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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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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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