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Tom Glaser, Chris Chou, Sue Tarle, Jon Pribila, Tanya Bardakjian, Adele Schneider, Christine Nelson, Tom Glaser; Dominant-negative RBP4 mutations cause congenital eye malformations through a maternal-fetal nutritional interaction. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4972.
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© ARVO (1962-2015); The Authors (2016-present)
Vitamin A (retinol) is an essential nutrient for retinal physiology and eye morphogenesis. Gestational vitamin A deficiency poses a risk for ocular malformations. We determined the molecular basis of autosomal dominant microphthalmia, anophthalmia and coloboma (MAC) disease in a large pedigree.
We performed linkage mapping and DNA sequence analysis in familial and sporadic cases, and biochemical and cellular assays to characterize the functional effects of coding mutations.
We identified novel missense mutations in RBP4 (p.A73T and p.A75T), in three unrelated families with autosomal dominant MAC. This trait exhibits low penetrance and a maternal parent-of-origin effect. The RBP4 gene encodes serum retinol binding protein (RBP), a 21 kD circulating lipocalin responsible for mobilizing hepatic vitamin A stores and transporting retinoids to peripheral tissues, including the placenta. At target tissues, RBP binds the STRA6 transmembrane receptor for cellular uptake of vitamin A (Kawaguchi et al. 2007). Previously reported RBP4 mutations (p.G93D and p.I59N) are associated with recessive night blindness (Biesalski et al. 1999). We systematically compared biochemical and functional properties of dominant and recessive RBP4 alleles, including cellular secretion, transthyretin (TTR) interaction, 3H-retinol and STRA6 receptor binding. The RBP4 p.A73T and p.A75T alleles encode stable, circulating forms that mimic wild-type protein but bind retinol poorly, consistent with predicted structural effects on the ligand pocket, whereas the recessive alleles grossly alter folding and destabilize RBP in the circulation.
The dominant alleles compete with wild-type RBP for STRA6 binding. This dominant-negative mechanism creates sequential “bottlenecks” that limit vitamin A delivery, at the maternal-fetal interface and fetal tissues, causing congenital eye malformations and explaining the unique maternal inheritance pattern. Our findings reveal a novel mechanism for genetic disease involving mimicry by a defective plasma cargo protein, a unique gene x environment interaction controlling penetrance, and a new explanation for maternal origin effects, which may apply broadly to other congenital diseases.
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