CYP1B1 deficiency can cause abnormal histological features and delayed development in human fetus eye globe
Fatemeh Suri1 *, Mozhgan Rezaei-Kanavi2 , Shahin Yazdani2 , Elahe Elahi3 , Mehraban Mirrahimi1 , Maryam Hajizadeh1 , Sepideh Khodaverdi4
- Ophthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Ocular Tissue Engineering Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- School of Biology, University College of Science, University of Tehran, Tehran, Iran
- Department of Obstetrics and Gynecology, Endometriosis Research Center, Iran University of Medical Sciences, Tehran, Iran
Abstract: Primary congenital glaucoma (PCG) is the most severe form of glaucoma and a major cause of childhood blindness. The disease is characterized by anatomical defects in the anterior chamber angle of the eye and neonatal or infantile onset of clinical manifestations. CYP1B1 gene mutations are by far the most common cause of PCG worldwide. Increased oxidative stress and abnormal extracellular matrix (ECM) morphology of the trabecular tissue (TM) are two common features of glaucoma. However, the underlying mechanism by which CYP1B1 deficiency affects glaucoma pathogenesis remains unknown. In this study for the first time, developmental and histopathological features of ocular tissues of a human fetus with mutation in CYP1B1 and thus predisposed to PCG were evaluated in comparison with an age-matched healthy eye globe.
Methods: The eyes of a fetus with CYP1B1 mutation and a control fetus without CYP1B1 mutations, both aborted at 17 weeks of gestation, were studied. Hematoxylin and eosin, Periodic acid-Schiff, Gomori’s trichrome, and Verhoeff–Van Gieson staining protocols in addition to immunohistochemistry staining using anti-CYP1B1, anti-fibrillin-1, and anti-4-Hydroxy-2-nonenal antibodies, as primary antibodies, were performed to assess the effect of the mutated CYP1B1 genotype on ocular tissues development, CYP1B1 protein expression, ECM structure, and oxidative stress status in the developing fetus eye. Quantitative analyses were performed using Image J software. Student’s t-test was used for statistical analysis and P-values less than 0.05 were considered statistically significant.
Results: Delayed development in ocular tissues including underdeveloped anterior chamber, posteriorly-located primitive TM and no evidence of anterior chamber angle formation, primitive iris, or appearance of Schlemm’s canal, accompanied with decreased expression of CYP1B1 protein, irregular ECM structure and increased oxidative stress biomarker in the eye tissues of the fetus with CYP1B1 mutations as compared to normal fetus have been shown in this study.
Conclusion: To the best of our knowledge this is the only study on human glaucomatous fetus that reveal the effect of CYP1B1 deficiency on development of ocular tissues and histopathological characteristics of the tissues including ECM disruptions and oxidative stress features early during fetus development contributing to evolvement of the glaucoma phenotype.
