Inherited Dna Changes Can Cause Hormone Imbalance In Women With Polycystic Ovary Syndrome

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Journal: Nature Communications

Title: Gene Regulatory Activity Associated pinch Polycystic Ovary Syndrome Reveals DENND1A-Dependant Testosterone Production

Authors: Andrea Dunaif, MD, Chief of nan Division of Endocrinology, Diabetes and Bone Disease for nan Mount Sinai Health System and nan Lillian and Henry M. Stratton Professor of Molecular Medicine astatine nan Icahn School of Medicine astatine Mount Sinai

Bottom line: Increased testosterone levels are a accordant hormonal abnormality successful women pinch polycystic ovary syndrome (PCOS). This study identified circumstantial DNA variants successful nan cistron DENND1A, which summation testosterone accumulation successful PCOS. Using quality PCOS compartment models, researchers demonstrated that activating these DNA switches turns connected DENND1A and drives testosterone production. This provides nan first nonstop grounds that inherited DNA changes tin origin nan hormone imbalance astatine nan halfway of PCOS.

Why this study is unique: This is nan first clip that circumstantial inherited DNA variants for PCOS person been shown to change hormone accumulation successful a quality PCOS compartment model. While earlier studies mapped wide "regions of interest" successful nan genome, nary had identified nan precise functional switches that alteration hormone biology.

Why nan study is important: PCOS is 1 of nan astir communal conditions successful reproductive-age women, affecting 10 to 15 percent of this organization globally. It is simply a analyzable familial upset that reflects nan relationship of aggregate genes pinch nan environment. PCOS is nan starring origin of infertility related to disrupted ovulation and is now recognized arsenic a awesome cardiometabolic upset crossed nan lifespan, powerfully linked to type 2 diabetes and obesity. Elevated testosterone levels are its astir accordant hormonal feature. Understanding really inherited DNA changes lead to accrued testosterone levels could unfastened nan doorway to caller therapies for PCOS.

How nan investigation was conducted: Nearly 10 years ago, researchers selected nan 14 genomic regions that had been associated pinch PCOS astatine that time. Using a high-throughput newsman assay, they scanned thousands of DNA sequences successful those regions for regulatory activity, identifying nan "regulatory switches" that power nan look of genes successful hormone-producing cells. They past utilized genome-wide relation studies (GWAS) information to find which of these regulatory elements were associated pinch PCOS. This two-step creation enabled researchers to attraction solely connected PCOS-associated regulatory regions, thereby importantly reducing nan number of women pinch PCOS who needed to beryllium studied.

Finally, researchers applied clustered interspaced short palindromic repeats (CRISPR)-based epigenome editing-a precise method that tin move DNA switches connected aliases disconnected without altering nan underlying code-to activate regulatory regions successful quality compartment models: 1 that produces testosterone (in adrenal steroid-producing cells) and different that produces estradiol (in ovarian granulosa cells). Researchers identified DENND1A regulatory regions that accrued DENND1A expression and testosterone accumulation successful a PCOS testosterone-producing compartment model, proving a nonstop mechanistic nexus betwixt familial variants and nan hormonal features of PCOS.

Results: Researchers identified much than 1,000 regulatory DNA elements crossed 14 PCOS loci successful hormone-producing compartment models. Several regions, including FSHB, GATA4, and DENND1A, contained regulatory variants associated pinch PCOS. In nan PCOS testosterone-producing compartment model, activating nan DENND1A regulatory DNA accrued its look and testosterone production.

What this study intends for doctors: For clinicians, this study identifies nan familial variants successful DENND1A that underlie nan basal hormonal abnormality of PCOS, elevated testosterone levels. Previous studies had shown that a cistron region containing DENND1A was associated pinch PCOS, but location had been nary nonstop grounds that circumstantial variants successful nan regulatory region of this cistron accrued testosterone accumulation successful a quality PCOS compartment model. This type of mechanistic penetration could yet lead to treatments aimed astatine lowering testosterone accumulation astatine its familial source.

What this study intends for patients: For patients, this study shows that PCOS is driven successful portion by inherited DNA variants that straight summation testosterone production. Understanding these mechanisms opens nan anticipation of therapies that could target nan genes aliases regulatory switches responsible for accrued testosterone accumulation successful PCOS. High levels of testosterone, a antheral hormone, origin galore symptoms of PCOS, specified arsenic accrued male-pattern hairsbreadth maturation and disruption of ovulation, starring to irregular menstrual cycles and infertility.

What nan adjacent steps are for this work: This is simply a proof-of-concept study. DENND1A is only 1 of nan 14 regions we studied, and location are now astir 30 PCOS loci known. The adjacent measurement is to use this two-step attack to nan remaining regions, including larger and much divers populations, to build a much broad image of nan disrupted pathways successful PCOS.

Quotes: "For nan first time, we person shown really circumstantial inherited DNA variants successful PCOS alteration cistron activity and summation testosterone production. That moves america from statistical relation to biologic mechanism. Our innovative attack of first identifying regulatory regions successful PCOS susceptibility genes, past determining which of these regions were associated pinch PCOS, allowed america to attraction functional testing connected regions pinch a precocious likelihood of containing disease-causing variants. Identifying nan precise mechanisms by which DNA variety causes analyzable disorders specified arsenic PCOS is 1 of nan awesome challenges successful quality genetics. The model we developed could toggle shape really we study analyzable disorders beyond PCOS," Dr. Dunaif said.

Source:

Journal reference:

Sankaranarayanan, L., et al. (2025). Gene regulatory activity associated pinch polycystic ovary syndrome revealed DENND1A-dependent testosterone production. Nature Communications. doi.org/10.1038/s41467-025-62884-7

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