Pitx2-associated early-onset glaucoma alters corneal innervation and sensory function in a sex-specific manner

Abstract

PurposePitx2-associated developmental glaucoma is characterized by anterior segment dysgenesis, ocular hypertension, and optic neuropathy. Its consequences for corneal sensory innervation remain poorly understood. We investigated whether this disease alters corneal nerve structure and sensory function in a sex-dependent manner. MethodsMale and female Pitx2egl1/egl1 and Pitx2+/+ mice were examined at 1 and 3 months. Ocular phenotyping included intraocular pressure, fundus imaging, visual evoked potentials, and optic nerve ultrastructure. RNA sequencing of corneas and trigeminal ganglia was performed at 3 months. Corneal innervation was assessed by {beta}III-tubulin immunofluorescence and volumetric quantification of nerve fibers. Corneal sensitivity was measured using Von Frey filaments. ResultsPitx2egl1/egl1 mice developed progressive ocular hypertension, fundus abnormalities, reduced visual evoked potential amplitudes, and optic nerve degeneration, supporting the model as early-onset glaucoma. Baseline sex-related transcriptional differences were limited in both cornea and trigeminal ganglia. In contrast, Pitx2 mutation induced sex-dependent molecular responses. Female corneas showed broader transcriptional changes enriched in inflammatory, stress-response, and tissue-remodeling pathways, whereas male corneas showed a more restricted response involving metabolic and homeostatic processes. Similar sex divergence was observed in trigeminal ganglia. Corneal nerve fiber volume was reduced in both sexes at 3 months but not at 1 month, whereas reduced sensitivity was detected only in mutant males. ConclusionsThis study identifies sexual dimorphism as a component of Pitx2-associated developmental glaucoma. Furthermore, our findings suggest that glaucoma affects the corneal sensory system beyond optic nerve pathology, highlighting a potentially overlooked dimension of disease relevant to ocular surface monitoring and patient management. HighlightsO_LIDisruption of the cornea-trigeminal ganglion axis with coordinated molecular and functional alterations in Pitx2-associated early-onset glaucoma C_LIO_LISex-dependent modifications in both cornea and trigeminal ganglion responses to early-onset glaucoma C_LIO_LIProgressive corneal neurodegeneration in early-onset glaucoma C_LI