DENND1A (DENN domain containing 1A) functions as a guanine nucleotide exchange factor (GEF) that regulates vesicular transport by activating RAB35 through GDP-to-GTP exchange 1. The gene is strongly implicated in polycystic ovary syndrome (PCOS) pathogenesis, with genome-wide association studies identifying multiple DENND1A polymorphisms (rs10818854, rs2479106, rs10986105) that increase PCOS risk 2. A specific splice variant, DENND1A.V2, is elevated in theca cells from PCOS patients and directly promotes androgen biosynthesis by increasing CYP17A1 expression 3. Mechanistically, DENND1A overexpression disrupts follicle stimulating hormone receptor (FSHR) trafficking in granulosa cells, promoting receptor internalization while inhibiting recycling, thereby reducing FSH responsiveness 1. This leads to subfertility, irregular estrous cycles, and increased testosterone production in transgenic mouse models 1. Rare variants in DENND1A are associated with specific PCOS subtypes, particularly the reproductive subtype characterized by higher luteinizing hormone levels 4. The gene shows evidence of positive evolutionary selection, suggesting its variants may have provided ancestral advantages despite their current association with reproductive dysfunction 5.