Biochemical basis for dominant inheritance, variable penetrance, and maternal effects in RBP4 congenital eye disease

Christopher M. Chou, Christine Nelson, Susan A. Tarlé, Jonathan T. Pribila, Tanya Bardakjian, Sean Woods, Adele Schneider, Thomas M Glaser

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)634-646
Number of pages13
JournalCell
Volume161
Issue number3
DOIs
StatePublished - Apr 23 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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