Biochemical Basis for Dominant Inheritance, Variable Penetrance, and Maternal Effects in RBP4 Congenital Eye Disease

Gestational vitamin A (retinol) deficiency poses a risk for ocular birth defects and blindness. We identified missense mutations in RBP4, encoding serum retinol binding protein, in three families with eye malformations of differing severity, including bilateral anophthalmia. The mutant phenotypes ex...

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Bibliographic Details
Published in:Cell 2015-04, Vol.161 (3), p.634-646
Main Authors: Chou, Christopher M, Nelson, Christine, Tarlé, Susan A, Pribila, Jonathan T, Bardakjian, Tanya, Woods, Sean, Schneider, Adele, Glaser, Tom
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
DNA Mutational Analysis
Eye Diseases, Hereditary - genetics
Female
Genes, Dominant
Humans
Male
Maternal-Fetal Exchange
Molecular Sequence Data
Mutation, Missense
Pedigree
Penetrance
Pregnancy
Retinol-Binding Proteins, Plasma - chemistry
Retinol-Binding Proteins, Plasma - genetics
Sequence Alignment
Vitamin A Deficiency - metabolism
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Summary:Gestational vitamin A (retinol) deficiency poses a risk for ocular birth defects and blindness. We identified missense mutations in RBP4, encoding serum retinol binding protein, in three families with eye malformations of differing severity, including bilateral anophthalmia. The mutant phenotypes exhibit dominant inheritance, but incomplete penetrance. Maternal transmission significantly increases the probability of phenotypic expression. RBP normally delivers retinol from hepatic stores to peripheral tissues, including the placenta and fetal eye. The disease mutations greatly reduce retinol binding to RBP, yet paradoxically increase the affinity of RBP for its cell surface receptor, STRA6. By occupying STRA6 nonproductively, the dominant-negative proteins disrupt vitamin A delivery from wild-type proteins within the fetus, but also, in the case of maternal transmission, at the placenta. These findings establish a previously uncharacterized mode of maternal inheritance, distinct from imprinting and oocyte-derived mRNA, and define a group of hereditary disorders plausibly modulated by dietary vitamin A.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2015.03.006