The spectrum of congenital eye malformations including microphthalmia (small eyes), anophthalmia (absent eyes) and coloboma (ventral eye defects), or MAC, causes blindness in approximately 1 in 10,000 children. We have discovered novel RBP4 coding and SOX3 regulatory mutations in patients with MAC disease. RBP4 encodes plasma retinol binding protein, a lipocalin that transports vitamin A, an essential nutrient for eye development, in the bloodstream. We show RBP4 missense mutations p.A73T and p.A75T alter the ligand-binding pocket, causing autosomal dominant MAC with reduced penetrance and a maternal parent-of-origin effect. Both mutant alleles encode dominant-negative RBPs that bind poorly to vitamin A but strongly to the STRA6 receptor on recipient cell membranes. Consequently, a vitamin A “bottleneck” is created at the maternal-fetal interface, which is likely to reduce vitamin A delivery to the fetus, particularly when the mutation is inherited from the mother. This is the first report of such a defective interfering allele for a blood cargo protein in human disease. In a separate case, we describe a novel SOX3 regulatory mutation in a 46,XX child with bilateral anophthalmia and SRY-negative female-to-male sex reversal. In this patient, a paternal de novo 9q21 Xq27 insertional translocation has juxtaposed TRPM3 exons 1 and 2 downstream from SOX3, at the midpoint of a 180-bp pallindrome. This implicates a dominant, gain-of-function mechanism whereby ectopic SOX3 transcription disrupts early eye and gonadal development. Transgenic mouse models test this hypothesis and reveal sensitivity of the developing eye to alterations in SoxB1 (Sox2) spatiotemporal activity. This thesis highlights genetic and environmental factors that influence eye development, and it has broad implications for other congenital disorders.PHDHuman GeneticsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/107085/1/chouster_1.pd
