SIX6 (SIX homeobox 6) is a homeodomain transcription factor that plays critical roles in eye development and circadian rhythm regulation. The protein functions as a DNA-binding transcription factor with RNA polymerase II-specific activity, primarily expressed in developing and adult retinal tissues 1. SIX6 is essential for early eye field formation, optic vesicle development, and retinal differentiation, working alongside other homeodomain factors like Pax6, Lhx2, and Six3 to control cell fate determination during retinogenesis 2. The gene also functions in suprachiasmatic nucleus (SCN) development, where it is required for proper circadian pacemaker function and vasoactive intestinal peptide expression 3. Disease relevance is significant, with SIX6 variants strongly associated with primary open-angle glaucoma (POAG) across multiple populations 4. Novel pathogenic mutations like p.R116G and p.R116E have been identified in POAG patients, with these variants predicted to disrupt DNA-protein interactions and correlate with earlier disease onset and more severe visual field damage 5. SIX6 haploinsufficiency due to chr14 deletions causes bilateral anophthalmia and pituitary anomalies, demonstrating its crucial role in craniofacial development 1. The gene's function appears conserved across species, with variants also conferring glaucoma susceptibility in dogs 6.