZR) in human adrenal glands. Although their colocalization has been reported in gonadal theca and Leydig cells this has not been studied in the human adrenal. Therefore, we immonolocalized HSD3B2 and CYB5A in normal human adrenal glands and first demonstrated their co-expression in the cortical cells located at the border between the ZF and ZR in normal human adrenal. Results of in vitro studies using the human adrenal H295R cells treated with the HSD3B2 inhibitor, trilostane, also demonstrated a markedly decreased androstenedione production. Decreasing CYB5A mRNA using its corresponding siRNA also resulted in significant inhibition of androstenedione production in the H295R cells. These findings together indicate that there are a group of cells co-expressing HSD3B2 and CYB5A with hybrid features of both ZF and ZR in human adrenal cortex, and these hybrid cortical cells may play an important role in androstenedione production in human adrenal gland.
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Clinical, Biochemical, and Molecular Characterization of Macronodular Adrenocortical Hyperplasia of the Zona Reticularis: A New Syndrome
Endocrinology, 2010Co-Authors: Hans K. Ghayee, Juilee Rege, William E. Rainey, Lori M Watumull, Fiemu E. Nwariaku, Kelley S. Carrick, Walter L. Miller, Richard J. AuchusAbstract:Context: Macronodular adrenocortical hyperplasia classically presents with progressive hypercortisolemia and Cushing syndrome. We describe a 29-year-old man with massive macronodular adrenocortical hyperplasia without hypercortisolemia but rather markedly elevated and nonsuppressible production of dehydroepiandrosterone (DHEA) and its sulfate (DHEAS). Objective: To characterize the clinical and molecular features of this case and to determine whether the tissue biochemically resembles the zona reticularis or fetal adrenal. Setting: University clinic, hospital, and laboratories. Design: Static and dynamic blood and urine testing were performed preoperatively. Tissue was studied by light microscopy, immunoblot, RNA microarray, and enzyme assay. Participant: A 29-year-old man with incidentally discovered bilateral adrenal enlargement. Intervention: Bilateral adrenalectomy. Main Outcome Measures: Molecular studies compared with control samples. Results: Hypercortisolism and 21-hydroxylase deficiency were excluded. DHEA, DHEAS, and 17-hydroxypregnenolone were markedly elevated and did not suppress with dexamethasone 2 mg/d for 4 days. Homogenates of the adrenals demonstrated high 17-hydroxylase, good 17,20-lyase, and low or absent 21-hydroxylase and 3β-hydroxysteroid dehydrogenase activities. Immunoblots confirmed robust expression of cytochrome P450c17 and AKR1C3 but not P450c21. Microarray analysis demonstrated high CYP11A1 and CYP17A1 expression but low or absent HSD3B1, HSD3B2, and CYP21A2 expression. Expression of mRNA for cytochrome b5 (CYB5A) and AKR1C3, markers of the zona reticularis, were markedly elevated. Conclusion: This is the first case of macronodular hyperplasia of the adrenal zona reticularis confirmed with studies of enzyme activity, mRNA expression, and protein identification. We speculate that this condition can be clinically silent in men but might cause severe hyperandrogenemia in women.
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Clinical, biochemical, and molecular characterization of macronodular adrenocortical hyperplasia of the zona reticularis: a new syndrome.
The Journal of clinical endocrinology and metabolism, 2010Co-Authors: Hans K. Ghayee, Juilee Rege, William E. Rainey, Lori M Watumull, Fiemu E. Nwariaku, Kelley S. Carrick, Walter L. Miller, Richard J. AuchusAbstract:Macronodular adrenocortical hyperplasia classically presents with progressive hypercortisolemia and Cushing syndrome. We describe a 29-yr-old man with massive macronodular adrenocortical hyperplasia without hypercortisolemia but rather markedly elevated and nonsuppressible production of dehydroepiandrosterone (DHEA) and its sulfate (DHEAS). To characterize the clinical and molecular features of this case and to determine whether the tissue biochemically resembles the zona reticularis or fetal adrenal. University clinic, hospital, and laboratories. Static and dynamic blood and urine testing were performed preoperatively. Tissue was studied by light microscopy, immunoblot, RNA microarray, and enzyme assay. A 29-yr-old man with incidentally discovered bilateral adrenal enlargement. Bilateral adrenalectomy. Molecular studies compared with control samples. Hypercortisolism and 21-hydroxylase deficiency were excluded. DHEA, DHEAS, and 17-hydroxypregnenolone were markedly elevated and did not suppress with dexamethasone 2 mg/d for 4 d. Homogenates of the adrenals demonstrated high 17-hydroxylase, good 17,20-lyase, and low or absent 21-hydroxylase and 3β-hydroxysteroid dehydrogenase activities. Immunoblots confirmed robust expression of cytochrome P450c17 and AKR1C3 but not P450c21. Microarray analysis demonstrated high CYP11A1 and CYP17A1 expression but low or absent HSD3B1, HSD3B2, and CYP21A2 expression. Expression of mRNA for cytochrome b(5) (CYB5A) and AKR1C3, markers of the zona reticularis, were markedly elevated. This is the first case of macronodular hyperplasia of the adrenal zona reticularis confirmed with studies of enzyme activity, mRNA expression, and protein identification. We speculate that this condition can be clinically silent in men but might cause severe hyperandrogenemia in women.
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The Farnesoid X Receptor Regulates Transcription of 3β- Hydroxysteroid Dehydrogenase Type 2 in Human Adrenal Cells
Molecular and cellular endocrinology, 2008Co-Authors: Yewei Xing, Yasuhiro Nakamura, J. Ian Mason, Bruce R. Carr, Karla Saner-amigh, Margaret M. Hinshelwood, William E. RaineyAbstract:Recent studies have shown that the adrenal cortex expresses high levels of farnesoid X receptor (FXR), but its function remains unknown. Herein, using microarray technology, we tried to identify candidate FXR targeting genes in the adrenal glands, and showed that FXR regulated 3beta-hydroxysteroid dehydrogenase type 2 (HSD3B2) expression in human adrenocortical cells. We further demonstrated that FXR stimulated HSD3B2 promoter activity and have defined the cis-element responsible for FXR regulation of HSD3B2 transcription. Transfection of H295R adrenocortical cells with FXR expression vector effectively increased FXR expression levels and additional treatment with chenodeoxycholic acid (CDCA) caused a 25-fold increase in the mRNA for organic solute transporter alpha (OSTalpha), a known FXR target gene. HSD3B2 mRNA levels also increased following CDCA treatment in a concentration-dependent manner. Cells transfected with a HSD3B2 promoter construct and FXR expression vector responded to CDCA with a 20-fold increase in reporter activity compared to control. Analysis of constructs containing sequential deletions of the HSD3B2 promoter suggested a putative regulatory element between -166 and -101. Mutation of an inverted repeat between -137 and -124 completely blocked CDCA/FXR induced reporter activity. Chromatin immunoprecipitation assays further confirmed the presence of a FXR response element in the HSD3B2 promoter. In view of the emerging role of FXR agonists as therapeutic treatment of diabetes and certain liver diseases, the effects of such agonists on other FXR expressing tissues should be considered. Our findings suggest that in human adrenal cells, FXR increases transcription and expression of HSD3B2. Alterations in this enzyme would influence the capacity of the adrenal gland to produce corticosteroids.
Jeffrey M. Trent - One of the best experts on this subject based on the ideXlab platform.
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joint effect of hsd3b1 and HSD3B2 genes is associated with hereditary and sporadic prostate cancer susceptibility
Cancer Research, 2002Co-Authors: Baoli Chang, Aubrey R Turner, Gregory A Hawkins, Siqun L. Zheng, Sarah D. Isaacs, Kathy E. Wiley, John D Carpten, Eugene R Bleecker, Patrick C. Walsh, Jeffrey M. TrentAbstract:3β-hydroxysteroid dehydrogenases (HSD3Bs), encoded by the HSD3B gene family at 1p13, have long been hypothesized to have a major role in prostate cancer susceptibility. The recent reports of a prostate cancer linkage at 1p13 provided additional evidence that HSD3B genes may be prostate cancer susceptibility genes. To evaluate the possible role of HSD3B genes in prostate cancer, we screened a panel of DNA samples collected from 96 men with or without prostate cancer for sequence variants in the putative promoter region, exons, exon-intron junctions, and 3′-untranslated region of HSD3B1 and HSD3B2 genes by direct sequencing. Eleven single nucleotide polymorphisms (SNPs) were identified, four of which, including a missense change (B1-N367T), were informative. These four SNPs were further genotyped in a total of 159 hereditary prostate cancer probands, 245 sporadic prostate cancer cases, and 222 unaffected controls. Although a weak association between prostate cancer risk and a missense SNP (B1-N367T) was found, stronger evidence for association was found when the joint effect of the two genes was considered. Men with the variant genotypes at either B1-N367T or B2-c7519g had a significantly higher risk to develop prostate cancer, especially the hereditary type of prostate cancer. Most importantly, the subset of hereditary prostate cancer probands, whose families provided evidence for linkage at 1p13, predominantly contributed to the observed association. Additional studies are warranted to confirm these findings.
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Joint Effect of HSD3B1 and HSD3B2 Genes Is Associated with Hereditary and Sporadic Prostate Cancer Susceptibility
Cancer research, 2002Co-Authors: Baoli Chang, Aubrey R Turner, Gregory A Hawkins, Siqun L. Zheng, Sarah D. Isaacs, Kathy E. Wiley, John D Carpten, Eugene R Bleecker, Patrick C. Walsh, Jeffrey M. TrentAbstract:3beta-hydroxysteroid dehydrogenases (HSD3Bs), encoded by the HSD3B gene family at 1p13, have long been hypothesized to have a major role in prostate cancer susceptibility. The recent reports of a prostate cancer linkage at 1p13 provided additional evidence that HSD3B genes may be prostate cancer susceptibility genes. To evaluate the possible role of HSD3B genes in prostate cancer, we screened a panel of DNA samples collected from 96 men with or without prostate cancer for sequence variants in the putative promoter region, exons, exon-intron junctions, and 3'-untranslated region of HSD3B1 and HSD3B2 genes by direct sequencing. Eleven single nucleotide polymorphisms (SNPs) were identified, four of which, including a missense change (B1-N367T), were informative. These four SNPs were further genotyped in a total of 159 hereditary prostate cancer probands, 245 sporadic prostate cancer cases, and 222 unaffected controls. Although a weak association between prostate cancer risk and a missense SNP (B1-N367T) was found, stronger evidence for association was found when the joint effect of the two genes was considered. Men with the variant genotypes at either B1-N367T or B2-c7519g had a significantly higher risk to develop prostate cancer, especially the hereditary type of prostate cancer. Most importantly, the subset of hereditary prostate cancer probands, whose families provided evidence for linkage at 1p13, predominantly contributed to the observed association. Additional studies are warranted to confirm these findings.
Berenice B. Mendonca - One of the best experts on this subject based on the ideXlab platform.
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Phenotypic variability and origins of mutations in the gene encoding 3beta-hydroxysteroid dehydrogenase type II
Journal of molecular endocrinology, 2000Co-Authors: S Mccartin, Jennifer Varley, A J Russell, R A Fisher, A M Wallace, Ivo J. P. Arnhold, J I Mason, Berenice B. Mendonca, R.g. SutcliffeAbstract:Mutations in HSD3B2, the gene for 3beta-hydroxysteroid dehydrogenase type II (3beta-HSD II) have been detected and activities analysed through the in vitro expression of mutant cDNAs. Two full sibs with male pseudohermaphroditism were found to be double heterozygotes: N100S/266DeltaA. This genotype leads to the most profound loss of 3beta-HSD II enzyme activity (1.3% of normal) described to date in cases without severe salt-loss. One sib (N100S/266DeltaA) is the first reported male case of type II deficiency affected with premature adrenarche. Three apparently independent kindreds had propositi affected with the HSD3B2 mutation A82T/A82T, which is associated with a non salt-losing phenotype with variable expressivity in females. These three families had the same extended HSD3B haplotype and are likely to have inherited the same ancestral mutation. The significance of this finding is discussed in the light of the presence of A82T mutation at a homologous position in pseudogene varphi5 that is present in the HSD3B cluster.
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Genotyping of the type II 3β-hydroxysteroid dehydrogenase gene (HSD3B2) in women with hirsutism and elevated ACTH-stimulated δ5-steroids
Fertility and sterility, 2000Co-Authors: Suemi Marui, Alan J. Russell, Francisco José Albuquerque De Paula, Ingrid Dick-de-paula, Jose A.m. Marcondes, Berenice B. MendoncaAbstract:Abstract Objective: Genotyping of the HSD3B2 gene in females with hirsutism and elevated ACTH-stimulated Δ5-steroids. Design: Fourteen adult females whose ACTH-stimulated 17-hydroxypregnenolone (17OH-PREG) levels were elevated (≥ 2.3 SD). Setting: University hospital outpatient clinic and molecular endocrinology laboratory. Patient(s): Thirteen women with hirsutism and one with virilization. Intervention(s): ACTH-stimulation test and genotyping of the HSD3B2 gene. Main Outcome Measure(s): The four exons and exon-intron boundaries of the HSD3B2 gene were amplified by the use of polymerase chain reaction and were screened for mutations by denaturing gradient gel electrophoresis. The fragments that were found to have abnormal migration on denaturing gradient gel electrophoresis were directly sequenced. Result(s): No mutations were found in 13 patients who had mild to moderate elevations in ACTH-stimulated 17OH-PREG levels, and the T259M mutation was identified in the woman with virilization and extremely high 17OH-PREG levels. Conclusion(s): Mutations in the HSD3B2 gene were not found in women with hirsutism and mild-to-moderate elevations in ACTH-stimulated 17OH-PREG levels.
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Mutations in the type II 3β‐hydroxysteroid dehydrogenase (HSD3B2) gene can cause premature pubarche in girls
Clinical endocrinology, 2000Co-Authors: Suemi Marui, Ivo J. P. Arnhold, Margaret De Castro, Ana Claudia Latronico, Lucila Leico Kagohara Elias, Ayrton Custódio Moreira, Berenice B. MendoncaAbstract:OBJECTIVE Most previous studies have failed to demonstrate any mutations in the type II 3β hydroxysteroid dehydrogenase (HSD3B2) gene in patients satisfying the hormonal criteria of nonclassic 3β-hydroxysteroid dehydrogenase deficiency, suggesting that a mutant 3β-hydroxysteroid dehydrogenase protein is not the cause of this disorder. We screened the HSD3B2 gene for mutations in girls with premature pubarche and a hormonal diagnosis of 3β-hydroxysteroid dehydrogenase deficiency. DESIGN From 30 girls with premature pubarche, we selected 9 whose ACTH-stimulated 17-hydroxypregnenolone levels were elevated (≥6 SD) and screened the HSD3B2 gene for mutations. MEASUREMENTS All patients were submitted to a standard ACTH stimulation test. Serum steroids were measured and compared to the mean level of pubertal stage matched control subjects. The four exons and exon-intron boundaries of the HSD3B2 gene were amplified by polymerase chain reaction and screened for mutations by denaturing gradient gel electrophoresis. The fragments with abnormal migration on denaturing gradient gel electrophoresis were directly sequenced. RESULTS A homozygous T259M mutation was identified in one girl and a new compound heterozygous G129R/P222H mutation was identified in two sisters. The highest ACTH-stimulated 17-hydroxypregnenolone levels, 147, 339 and 351 nmol/l, were found in those patients with mutations in the HSD3B2 gene. In the patients without mutations, ACTH-stimulated 17-hydroxypregnenolone ranged from 48 to 111 nmol/l. ACTH-stimulated dehydroepiandrosterone levels had an overlap among the girls with and without mutations and the normal controls. CONCLUSIONS Premature pubarche can be caused by mutations in the type II 3β hydroxysteroid dehydrogenase gene.
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mutations in the type ii 3β hydroxysteroid dehydrogenase HSD3B2 gene can cause premature pubarche in girls
Clinical Endocrinology, 2000Co-Authors: Suemi Marui, Ivo J. P. Arnhold, Margaret De Castro, Ana Claudia Latronico, Lucila Leico Kagohara Elias, Ayrton Custódio Moreira, Berenice B. MendoncaAbstract:OBJECTIVE Most previous studies have failed to demonstrate any mutations in the type II 3β hydroxysteroid dehydrogenase (HSD3B2) gene in patients satisfying the hormonal criteria of nonclassic 3β-hydroxysteroid dehydrogenase deficiency, suggesting that a mutant 3β-hydroxysteroid dehydrogenase protein is not the cause of this disorder. We screened the HSD3B2 gene for mutations in girls with premature pubarche and a hormonal diagnosis of 3β-hydroxysteroid dehydrogenase deficiency. DESIGN From 30 girls with premature pubarche, we selected 9 whose ACTH-stimulated 17-hydroxypregnenolone levels were elevated (≥6 SD) and screened the HSD3B2 gene for mutations. MEASUREMENTS All patients were submitted to a standard ACTH stimulation test. Serum steroids were measured and compared to the mean level of pubertal stage matched control subjects. The four exons and exon-intron boundaries of the HSD3B2 gene were amplified by polymerase chain reaction and screened for mutations by denaturing gradient gel electrophoresis. The fragments with abnormal migration on denaturing gradient gel electrophoresis were directly sequenced. RESULTS A homozygous T259M mutation was identified in one girl and a new compound heterozygous G129R/P222H mutation was identified in two sisters. The highest ACTH-stimulated 17-hydroxypregnenolone levels, 147, 339 and 351 nmol/l, were found in those patients with mutations in the HSD3B2 gene. In the patients without mutations, ACTH-stimulated 17-hydroxypregnenolone ranged from 48 to 111 nmol/l. ACTH-stimulated dehydroepiandrosterone levels had an overlap among the girls with and without mutations and the normal controls. CONCLUSIONS Premature pubarche can be caused by mutations in the type II 3β hydroxysteroid dehydrogenase gene.
Baoli Chang - One of the best experts on this subject based on the ideXlab platform.
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joint effect of hsd3b1 and HSD3B2 genes is associated with hereditary and sporadic prostate cancer susceptibility
Cancer Research, 2002Co-Authors: Baoli Chang, Aubrey R Turner, Gregory A Hawkins, Siqun L. Zheng, Sarah D. Isaacs, Kathy E. Wiley, John D Carpten, Eugene R Bleecker, Patrick C. Walsh, Jeffrey M. TrentAbstract:3β-hydroxysteroid dehydrogenases (HSD3Bs), encoded by the HSD3B gene family at 1p13, have long been hypothesized to have a major role in prostate cancer susceptibility. The recent reports of a prostate cancer linkage at 1p13 provided additional evidence that HSD3B genes may be prostate cancer susceptibility genes. To evaluate the possible role of HSD3B genes in prostate cancer, we screened a panel of DNA samples collected from 96 men with or without prostate cancer for sequence variants in the putative promoter region, exons, exon-intron junctions, and 3′-untranslated region of HSD3B1 and HSD3B2 genes by direct sequencing. Eleven single nucleotide polymorphisms (SNPs) were identified, four of which, including a missense change (B1-N367T), were informative. These four SNPs were further genotyped in a total of 159 hereditary prostate cancer probands, 245 sporadic prostate cancer cases, and 222 unaffected controls. Although a weak association between prostate cancer risk and a missense SNP (B1-N367T) was found, stronger evidence for association was found when the joint effect of the two genes was considered. Men with the variant genotypes at either B1-N367T or B2-c7519g had a significantly higher risk to develop prostate cancer, especially the hereditary type of prostate cancer. Most importantly, the subset of hereditary prostate cancer probands, whose families provided evidence for linkage at 1p13, predominantly contributed to the observed association. Additional studies are warranted to confirm these findings.
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Joint Effect of HSD3B1 and HSD3B2 Genes Is Associated with Hereditary and Sporadic Prostate Cancer Susceptibility
Cancer research, 2002Co-Authors: Baoli Chang, Aubrey R Turner, Gregory A Hawkins, Siqun L. Zheng, Sarah D. Isaacs, Kathy E. Wiley, John D Carpten, Eugene R Bleecker, Patrick C. Walsh, Jeffrey M. TrentAbstract:3beta-hydroxysteroid dehydrogenases (HSD3Bs), encoded by the HSD3B gene family at 1p13, have long been hypothesized to have a major role in prostate cancer susceptibility. The recent reports of a prostate cancer linkage at 1p13 provided additional evidence that HSD3B genes may be prostate cancer susceptibility genes. To evaluate the possible role of HSD3B genes in prostate cancer, we screened a panel of DNA samples collected from 96 men with or without prostate cancer for sequence variants in the putative promoter region, exons, exon-intron junctions, and 3'-untranslated region of HSD3B1 and HSD3B2 genes by direct sequencing. Eleven single nucleotide polymorphisms (SNPs) were identified, four of which, including a missense change (B1-N367T), were informative. These four SNPs were further genotyped in a total of 159 hereditary prostate cancer probands, 245 sporadic prostate cancer cases, and 222 unaffected controls. Although a weak association between prostate cancer risk and a missense SNP (B1-N367T) was found, stronger evidence for association was found when the joint effect of the two genes was considered. Men with the variant genotypes at either B1-N367T or B2-c7519g had a significantly higher risk to develop prostate cancer, especially the hereditary type of prostate cancer. Most importantly, the subset of hereditary prostate cancer probands, whose families provided evidence for linkage at 1p13, predominantly contributed to the observed association. Additional studies are warranted to confirm these findings.