Anophthalmia, microphthalmia and coloboma (MAC) are birth defects in which the eyes are absent or very small, or where the choroid fissure fails to close in the optic cup. Most cases are sporadic, but Mendelian pedigrees have been described, typically with low penetrance. Few genes have been identified, encoding transcription and growth factors (e.g. SOX2, BMP4) active during early eye development. Most cases are unexplained. Maternal nutrition may contribute to the etiology. We found mutations in three retinoid (vitamin A) pathway genes (RBP4, STRA6, ALDH1A3) account for >5% of MAC cases, including a new gain-of-function mechanism for this disease. The RBP4 alleles encode dominant-negative serum retinol binding proteins, which bind retinol cargo poorly but adhere to the STRA6 cell surface receptor too tightly (40-fold higher affinity) ? so may disrupt retinol transfer across the yolk sac and placenta, to the embryo. The dnRBP4 mutations define a new mode of maternal inheritance and illuminate a critical protein- receptor interaction. In addition, clustered hypomorphic STRA6 alleles suggest a new domain function for this polytopic receptor. We will investigate the mechanism for increased RBP affinity and critical features of the RBP-STRA6 interaction, and test the receptor competition model for MAC pathogenesis  in vitro and  in vivo, using a comprehensive biochemical, cell-based, radioisotopic and histological approach, mouse models with specific knock-out or genome-edited (CRISPR/Cas9) alleles, and dietary manipulation. In addition,  we will systematically screen a cohort of MAC patients using whole exome sequencing (WES) and segmental dosage (SNP) analysis to find causative mutations in new genes.
We will investigate gene defects in children whose eyes are absent (anophthalmia), very small or malformed (coloboma), using biochemical methods, mouse models and genome sequencing. Our study is centered on new mutations that appear to block retinol (vitamin A) transport and metabolism, or the separation of neural and pigmented layers in the developing retina. We will test new models for hereditary disease, establish a nutritional basis for maternal inheritance of disease traits in pedigrees, and explore the earliest steps in eye formation. The results should improve diagnosis and understanding of eye malformations, and complex genetic factors underlying birth defects.
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