Affinage

DENND1A

DENN domain-containing protein 1A · UniProt Q8TEH3

Length
1009 aa
Mass
110.6 kDa
Annotated
2026-06-09
30 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DENND1A is a Rab35 guanine nucleotide exchange factor whose DENN domain GEF activity drives endocytic recycling of specific membrane cargos required for epithelial polarity and developmental signaling (PMID:31992598). Its DENN domain activates Rab35 to direct apical trafficking of podocalyxin in three-dimensional epithelial cysts, a function abolished by GEF-dead domain mutants (PMID:31992598), and the same GEF axis is engaged downstream of EGFR via a Grb2 interaction—mediated by the DENND1A proline-rich domain binding the Grb2 SH3 domains—to promote cell migration and invasion (PMID:30524285). In the female reproductive system, full-length DENND1A is required for embryogenesis, with knockout causing embryonic lethality, defective Wnt/β-catenin-dependent brain and hepatic development, and loss of primordial germ cells (PMID:30884041), and for somatic-cell control of fetal oogenesis and meiotic initiation through Wnt5a- and retinoic acid-dependent activation of Sohlh2, Stra8, and Rec8 (PMID:34994166); in granulosa cells DENND1A overexpression desensitizes cells to FSH by accelerating FSH receptor internalization and blocking its recycling (PMID:38709439). A truncated splice isoform, DENND1A.V2—generated by exonization of intron 20 to create a unique C-terminus (PMID:27297658)—is elevated in PCOS theca cells, where it drives transcription of the androgen biosynthetic enzymes CYP17A1 and CYP11A1 and increases androgen production (PMID:24706793); this isoform is held in check by miR-130b-3p, itself controlled by the transcription factor ZNF217, so that loss of this regulatory axis raises DENND1A.V2 and androgen output (PMID:31184707, PMID:35668995). Manipulation of endogenous DENND1A regulatory elements causally elevates testosterone in adrenal cells, confirming DENND1A expression level as a determinant of androgen biosynthesis (PMID:40825976).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2014 High

    Established that a DENND1A isoform, rather than the gene generically, is the functional driver of the PCOS theca-cell androgen excess phenotype.

    Evidence Reciprocal overexpression and siRNA knockdown of DENND1A.V2 in primary human theca cells with androgen biosynthesis and CYP17A1/CYP11A1 readouts

    PMID:24706793

    Open questions at the time
    • Did not define how V2 is generated at the transcript level
    • Mechanism linking V2 to steroidogenic gene transcription not resolved
  2. 2016 Medium

    Defined the molecular origin of the disease-associated isoform, showing V2 arises by exonization of intron 20 to encode a unique truncated C-terminus.

    Evidence Minigene expression vectors, sequencing, and RT-PCR with overexpression in NCI-H295A adrenal cells

    PMID:27297658

    Open questions at the time
    • Single lab
    • How the unique C-terminus mechanistically alters function versus full-length protein unknown
  3. 2018 Medium

    Connected DENND1A to receptor tyrosine kinase signaling, showing it is recruited via Grb2 to activate Rab35 and promote tumor cell motility.

    Evidence GST-pulldown and Co-IP mapping the PRD–Grb2 SH3 interaction, Rab35 activation assay, and knockdown migration/invasion assays in gastric cancer cells

    PMID:30524285

    Open questions at the time
    • Single lab
    • Cargo recycled downstream of Rab35 in this context not identified
  4. 2019 Medium

    Demonstrated full-length DENND1A is essential for embryogenesis and links its function to developmental signaling pathways.

    Evidence Homozygous Dennd1a knockout mouse with embryonic lethality, histology, and Wnt/β-catenin and Fgf8 pathway marker analysis

    PMID:30884041

    Open questions at the time
    • Specific recycled cargos underlying each developmental defect not identified
    • Single lab
  5. 2019 Medium

    Identified an upstream post-transcriptional brake on the androgenic isoform, explaining why V2 is elevated in PCOS.

    Evidence miR-seq and miR-130b-3p mimic transfection in theca cells with DENND1A.V2/CYP17A1 and androgen readouts

    PMID:31184707

    Open questions at the time
    • Direct target-site binding not validated by reporter assay
    • Single lab
  6. 2020 High

    Provided definitive mechanistic proof that DENND1A acts through DENN-domain GEF activity on Rab35 for cargo-specific apical trafficking.

    Evidence DENND1A-knockout MDCK 3D/2D cysts, PODXL localization imaging, and GEF-dead domain mutant rescue

    PMID:31992598

    Open questions at the time
    • Context-specificity (3D vs 2D, FLCN vs DENND1A) mechanism incompletely defined
  7. 2020 Medium

    Tested the androgenic isoform in vivo, showing transgenic V2 raises steroidogenic enzyme expression and steroid output.

    Evidence Human DENND1A.V2 transgenic mice with ovary/adrenal Cyp17a1 mRNA and theca interstitial cell steroid assays

    PMID:32268539

    Open questions at the time
    • Weak protein-level detection (IHC only)
    • No endogenous mouse V2 equivalent, limiting physiological modeling
  8. 2021 Medium

    Established a somatic-cell role for DENND1A in fetal ovary development controlling oogenesis and meiotic initiation.

    Evidence Dennd1a knockout mice plus ex vivo adenoviral shRNA knockdown in E12.5 gonads with Sohlh2/Figla/Stra8/Rec8 marker analysis

    PMID:34994166

    Open questions at the time
    • How DENND1A trafficking controls Wnt5a and retinoic acid production not mechanistically resolved
    • Single lab
  9. 2022 Medium

    Placed a GWAS-implicated transcription factor upstream of the V2/miR-130b-3p axis, building a regulatory hierarchy for androgen excess.

    Evidence ZNF217 overexpression and lentiviral knockdown in primary human theca cells with DENND1A.V2, CYP17A1, miR-130b-3p, and androgen readouts

    PMID:35668995

    Open questions at the time
    • Direct ZNF217 regulation of miR-130b-3p versus DENND1A not distinguished mechanistically
    • Single lab
  10. 2024 Medium

    Identified a granulosa-cell mechanism whereby DENND1A dosage disrupts FSH responsiveness through receptor trafficking.

    Evidence Dennd1a transgenic mice with FSHR internalization/recycling assays, ovarian histology, hormone measurement, and FSH-priming gene expression

    PMID:38709439

    Open questions at the time
    • Whether Rab35 GEF activity mediates the FSHR effect not tested
    • Single lab
  11. 2025 Medium

    Demonstrated a causal, dose-dependent link between endogenous DENND1A expression level and androgen biosynthesis via regulatory-element perturbation.

    Evidence MPRA and CRISPR-based epigenome editing of regulatory elements with testosterone measurement in an adrenal cell model

    PMID:40825976

    Open questions at the time
    • Did not distinguish contribution of full-length versus V2 isoform
    • Causal regulatory variants in patients not pinpointed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the truncated DENND1A.V2 isoform—lacking canonical trafficking function—mechanistically activates steroidogenic gene transcription remains unresolved.
  • No defined transcriptional or signaling effector linking V2 to CYP17A1/CYP11A1 promoters
  • No structural model of the V2 unique C-terminus
  • Relationship between V2's androgenic activity and full-length GEF function unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2 GO:0060090 molecular adaptor activity 1
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-1430728 Metabolism 2 R-HSA-5653656 Vesicle-mediated transport 2
Partners
EGFRGRB2RAB35

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 DENND1A variant 2 (DENND1A.V2), a truncated isoform, is elevated in PCOS theca cells and drives augmented CYP17A1 and CYP11A1 gene transcription and androgen biosynthesis. Forced overexpression of DENND1A.V2 in normal theca cells conferred a PCOS phenotype of increased androgen production; knockdown in PCOS theca cells reduced androgen biosynthesis and CYP17A1/CYP11A1 mRNA. Overexpression and siRNA knockdown in primary human theca cells with mRNA/protein quantification and androgen biosynthesis assays Proceedings of the National Academy of Sciences of the United States of America High 24706793
2016 DENND1A variant 2 (DENND1A.V2) is generated by alternative splicing via exonization of intronic sequences (intron 20), producing a unique exon 20A that encodes the unique C-terminus of the 559-amino-acid isoform. Forced expression of V2 in adrenal NCI-H295A cells increased CYP17A1 and CYP11A1 mRNAs, consistent with its role in androgen biosynthesis. Minigene expression vectors, sequencing, RT-PCR in NCI-H295A cells, overexpression assay Molecular and cellular endocrinology Medium 27297658
2018 DENND1A interacts with the N-terminal and C-terminal SH3 domains of the adaptor protein Grb2 through its proline-rich domain (PRD). Upon EGF stimulation, EGFR recruits the Grb2-DENND1A complex, leading to Rab35 activation and promotion of gastric cancer cell migration and invasion. GST-pulldown, co-immunoprecipitation, Rab35 activation assay (GST-pulldown), siRNA knockdown with wound healing and transwell migration assays Frontiers in pharmacology Medium 30524285
2019 miR-130b-3p targets DENND1A.V2 transcripts post-transcriptionally. miR-130b-3p expression is decreased in PCOS theca cells, correlating with increased DENND1A.V2 and CYP17A1 mRNA. miR-130b-3p mimic transfection reduced DENND1A.V2 and CYP17A1 expression and androgen biosynthesis. Small RNA deep sequencing (miR-seq), miR-130b-3p mimic transfection in theca cells, RT-qPCR for DENND1A.V2 and CYP17A1 Endocrinology Medium 31184707
2019 Homozygous Dennd1a knockout mice die around embryonic day 14.5, exhibiting defects in brain development (dysregulated cell division and survival in telencephalon with ectopic Fgf8 expression and decreased active β-catenin/Axin2), impaired hepatic cell proliferation and differentiation, and loss of primordial germ cells. These phenotypes implicate DENND1A in endocytic recycling of cargos essential for developmental signaling. Dennd1a knockout mouse model, embryonic lethality assessment, immunostaining, mRNA expression analysis, histology Developmental dynamics Medium 30884041
2020 DENND1A (via its DENN domain GEF activity toward Rab35) is required for proper apical trafficking of podocalyxin (PODXL) in three-dimensional MDCK epithelial cysts but not in two-dimensional cultures. DENND1A-knockout cysts showed inverted (basolateral) PODXL localization similar to Rab35-knockout cysts; FLCN rather than DENND1A was required for Rab35-dependent PODXL trafficking in 2D cultures. The DENN domain GEF activity was required for this function. DENND1A knockout MDCK cells in 3D and 2D culture, immunofluorescence localization of PODXL, DENN domain mutant rescue experiments The Journal of biological chemistry High 31992598
2020 Human DENND1A.V2 transgenic mice (CMV promoter) showed elevated Cyp17a1 mRNA in ovaries and adrenals, and increased steroid production from isolated theca interstitial cells, consistent with a role of DENND1A.V2 in upregulating androgen biosynthetic enzymes in vivo. Murine Dennd1a knockout is embryonically lethal, and there is no endogenous mouse equivalent of the V2 isoform. Transgenic mouse overexpression (CMV, Lhcgr, TetOn promoters), immunohistochemistry, RT-qPCR, theca interstitial cell steroid production assay International journal of molecular sciences Medium 32268539
2021 In the fetal mouse ovary, Dennd1a in somatic cells regulates oogenesis and meiosis by controlling production of Wnt5a (required for Sohlh2 expression and early oocyte differentiation) and retinoic acid (required for meiotic initiation via Stra8 and Rec8 expression). Ex vivo adenoviral shRNA knockdown of Dennd1a in E12.5 female gonads blocked activation of Sohlh2, Figla, Stra8, and Rec8 transcription. Dennd1a knockout mice, ex vivo fetal gonad culture with adenoviral shRNA knockdown, RT-qPCR for oogenesis/meiosis markers Frontiers in bioscience (Landmark edition) Medium 34994166
2022 ZNF217, a PCOS GWAS candidate gene and transcription factor, inversely regulates DENND1A.V2 expression in theca cells. ZNF217 overexpression in PCOS theca cells reduced DENND1A.V2 mRNA, CYP17A1 mRNA, and androgen production while increasing miR-130b-3p; ZNF217 knockdown in normal theca cells increased DENND1A.V2 and CYP17A1 mRNA. The effect is proposed to be mediated by miR-130b-3p targeting DENND1A.V2. ZNF217 overexpression and shRNA lentiviral knockdown in primary human theca cells, RT-qPCR, Western blot, androgen biosynthesis assay Journal of the Endocrine Society Medium 35668995
2024 DENND1A overexpression in granulosa cells disrupts intracellular trafficking of follicle-stimulating hormone receptor (FSHR) by promoting its internalization and inhibiting recycling back to the cell surface, thereby desensitizing granulosa cells to FSH. Transgenic mice overexpressing Dennd1a showed subfertility, irregular estrous cycles, smaller ovaries, poorly developed follicles, increased testosterone after PMSG stimulation, and diminished FSH-priming gene expression. Dennd1a transgenic mouse model, FSHR trafficking assay (internalization/recycling), ovarian histology, hormone measurements, FSH-priming gene expression Science China. Life sciences Medium 38709439
2025 Increasing endogenous DENND1A expression by perturbing candidate regulatory elements (identified via high-throughput reporter assays and CRISPR-based epigenome editing) causes elevated testosterone levels in an adrenal cell model, establishing a causal link between DENND1A expression level and androgen biosynthesis. High-throughput reporter assays (MPRA), CRISPR-based epigenome editing of regulatory elements, testosterone measurement in adrenal cell model Nature communications Medium 40825976

Source papers

Stage 0 corpus · 30 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype. Proceedings of the National Academy of Sciences of the United States of America 171 24706793
2011 Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts. Journal of medical genetics 141 22180642
2012 Variants in DENND1A are associated with polycystic ovary syndrome in women of European ancestry. The Journal of clinical endocrinology and metabolism 116 22547425
2019 Family-Based Quantitative Trait Meta-Analysis Implicates Rare Noncoding Variants in DENND1A in Polycystic Ovary Syndrome. The Journal of clinical endocrinology and metabolism 55 31038695
2020 PCOS-GWAS Susceptibility Variants in THADA, INSR, TOX3, and DENND1A Are Associated With Metabolic Syndrome or Insulin Resistance in Women With PCOS. Frontiers in endocrinology 46 32425888
2019 miRNA Profiling Reveals miRNA-130b-3p Mediates DENND1A Variant 2 Expression and Androgen Biosynthesis. Endocrinology 37 31184707
2016 Alternative splicing of DENND1A, a PCOS candidate gene, generates variant 2. Molecular and cellular endocrinology 28 27297658
2013 Genetic alterations within the DENND1A gene in patients with polycystic ovary syndrome (PCOS). PloS one 28 24086769
2022 Nimbin analog N2 alleviates high testosterone induced oxidative stress in CHO cells and alters the expression of Tox3 and Dennd1a signal transduction pathway involved in the PCOS zebrafish. Phytotherapy research : PTR 23 36450691
2022 The PCOS GWAS Candidate Gene ZNF217 Influences Theca Cell Expression of DENND1A.V2, CYP17A1, and Androgen Production. Journal of the Endocrine Society 22 35668995
2015 DENND1A gene variants in Bahraini Arab women with polycystic ovary syndrome. Gene 20 25626177
2020 Human DENND1A.V2 Drives Cyp17a1 Expression and Androgen Production in Mouse Ovaries and Adrenals. International journal of molecular sciences 19 32268539
2018 Differential association of DENND1A genetic variants with polycystic ovary syndrome in Tunisian but not Bahraini Arab women. Gene 18 29325736
2021 chi-miR-324-3p Regulates Goat Granulosa Cell Proliferation by Targeting DENND1A. Frontiers in veterinary science 17 34869714
2016 The association of DENND1A gene polymorphisms and polycystic ovary syndrome risk: a systematic review and meta-analysis. Archives of gynecology and obstetrics 17 27488699
2012 Variants in DENND1A and LHCGR are associated with endometrioid adenocarcinoma. Gynecologic oncology 15 22902918
2021 Genetic variations of bovine PCOS-related DENND1A gene identified in GWAS significantly affect female reproductive traits. Gene 14 34352299
2018 EGF Stimulates Rab35 Activation and Gastric Cancer Cell Migration by Regulating DENND1A-Grb2 Complex Formation. Frontiers in pharmacology 14 30524285
2019 Dennd1a, a susceptibility gene for polycystic ovary syndrome, is essential for mouse embryogenesis. Developmental dynamics : an official publication of the American Association of Anatomists 13 30884041
2015 Association of DENND1A Gene Polymorphisms with Polycystic Ovary Syndrome: A Meta-Analysis. Journal of clinical research in pediatric endocrinology 12 26757598
2020 Rab35-GEFs, DENND1A and folliculin differentially regulate podocalyxin trafficking in two- and three-dimensional epithelial cell cultures. The Journal of biological chemistry 9 31992598
2020 Association analysis between the tag single nucleotide polymorphisms of DENND1A and the risk of polycystic ovary syndrome in Chinese Han women. BMC medical genetics 8 31941453
2025 Gene regulatory activity associated with polycystic ovary syndrome revealed DENND1A-dependent testosterone production. Nature communications 6 40825976
2024 Tanshinone IIA from Salvia miltiorrhiza alleviates follicular maturation arrest symptoms in zebrafish via binding to the human androgen receptors and modulating Tox3 and Dennd1a. Tissue & cell 6 38759521
2018 Association study between variants in LHCGR DENND1A and THADA with preeclampsia risk in Han Chinese populations. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 6 29727258
2023 Association of FSHR and DENND1A polymorphisms with polycystic ovary syndrome: a meta-analysis. JBRA assisted reproduction 4 36350975
2018 The role of DENND1A and CYP19A1 gene variants in individual susceptibility to obesity in Turkish population-a preliminary study. Molecular biology reports 4 30232779
2024 DENND1A desensitizes granulosa cells to FSH by arresting intracellular FSHR transportation. Science China. Life sciences 2 38709439
2023 Unraveling the Genetic Associations of DENND1A (rs9696009) and ERBB4 (rs2178575) with Infertile Polycystic Ovary Syndrome Females in Pakistan. Biochemical genetics 1 37870708
2021 Initiation of oogenesis and meiosis in the fetal ovary depends on Dennd1a-mediated production of Wnt5a and retinoic acid from the somatic niches. Frontiers in bioscience (Landmark edition) 1 34994166

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