Human DENND1A.V2 Drives Cyp17a1 Expression and Androgen Production in Mouse Ovaries and Adrenals

Teves, María E.; Modi, Bhavi P.; Kulkarni, Rewa; Han, Angela X; Marks, Jamaia S; Subler, Mark A.; Windle, Jolene J.; Newall, Jordan M; McAllister, Jan M.; Strauss, Jerome F.

doi:10.3390/ijms21072545

Cited by 15 publications

(4 citation statements)

References 24 publications

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“…However, they display reduced placenta size [ 63 , 64 ] in contrast to the normal Atxn2l −/− placentas. Mid-gestation embryonic lethality was recently also documented for factors of endocytic uptake, such as DENND1A and VPS54 [ 65 , 66 ].…”

Section: Resultsmentioning

confidence: 99%

Mid-Gestation lethality of Atxn2l-Ablated Mice

Key

Harter

Sen

et al. 2020

IJMS

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Depletion of yeast/fly Ataxin-2 rescues TDP-43 overexpression toxicity. In mouse models of Amyotrophic Lateral Sclerosis via TDP-43 overexpression, depletion of its ortholog ATXN2 mitigated motor neuron degeneration and extended lifespan from 25 days to >300 days. There is another ortholog in mammals, named ATXN2L (Ataxin-2-like), which is almost uncharacterized but also functions in RNA surveillance at stress granules. We generated mice with Crispr/Cas9-mediated deletion of Atxn2l exons 5-8, studying homozygotes prenatally and heterozygotes during aging. Our novel findings indicate that ATXN2L absence triggers mid-gestational embryonic lethality, affecting female animals more strongly. Weight and development stages of homozygous mutants were reduced. Placenta phenotypes were not apparent, but brain histology showed lamination defects and apoptosis. Aged heterozygotes showed no locomotor deficits or weight loss over 12 months. Null mutants in vivo displayed compensatory efforts to maximize Atxn2l expression, which were prevented upon nutrient abundance in vitro. Mouse embryonal fibroblast cells revealed more multinucleated giant cells upon ATXN2L deficiency. In addition, in human neural cells, transcript levels of ATXN2L were induced upon starvation and glucose and amino acids exposure, but this induction was partially prevented by serum or low cholesterol administration. Neither ATXN2L depletion triggered dysregulation of ATXN2, nor a converse effect was observed. Overall, this essential role of ATXN2L for embryogenesis raises questions about its role in neurodegenerative diseases and neuroprotective therapies.

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Section: Resultsmentioning

confidence: 99%

Mid-Gestation lethality of Atxn2l-Ablated Mice

Key

Harter

Sen

et al. 2020

IJMS

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“…Conversely, a knockdown model whereby DENND1A.V2 expression was silenced in PCOS theca cells demonstrated a reduction in steroidogenesis [ 23 ]. A model creating transgenic hDENND1A.V2 mice lines has further demonstrated these concepts; elevation of both ovarian and adrenal Cyp17a1 mRNA levels as well as transgenic ovarian thecal cell steroid production was observed in those mice expressing hDENND1A.V2 transcripts demonstrating impacts on both ovarian and adrenal steroidogenesis [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Body mass index stratified meta-analysis of genome-wide association studies of polycystic ovary syndrome in women of European ancestry

Burns,

Mullin,

Moolhuijsen

et al. 2024

BMC Genomics

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Background Polycystic ovary syndrome (PCOS) is a complex multifactorial disorder with a substantial genetic component. However, the clinical manifestations of PCOS are heterogeneous with notable differences between lean and obese women, implying a different pathophysiology manifesting in differential body mass index (BMI). We performed a meta-analysis of genome-wide association study (GWAS) data from six well-characterised cohorts, using a case–control study design stratified by BMI, aiming to identify genetic variants associated with lean and overweight/obese PCOS subtypes. Results The study comprised 254,588 women (5,937 cases and 248,651 controls) from individual studies performed in Australia, Estonia, Finland, the Netherlands and United States of America, and separated according to three BMI stratifications (lean, overweight and obese). Genome-wide association analyses were performed for each stratification within each cohort, with the data for each BMI group meta-analysed using METAL software. Almost half of the total study population (47%, n = 119,584) were of lean BMI (≤ 25 kg/m2). Two genome-wide significant loci were identified for lean PCOS, led by rs12000707 within DENND1A (P = 1.55 × 10–12) and rs2228260 within XBP1 (P = 3.68 × 10–8). One additional locus, LINC02905, was highlighted as significantly associated with lean PCOS through gene-based analyses (P = 1.76 × 10–6). There were no significant loci observed for the overweight or obese sub-strata when analysed separately, however, when these strata were combined, an association signal led by rs569675099 within DENND1A reached genome-wide significance (P = 3.22 × 10–9) and a gene-based association was identified with ERBB4 (P = 1.59 × 10–6). Nineteen of 28 signals identified in previous GWAS, were replicated with consistent allelic effect in the lean stratum. There were less replicated signals in the overweight and obese groups, and only 4 SNPs were replicated in each of the three BMI strata. Conclusions Genetic variation at the XBP1, LINC02905 and ERBB4 loci were associated with PCOS within unique BMI strata, while DENND1A demonstrated associations across multiple strata, providing evidence of both distinct and shared genetic features between lean and overweight/obese PCOS-affected women. This study demonstrated that PCOS-affected women with contrasting body weight are not only phenotypically distinct but also show variation in genetic architecture; lean PCOS women typically display elevated gonadotrophin ratios, lower insulin resistance, higher androgen levels, including adrenal androgens, and more favourable lipid profiles. Overall, these findings add to the growing body of evidence supporting a genetic basis for PCOS as well as differences in genetic patterns relevant to PCOS BMI-subtype.

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“…DENND1A is a guanine nucleotide exchange factor involved in clathrin-mediated endocytosis 54,55 . DENND1A expression has been implicated in androgen biosynthesis [22][23][24] , including in H295R cell model 56 . Therefore, we focused on understanding the role of regulatory elements in controlling DENND1A expression and activity in H295R cells.…”

Section: Allele-specific Regulatory Variants Identified In Dennd1a Locusmentioning

confidence: 99%

“…DENND1A was first identified as a PCOS candidate gene in GWAS 1 . DENND1A was subsequently shown to be an important regulator of theca cell androgen biosynthesis where ectopic overexpression led to increased androgen production [22][23][24] . Collectively, rare variants in DENND1A were associated with PCOS quantitative traits in 50% of affected families 24 .…”

Section: Introductionmentioning

confidence: 99%

Gene regulatory activity associated with PCOS revealedDENND1A-dependent testosterone production

Sankaranarayanan,

Brewer,

Johnson

et al. 2024

Preprint

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Polycystic ovary syndrome (PCOS) is among the most common disorders affecting up to 15% of the menstruating population globally. It is the leading cause of anovulatory infertility and a major risk factor for type 2 diabetes. Elevated testosterone levels are a core endophenotype. Despite that prevalence, the underlying causes remain unknown. PCOS genome-wide association studies (GWAS) have reproducibly mapped a number of susceptibility loci, including one encompassing a gene regulating androgen biosynthesis, DENND1A. Identifying the causal variants within these loci will provide fundamental insight into the precise biological pathways that are disrupted in PCOS. We report the discovery of gene regulatory mechanisms that help explain genetic association with PCOS in the GATA4, FSHB and DENND1A loci using a combination of high throughput reporter assays, CRISPR-based epigenome editing, and genetic association analysis from PCOS case and control populations. In addition, we found that increased endogenous DENND1A expression causes elevated testosterone levels in an adrenal cell model, specifically by perturbing candidate regulatory elements. These results further highlight the potential for combining genetic variant analyses with experimental approaches to fine map genetic associations with disease risk.

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Human DENND1A.V2 Drives Cyp17a1 Expression and Androgen Production in Mouse Ovaries and Adrenals

Cited by 15 publications

References 24 publications

Mid-Gestation lethality of Atxn2l-Ablated Mice

Mid-Gestation lethality of Atxn2l-Ablated Mice

Body mass index stratified meta-analysis of genome-wide association studies of polycystic ovary syndrome in women of European ancestry

Gene regulatory activity associated with PCOS revealedDENND1A-dependent testosterone production

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