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Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype
Open accessAbstract
Polycystic ovary syndrome (PCOS), characterized by increased ovarian androgen biosynthesis, anovulation, and infertility, affects 5-7% of reproductive-age women. Genome-wide association studies identified PCOS candidate loci that were replicated in subsequent reports, including DENND1A, which encodes a protein associated with clathrin-coated pits where cell-surface receptors reside. However, these studies provided no information about functional roles for DENND1A in the pathogenesis of PCOS. DENND1A protein was located in the cytoplasm as well as nuclei of theca cells, suggesting a possible role in gene regulation. DENND1A immunostaining was more intense in the theca of PCOS ovaries. Using theca cells isolated and propagated from normal cycling and PCOS women, we found that DENND1A variant 2 (DENND1A.V2) protein and mRNA levels are increased in PCOS theca cells. Exosomal DENND1A.V2 RNA was significantly elevated in urine from PCOS women compared with normal cycling women. Forced overexpression of DENND1A.V2 in normal theca cells resulted in a PCOS phenotype of augmented CYP17A1 and CYP11A1 gene transcription, mRNA abundance, and androgen biosynthesis. Knock-down of DENND1A.V2 in PCOS theca cells reduced androgen biosynthesis and CYP17A1 and CYP11A1 gene transcription. An IgG specific to DENND1A.V2 also reduced androgen biosynthesis and CYP17 and CYP11A1 mRNA when added to the medium of cultured PCOS theca cells. We conclude that the PCOS candidate gene, DENND1A, plays a key role in the hyperandrogenemia associated with PCOS. These observations have both diagnostic and therapeutic implications for this common disorder.
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“Overexpression of the alternative spliced variant, DENND1A.V2, of this gene recapitulated a PCOS phenotype in cultured theca cells obtained from normal women, indicating a role for this variant in the excessive theca cell androgen production [27].”
From Polycystic Ovary Syndrome: Pathophysiology, Presentation, and Treatment With Emphasis on Adolescent Girls (2019) · cites this paper as [27]
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Cites
A new technique for the assay of infectivity of human adenovirus 5 DNA
Graham, F. L., & van der Eb, A. J. (1973) · Virology · doi:10.1016/0042-6822(73)90341-3 · Cited by 9,302
(2004) · Fertility and Sterility · doi:10.1016/j.fertnstert.2003.10.004 · Cited by 9,050
The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group (2004) · Human Reproduction · doi:10.1093/humrep/deh098 · Cited by 6,138
Rab GTPases as coordinators of vesicle traffic
Stenmark, H. (2009) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2728 · Cited by 3,413
Azziz, R., Carmina, E., Dewailly, D., Diamanti-Kandarakis, E., Escobar-Morreale, H. F., Futterweit, W., Janssen, O. E., Legro, R. S., Norman, R. J., Taylor, A. E., et al. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-0178 · Cited by 2,143
Legro, R. S., Arslanian, S. A., Ehrmann, D. A., Hoeger, K. M., Murad, M. H., Pasquali, R., & Welt, C. K. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-2350 · Cited by 1,919
Polycystic ovary syndrome: etiology, pathogenesis and diagnosis
Goodarzi, M. O., Dumesic, D. A., Chazenbalk, G., & Azziz, R. (2011) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2010.217 · Cited by 1,488
Chen, Z.-J., Zhao, H., He, L., Shi, Y., Qin, Y., Shi, Y., Li, Z., You, L., Zhao, J., Liu, J., et al. (2011) · Nature Genetics · doi:10.1038/ng.732 · Cited by 782
Stenmark, H., & Olkkonen, V. M. (2001) · Genome biology · doi:10.1186/gb-2001-2-5-reviews3007 · Cited by 740
Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome
Legro, R. S., Driscoll, D., Strauss, J. F., Fox, J., & Dunaif, A. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.25.14956 · Cited by 699
Research works printed but not linked: 2
- J Zawadzki, A Dunaif Diagnostic Criteria for Polycystic Ovary Syndrome: Towards a Rational Approach (Blackwell Scientific, Boston), pp. 377–384 (1992).
- J McAllister, E Simpson, Human theca interna cells in culture. Methods in Toxicology, eds JJ Heindel, RE Chapin (Academic, San Diego), pp. 330–339 (1993).
Cited by
Sorted by citations
The Diagnosis of Polycystic Ovary Syndrome during Adolescence
Witchel, S. F., Oberfield, S., Rosenfield, R. L., Codner, E., Bonny, A., Ibáñez, L., Pena, A., Horikawa, R., Gomez-Lobo, V., Joel, D., et al. (2015) · Hormone Research in Paediatrics · doi:10.1159/000375530 · Cited by 3,113
Azziz, R., Carmina, E., Chen, Z., Dunaif, A., Laven, J. S. E., Legro, R. S., Lizneva, D., Natterson-Horowtiz, B., Teede, H. J., & Yildiz, B. O. (2016) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2016.57 · Cited by 2,005
Rosenfield, R. L., & Ehrmann, D. A. (2016) · Endocrine Reviews · doi:10.1210/er.2015-1104 · Cited by 1,603
“V2 in PCOS theca cells reduced androgen biosynthesis and CYP17A1 and CYP11A1 gene expression” (108).”
BackgroundDumesic, D. A., Oberfield, S. E., Stener-Victorin, E., Marshall, J. C., Laven, J. S., & Legro, R. S. (2015) · Endocrine Reviews · doi:10.1210/er.2015-1018 · Cited by 1,020
Self-citationDay, F., Karaderi, T., Jones, M. R., Meun, C., He, C., Drong, A., Kraft, P., Lin, N., Huang, H., Broer, L., et al. (2018) · PLOS Genetics · doi:10.1371/journal.pgen.1007813 · Cited by 619
Intraovarian Control of Early Folliculogenesis
Hsueh, A. J. W., Kawamura, K., Cheng, Y., & Fauser, B. C. J. M. (2014) · Endocrine Reviews · doi:10.1210/er.2014-1020 · Cited by 708
The Prevalence of Polycystic Ovary Syndrome: A Brief Systematic Review
Pundir, C., Deswal, R., Narwal, V., & Dang, A. (2020) · Journal of Human Reproductive Sciences · doi:10.4103/jhrs.jhrs_95_18 · Cited by 657
Witchel, S. F., Oberfield, S. E., & Peña, A. S. (2019) · Journal of the Endocrine Society · doi:10.1210/js.2019-00078 · Cited by 653
“V2, of this gene recapitulated a PCOS phenotype in cultured theca cells obtained from normal women, indicating a role for this variant in the excessive theca cell androgen production [27].”
BackgroundMcCartney, C. R., & Marshall, J. C. (2016) · New England Journal of Medicine · doi:10.1056/nejmcp1514916 · Cited by 643
“A recent study suggests that increased expression of a DENND1A splice variant drives a polycystic ovary syndrome–like steroidogenic phenotype in theca cells.(7) The polycystic ovary syndrome is associated with insulin resistance — which is at least partly independent of obesity — and compensatory hyperinsulinemia.”
BackgroundOvulation: Parallels With Inflammatory Processes
Duffy, D. M., Ko, C. J., Jo, M., Brännström, M., & Curry, T. E. (2018) · Endocrine Reviews · doi:10.1210/er.2018-00075 · Cited by 530
Stener-Victorin, E., Teede, H., Norman, R. J., Legro, R., Goodarzi, M. O., Dokras, A., Laven, J., Hoeger, K., & Piltonen, T. T. (2024) · Nature Reviews Disease Primers · doi:10.1038/s41572-024-00511-3 · Cited by 495
“A previously unrecognized gene variant identified by GWAS, DENND1A 78 , has been recognized in PCOS as a significant stimulator of the androgen pathway with several microRNA variants also implicated in the pathophysiology 117 .”
Ibáñez, L., Oberfield, S. E., Witchel, S., Auchus, R. J., Chang, R. J., Codner, E., Dabadghao, P., Darendeliler, F., Elbarbary, N. S., Gambineri, A., et al. (2017) · Hormone Research in Paediatrics · doi:10.1159/000479371 · Cited by 463
Leeners, B., Geary, N., Tobler, P. N., & Asarian, L. (2017) · Human Reproduction Update · doi:10.1093/humupd/dmw045 · Cited by 407
Prenatal Androgen Exposure and Transgenerational Susceptibility to Polycystic Ovary Syndrome
Risal, S., Pei, Y., Lu, H., Manti, M., Fornes, R., Pui, H.-P., Zhao, Z., Massart, J., Ohlsson, C., Lindgren, E., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0666-1 · Cited by 356
Animal Models to Understand the Etiology and Pathophysiology of Polycystic Ovary Syndrome
Stener‐Victorin, E., Padmanabhan, V., Walters, K. A., Campbell, R. E., Benrick, A., Giacobini, P., Dumesic, D. A., & Abbott, D. H. (2020) · Endocrine Reviews · doi:10.1210/endrev/bnaa010 · Cited by 391
“V2) is overexpressed in women with PCOS and is functionally implicated in ovarian theca cell hyperandrogenism (204).”
BackgroundGenome-wide analysis identifies 12 loci influencing human reproductive behavior
Barban, N., Study, L. C., Jansen, R., de Vlaming, R., Vaez, A., Mandemakers, J. J., Tropf, F. C., Shen, X., Wilson, J. F., Chasman, D. I., et al. (2016) · Nature Genetics · doi:10.1038/ng.3698 · Cited by 324
“The locus on chromosome 1 also harbors DENND4B , a paralog of DENND1A , implicated in polycistic ovary syndrome (PCOS) 46 .”
Dapas, M., Lin, F. T. J., Nadkarni, G. N., Sisk, R., Legro, R. S., Urbanek, M., Hayes, M. G., & Dunaif, A. (2020) · PLOS Medicine · doi:10.1371/journal.pmed.1003132 · Cited by 297
Self-citationDeconstructing a Syndrome: Genomic Insights Into PCOS Causal Mechanisms and Classification
Dapas, M., & Dunaif, A. (2022) · Endocrine Reviews · doi:10.1210/endrev/bnac001 · Cited by 300
Liu, C., Jia, P., Matzuk, M. M., & Yao, H. H. (2015) · Nature Communications · doi:10.1038/ncomms7934 · Cited by 257
Functional genomics of PCOS: from GWAS to molecular mechanisms
McAllister, J. M., Legro, R. S., Modi, B. P., & Strauss, J. F. (2015) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2014.12.004 · Cited by 227
Extracellular Vesicles in Human Reproduction in Health and Disease
Simón, C., Greening, D. W., Bolumar, D., Balaguer, N., Salamonsen, L. A., & Vilella, F. (2018) · Endocrine Reviews · doi:10.1210/er.2017-00229 · Cited by 218
Ovarian Follicular Theca Cell Recruitment, Differentiation, and Impact on Fertility: 2017 Update
Richards, J. S., Ren, Y. A., Candelaria, N. R., Adams, J. E., & Rajkovic, A. (2017) · Endocrine Reviews · doi:10.1210/er.2017-00164 · Cited by 212
Exosomes as Biomarkers for Female Reproductive Diseases Diagnosis and Therapy
Esfandyari, S., Elkafas, H., Chugh, R. M., Park, H.-S., Navarro, A., & Al-Hendy, A. A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22042165 · Cited by 160
“V2 protein was higher in PCOS theca cells [74].”
BackgroundYates, A. G., Pink, R. C., Erdbrügger, U., Siljander, P. R. M., Dellar, E. R., Pantazi, P., Akbar, N., Cooke, W. R., Vatish, M., Dias‐Neto, E., et al. (2022) · Journal of Extracellular Vesicles · doi:10.1002/jev2.12190 · Cited by 155
MicroRNAs Related to Polycystic Ovary Syndrome (PCOS)
Sørensen, A. E., Wissing, M., Salö, S., Englund, A. L. M., & Dalgaard, L. T. (2014) · Genes · doi:10.3390/genes5030684 · Cited by 150
“It might be possible that identified PCOS susceptibility genes, such as DENND1A [59], which interestingly also encodes miR-601 [60], could result in genetic and epigenetic factors overlapping,”
BackgroundAn update of genetic basis of PCOS pathogenesis
Crespo, R. P., Bachega, T. A. S. S., Mendonça, B. B., & Gomes, L. G. (2018) · Archives of Endocrinology and Metabolism · doi:10.20945/2359-3997000000049 · Cited by 138
“V2), which encodes a truncated 559-aa protein that contains the DENN domain and a clathrin-binding domain; however, the protein lacks the proline-rich domain and includes a C-terminal 33-aa sequence that is not found in the larger connecdenn variant 1 (49).”
BackgroundNew insights into the genetics of polycystic ovary syndrome
Azziz, R. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2015.230 · Cited by 145
Enhanced Inflammatory Transcriptome in the Granulosa Cells of Women With Polycystic Ovarian Syndrome
Adams, J. E., Liu, Z., Ren, Y. A., Wun, W.-S. A., Zhou, W. J., Kenigsberg, S., Librach, C. L., Valdés, C. T., Gibbons, W. E., & Richards, J. S. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-4275 · Cited by 133
The diagnosis and treatment of PCOS in adolescents: an update
Witchel, S. F., Burghard, A. C., Tao, R., & Oberfield, S. E. (2019) · Current Opinion in Pediatrics · doi:10.1097/mop.0000000000000778 · Cited by 128
Genetic determinants of polycystic ovary syndrome: Progress and future directions
Jones, M. R., & Goodarzi, M. O. (2016) · Fertility and Sterility · doi:10.1016/j.fertnstert.2016.04.040 · Cited by 117
Alternative splicing of the androgen receptor in polycystic ovary syndrome
Wang, F., Pan, J., Liu, Y., Meng, Q., Lv, P., Qu, F., Ding, G., Klausen, C., Leung, P. C. K., Chan, H. C., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1418216112 · Cited by 114
“On the other hand, much of the production of testosterone occurs in the theca cells (24) that surround the follicle and the GCs.”
BackgroundAndrogen excess: a hallmark of polycystic ovary syndrome
Wang, K., Lǐ, Y., & Chen, Y. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1273542 · Cited by 133
Jones, M. R., Brower, M. A., Xu, N., Cui, J., Mengesha, E., Chen, Y. I., Taylor, K. D., Azziz, R., & Goodarzi, M. O. (2015) · PLoS Genetics · doi:10.1371/journal.pgen.1005455 · Cited by 111
“Functional studies of DENND1A demonstrated increased expression of DENND1Av2 and increased androgen synthesis in the theca cells of PCOS women [13].”
BackgroundInfluentialFranks, S., & Hardy, K. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00452 · Cited by 109
Genetics of polycystic ovary syndrome
Mykhalchenko, K., Lizneva, D., Trofimova, T., Walker, W., Сутурина, Л. В., Diamond, M. P., & Azziz, R. (2017) · Expert Review of Molecular Diagnostics · doi:10.1080/14737159.2017.1340833 · Cited by 128
“V2 (knockdown or ablation) in PCOS theca cells with specific blocking antibodies converted the cells to a normal morphology or phenotype [78,91].”
BackgroundPolycystic ovary syndrome: Understanding the role of the brain
Moore, A. M., & Campbell, R. E. (2017) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2017.05.002 · Cited by 100
“DENDD1A is significantly upregulated in theca cells isolated from PCOS patients, and the manipulation of DENDD1A variant 2 in theca cells successfully alters androgen biosynthesis (McAllister et al., 2014).”
BackgroundDapas, M., Sisk, R. K., Legro, R. S., Urbanek, M., Dunaif, A. E., & Hayes, M. G. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-02496 · Cited by 93
Bruni, V., Capozzi, A., & Lello, S. (2021) · Reproductive Sciences · doi:10.1007/s43032-021-00515-4 · Cited by 102
Józkowiak, M., Piotrowska‐Kempisty, H., Kobylarek, D., Gorska, N., Mozdziak, P. E., Kempisty, B., Rachoń, D., & Spaczyński, R. (2022) · Cells · doi:10.3390/cells12010174 · Cited by 96
Polycystic Ovary Syndrome-Epigenetic Mechanisms and Aberrant MicroRNA
Ilie, I. R. P., & Georgescu, C. E. (2015) · Advances in clinical chemistry · doi:10.1016/bs.acc.2015.06.001 · Cited by 84
Chugh, R. M., Park, H.-S., Andaloussi, A. E., Elsharoud, A., Esfandyari, S., Ulin, M., Bakir, L. V., Aboalsoud, A., Ali, M. K., Ashour, D., et al. (2021) · Stem Cell Research & Therapy · doi:10.1186/s13287-021-02472-w · Cited by 80
The exosome: a review of current therapeutic roles and capabilities in human reproduction
Dimik, M., Abeysinghe, P., Logan, J., & Mitchell, M. D. (2022) · Drug Delivery and Translational Research · doi:10.1007/s13346-022-01225-3 · Cited by 86
“V2 protein was higher in PCOS theca cells compared to that in controls, which may have an indirect downstream effect on insulin and luteinising hormone through the RAB5B system [70].”
BackgroundCurrent concepts of polycystic ovary syndrome pathogenesis
Rosenfield, R. L. (2020) · Current Opinion in Pediatrics · doi:10.1097/mop.0000000000000945 · Cited by 77
“Recent genetic linkage studies discussed below showed that this is explicable by a variant in a previously unknown regulatory protein family, differentially expressed in normal and neoplastic development (DENND) [1,10].”
BackgroundPerspectives in polycystic ovary syndrome: From hair to eternity
Dunaif, A. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-3780 · Cited by 87
Tian, Y., Li, J., Su, S., Cao, Y., Wang, Z., Zhao, S., & Zhao, H. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00274 · Cited by 77
Brower, M. A., Jones, M. R., Rotter, J. I., Krauss, R. M., Legro, R. S., Azziz, R., & Goodarzi, M. O. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-2689 · Cited by 70
Polycystic Ovarian Syndrome: A Complex Disease with a Genetics Approach
Nautiyal, H., Imam, S. S., Alshehri, S., Ghoneim, M. M., Afzal, M., Alzarea, S. I., Güven, E., Al-Abbasi, F. A., & Kazmi, I. A. (2022) · Biomedicines · doi:10.3390/biomedicines10030540 · Cited by 80
“The protein, which lacks proline-rich domain but includes C terminal 33-aa sequence, is not available in connecdenn-1 [77].”
BackgroundMicroRNAs related to androgen metabolism and polycystic ovary syndrome
Sørensen, A. E., Udesen, P. B., Wissing, M. L., Englund, A. L. M., & Dalgaard, L. T. (2016) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2016.06.008 · Cited by 65
Clustering of PCOS-like traits in naturally hyperandrogenic female rhesus monkeys
Abbott, D. H., Rayome, B. H., Dumesic, D. A., Lewis, K. C., Edwards, A. K., Wallen, K., Wilson, M. E., Appt, S. E., & Levine, J. E. (2017) · Human Reproduction · doi:10.1093/humrep/dex036 · Cited by 66
Stouffer, R. L., & Woodruff, T. K. (2017) · ILAR Journal · doi:10.1093/ilar/ilx027 · Cited by 65
“Recent genome-wide association studies identified mutations or polymorphisms in areas associated with over 20 genes (Puttabyatappa et al. 2016), but to date the functionality of only one gene, DENND1a, has been documented (McAllister et al. 2014).”
BackgroundThe HMGA2-IMP2 Pathway Promotes Granulosa Cell Proliferation in Polycystic Ovary Syndrome
Li, M., Zhao, H., Zhao, S., Wei, D., Zhao, Y., Huang, T., Muhammad, T., Yan, L., Gao, F., Li, L., et al. (2018) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-00544 · Cited by 64
Polycystic ovary syndrome as a plausible evolutionary outcome of metabolic adaptation
Dumesic, D. A., Padmanabhan, V., Chazenbalk, G. D., & Abbott, D. H. (2022) · Reproductive Biology and Endocrinology · doi:10.1186/s12958-021-00878-y · Cited by 63
“v2, is over-expressed in some women with PCOS [73], while experimentally-induced DENND1A.”
BackgroundGenetic Studies on Polycystic Ovary Syndrome
Zhao, H., Lv, Y., Li, L., & Chen, Z. (2016) · Best Practice & Research Clinical Obstetrics & Gynaecology · doi:10.1016/j.bpobgyn.2016.04.002 · Cited by 60
Current and experimental drug therapy for the treatment of polycystic ovarian syndrome
Corte, L. D., Foreste, V., Barra, F., Gustavino, C., Alessandri, F., Centurioni, M. G., Ferrero, S., Bifulco, G., & Giampaolino, P. (2020) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2020.1781815 · Cited by 65
Kharazi, U., & Badalzadeh, R. (2020) · Reproductive Biology · doi:10.1016/j.repbio.2020.07.002 · Cited by 58
Romero‐Ruíz, A., Skorupskaite, K., Gaytán, F., Torres, E., Perdices-López, C., Mannaerts, B. M. J. L., Qi, S., León, S., Manfredi-Lozano, M., Lopez-Rodriguez, C., et al. (2019) · Human Reproduction · doi:10.1093/humrep/dez205 · Cited by 59
Lizneva, D., Atabiekov, I., & Azziz, R. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.64517-8 · Cited by 58
Polycystic ovary syndrome: Current scenario and future insights
Kulkarni, S., Gupta, K. A., Ratre, P., Mishra, P. K., Singh, Y., Biharee, A., & Thareja, S. (2023) · Drug Discovery Today · doi:10.1016/j.drudis.2023.103821 · Cited by 59
Bhatt, M. R., Khatri, Y., Rodgers, R. J., & Martin, L. L. (2016) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2016.02.033 · Cited by 54
The neuroendocrine genesis of polycystic ovary syndrome: A role for arcuate nucleus GABA neurons
Moore, A. M., & Campbell, R. E. (2015) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2015.10.002 · Cited by 54
The post-translational regulation of 17,20 lyase activity
Miller, W. L., & Tee, M. K. (2014) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2014.09.010 · Cited by 52
“V2 mRNA and protein are over-expressed in PCOS theca cells and V2 mRNA is abundant in urinary exosomes of women with PCOS but not normally-cycling women (McAllister et al., 2014).”
BackgroundMcAllister, J. M., Han, A. X., Modi, B. P., Teves, M. E., Mavodza, G. R., Anderson, Z. L., Shen, T., Christenson, L. K., Archer, K. J., & Strauss, J. F. (2019) · Endocrinology · doi:10.1210/en.2019-00013 · Cited by 53
“Fourth passage normal and PCOS theca cells for these studies were grown until subconfluent and were treated with and without 20 mM forskolin for 16 hours in defined serum-free media (61, 62).”
BackgroundMethodResultInfluentialSteroid biomarkers in human adrenal disease
Rege, J., Turcu, A. F., Else, T., Auchus, R. J., & Rainey, W. E. (2019) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2019.01.018 · Cited by 47
Cui, L., Li, G., Zhong, W., Bian, Y., Su, S., Sheng, Y., Shi, Y., Wei, D., Zhang, W., Zhao, H., et al. (2015) · Human Reproduction · doi:10.1093/humrep/deu361 · Cited by 44
“Downloaded from https://academic.oup.com/humrep/article-abstract/30/3/732/662076 by guest on 25 July 2018 phenotypes with PCOM and androgen biosynthesis (Cui et al., 2013; McAllister et al., 2014).”
MethodGenetics of Polycystic Ovary Syndrome
Welt, C. K. (2021) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2020.10.006 · Cited by 43
Ovarian and extra-ovarian mediators in the development of polycystic ovary syndrome
Puttabyatappa, M., & Padmanabhan, V. (2018) · Journal of Molecular Endocrinology · doi:10.1530/jme-18-0079 · Cited by 43
Polycystic Ovary Syndrome and Hyperandrogenic States
Chang, R. J., & Dumesic, D. A. (2019) · Elsevier eBooks · doi:10.1016/b978-0-323-47912-7.00021-4 · Cited by 41
Abbott, D. H., Rogers, J., Dumesic, D. A., & Levine, J. E. (2019) · Medical Sciences · doi:10.3390/medsci7120107 · Cited by 42
“V2) is over-expressed in women with PCOS and is functionally implicated in ovarian theca cell hyperandrogenism [43].”
BackgroundMcCartney, C. R., & Marshall, J. C. (2016) · New England Journal of Medicine · doi:10.1056/nejmc1610000 · Cited by 43
Human DENND1A.V2 Drives Cyp17a1 Expression and Androgen Production in Mouse Ovaries and Adrenals
Teves, M. E., Modi, B. P., Kulkarni, R., Han, A. X., Marks, J. S., Subler, M. A., Windle, J. J., Newall, J. M., McAllister, J. M., & Strauss, J. F. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21072545 · Cited by 38
“V2 in PCOS theca cells reduced the expression of the steroidogenic genes and thus androgen production [8].”
BackgroundInfluentialEpigenetic inheritance of PCOS by developmental programming and germline transmission
Stener‐Victorin, E., & Deng, Q. (2024) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2024.12.002 · Cited by 40
Update on Animal Models of Polycystic Ovary Syndrome
Stener‐Victorin, E. (2022) · Endocrinology · doi:10.1210/endocr/bqac164 · Cited by 40
Kulkarni, R., Teves, M. E., Han, A. X., McAllister, J. M., & Strauss, J. F. (2019) · Journal of the Endocrine Society · doi:10.1210/js.2019-00169 · Cited by 35
“V2 diminishes androgen production in PCOS theca cells [16].”
BackgroundResultInfluentialGuo, X., Puttabyatappa, M., Thompson, R. C., & Padmanabhan, V. (2019) · Endocrinology · doi:10.1210/en.2019-00389 · Cited by 38
Alternative splicing of DENND1A, a PCOS candidate gene, generates variant 2
Tee, M. K., Speek, M., Legeza, B., Modi, B. P., Teves, M. E., McAllister, J. M., Strauss, J. F., & Miller, W. L. (2016) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2016.06.011 · Cited by 35
“Recent work has directly implicated V2 in the pathophysiology of PCOS: V2 mRNA was abundant in urinary exosomes of PCOS women but not normally-cycling women; V2 mRNA and protein were over-expressed in PCOS theca cells compared to normal theca cells; over-expression of V2 in normal theca cells increased the abundance o…”
BackgroundMethodResultInfluentialAbbott, D., Levine, J. E., & Dumesic, D. A. (2016) · Current Pharmaceutical Design · doi:10.2174/1381612822666160715133437 · Cited by 36
Relationship between the characteristic traits of polycystic ovary syndrome and susceptibility genes
Hong, S.-H., Hong, Y. S., Jeong, K., Chung, H., Lee, H., & Sung, Y.-A. (2020) · Scientific Reports · doi:10.1038/s41598-020-66633-2 · Cited by 32
Polycystic Ovary Syndrome, Insulin Resistance, and Cardiovascular Disease
Dubey, P., Reddy, S., Sharma, K., Johnson, S., Hardy, G., & Dwivedi, A. K. (2024) · Current Cardiology Reports · doi:10.1007/s11886-024-02050-5 · Cited by 38
VCAM1 Is Induced in Ovarian Theca and Stromal Cells in a Mouse Model of Androgen Excess
Candelaria, N. R., Padmanabhan, A., Stossi, F., Ljungberg, M. C., Shelly, K. E., Pew, B., Solis, M., Rossano, A. M., McAllister, J. M., Wu, S., et al. (2019) · Endocrinology · doi:10.1210/en.2018-00731 · Cited by 32
“The diagnosis of PCOS was made according to National Institutes of Health consensus guidelines, which include hyperandrogenemia, oligoovulation, polycystic ovaries, and the exclusion of 21-hydroxylase deficiency, Cushing syndrome, and hyperprolactinemia, as we have described previously (29).”
BackgroundMethodInfluentialWhole genome detection of sequence and structural polymorphism in six diverse horses
Al‐Abri, M., Holl, H. M., Kalla, S. E., Sutter, N. B., & Brooks, S. A. (2020) · PLoS ONE · doi:10.1371/journal.pone.0230899 · Cited by 35
“Overexpression of DENND1A produces a polycystic ovary syndrome theca phenotype [51].”
BackgroundŻeber‐Lubecka, N., & Hennig, E. E. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.606620 · Cited by 35
“expression of genes encoding cytochrome P450 isoforms (CYP17A1 and CYP11A1) and higher androgen production (81, 82).”
BackgroundHarris, R. A., McAllister, J. M., & Strauss, J. F. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241310611 · Cited by 33
“Theca cells from normal cycling and PCOS follicles were isolated and grown as previously reported in detail [7,20,40,49,50].”
BackgroundMethodInfluentialHadidi, M., Karimabadi, K., Ghanbari, E., Rezakhani, L., & Khazaei, M. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1269266 · Cited by 31
“V2 protein at a greater level (80).”
The Hypothalamic-Pituitary-Ovarian Axis, Ovarian Disorders, and Brain Aging
Valera, H., Chen, A., & Grive, K. J. (2025) · Endocrinology · doi:10.1210/endocr/bqaf137 · Cited by 46
Castillo-Higuera, T., Alarcón-Granados, M. C., Marín-Suarez, J., Moreno-Ortíz, H., Esteban-Pérez, C. I., Ferrebuz, A., Forero‐Castro, M., & Villalba, G. E. C. (2020) · Reproductive Sciences · doi:10.1007/s43032-020-00375-4 · Cited by 34
Chiu, W.-L., Boyle, J. A., Vincent, A. J., Teede, H. J., & Moran, L. (2016) · Neuroendocrinology · doi:10.1159/000455233 · Cited by 31
Is polycystic ovary syndrome a sexual conflict? A review
Casarini, L., Simoni, M., & Brigante, G. (2016) · Reproductive BioMedicine Online · doi:10.1016/j.rbmo.2016.01.011 · Cited by 28
“DENND1A overexpression results in a PCOS-like phenotype of theca cells, characterized by increased androgen biosynthesis (McAllister et al., 2014), revealing that this gene may give a strong contribution to the establishment of hyperandrogenic PCOS phenotypes.”
BackgroundPolycystic Ovary Syndrome in Adolescents
Witchel, S. F., Roumimper, H., & Oberfield, S. E. (2016) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2016.01.004 · Cited by 32
Jiang, P., Hou, Z., Bolin, J. M., Thomson, J., & Stewart, R. (2017) · Toxicological Sciences · doi:10.1093/toxsci/kfx129 · Cited by 27
Kempná, P., Marti, N., Udhane, S., & Flück, C. E. (2015) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2014.12.015 · Cited by 29
Genetic and Epigenetic Landscape for Drug Development in Polycystic Ovary Syndrome
Chen, Y., Wang, G., Chen, J., Wang, C., Dong, X., Chang, H., Yuan, S., Zhao, Y., & Mu, L. (2024) · Endocrine Reviews · doi:10.1210/endrev/bnae002 · Cited by 33
Polycystic Ovarian Syndrome Genetics and Epigenetics
COMBS, J. C., HILL, M. J., & DECHERNEY, A. H. (2020) · Clinical Obstetrics & Gynecology · doi:10.1097/grf.0000000000000581 · Cited by 31
Clinical Phenotypes of PCOS: a Cross-Sectional Study
Elsayed, A. M., Al-Kaabi, L. S. S. A., Al-Abdulla, N. M., Al-Kuwari, M. S., Almulla, A., Al-Shamari, R. S., Alhusban, A. K., AlNajjar, A. A., & Doi, S. A. R. (2023) · Reproductive Sciences · doi:10.1007/s43032-023-01262-4 · Cited by 36
Multi-ancestry genome-wide association analyses of polycystic ovary syndrome
Zhao, H., Xu, Y., Xue, B., Zhao, S., Zhang, M., Wu, X., Wang, T., Wen, Y., Li, S., Zhang, Q., et al. (2025) · Nature Genetics · doi:10.1038/s41588-025-02393-x · Cited by 28
Wan, P., Meng, L., Huang, C. B., Dai, B., Jin, Y., Chai, L., Gu, X., Chen, B., & Quan, S. (2021) · Journal of Assisted Reproduction and Genetics · doi:10.1007/s10815-021-02291-1 · Cited by 26
“Of note, elevation of circulating testosterone and androstenedione levels is the most common biochemical perturbation in PCOS patients [59].”
BackgroundOptimal management of polycystic ovary syndrome in adolescence
Baldauff, N. H., & Arslanian, S. A. (2015) · Archives of Disease in Childhood · doi:10.1136/archdischild-2014-306471 · Cited by 27
The contribution of rare genetic variants to the pathogenesis of polycystic ovary syndrome
Dapas, M., & Dunaif, A. E. (2020) · Current Opinion in Endocrine and Metabolic Research · doi:10.1016/j.coemr.2020.02.011 · Cited by 28
“Subsequent studies demonstrated that DENND1A is an important regulator of human ovarian androgen biosynthesis (73,74).”
BackgroundJaton, C., Schenkel, F. S., Sargolzaei, M., Cánova, A., Malchiodi, F., Price, C. A., Baes, C. F., & Miglior, F. (2018) · Journal of Dairy Science · doi:10.3168/jds.2017-13848 · Cited by 26
Burns, K. A., Mullin, B. H., Moolhuijsen, L. M. E., Laisk, T., Tyrmi, J. S., Cui, J., Actkins, K. V., Louwers, Y. V., Metspalu, A., Milani, L. A., et al. (2024) · BMC Genomics · doi:10.1186/s12864-024-09990-w · Cited by 26
Hartanti, M. D., Rosario, R., Hummitzsch, K., Bastian, N. A., Hatzirodos, N., Bonner, W. M., Bayne, R. A. L., Irving‐Rodgers, H. F., Anderson, R. A., & Rodgers, R. J. (2020) · PLoS ONE · doi:10.1371/journal.pone.0229351 · Cited by 26
Metadata
- Authors
- McAllister, J. M., Modi, B., Miller, B. A., Biegler, J., Bruggeman, R., Legro, R. S., & Strauss, J. F.
- Affiliations
- Pennsylvania State University (US)
- Virginia Commonwealth University (US)
- Departments of aPathology and
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-03-31
- Volume
- 111
- Issue
- 15
- Pages
- E1519-27
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3992676
- OpenAlex
- W1984174412
- Cited by
- 250
- References
- 54
- Citations by year
- 2026: 10 · 2025: 23 · 2024: 32 · 2023: 13 · 2022: 19 · 2021: 25 · 2020: 24 · 2019: 19 · 2018: 16 · 2017: 15 · 2016: 25 · 2015: 20 · 2014: 9
- FWCI
- 27.87
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Virginia Commonwealth University
- National Institutes of Health (UL1TR000127, U54HD344449)
- U.S. Public Health Service (UL1T000058, UL1T0000127)
- National Center for Advancing Translational Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD33852, U54HD344449, R01HD033852, R01HD058300)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
- Health Sciences › Medicine › Reproductive Medicine › Reproductive Biology and Fertility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Keywords
- polycystic ovary syndrome, DENND1A, theca cells, androgen production, CYP17A1, CYP11A1, hyperandrogenemia, exosomal RNA, urinary biomarkers, clathrin-coated pits, gene overexpression
- MeSH terms
- Analysis of Variance, Androgens, Cholesterol Side-Chain Cleavage Enzyme, Enzyme-Linked Immunosorbent Assay, Female, Humans, Immunoglobulin G, Immunohistochemistry, Polycystic Ovary Syndrome, Steroid 17-alpha-Hydroxylase, Theca Cells, Hyperandrogenism, Protein Isoforms, Guanine Nucleotide Exchange Factors, Death Domain Receptor Signaling Adaptor Proteins, Genome-Wide Association Study, Real-Time Polymerase Chain Reaction
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