2. Academic Validation
  3. Biochemical Basis for Dominant Inheritance, Variable Penetrance, and Maternal Effects in RBP4 Congenital Eye Disease

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

  • Cell. 2015 Apr 23;161(3):634-646. doi: 10.1016/j.cell.2015.03.006.
Christopher M Chou 1,  Christine Nelson 2,  Susan A Tarlé 1,  Jonathan T Pribila 2,  Tanya Bardakjian 3,  Sean Woods 4,  Adele Schneider 3,  Tom Glaser 5
Affiliations

Affiliations

  • 1 Departments of Human Genetics and Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • 2 Department of Ophthalmology, Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • 3 Division of Genetics, Einstein Medical Center, Philadelphia, PA 19141, USA.
  • 4 Department of Cell Biology and Human Anatomy, Congenital Eye Disease Study Group, University of California, Davis School of Medicine, Davis, CA 95616, USA.
  • 5 Departments of Human Genetics and Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Cell Biology and Human Anatomy, Congenital Eye Disease Study Group, University of California, Davis School of Medicine, Davis, CA 95616, USA. Electronic address: [email protected].
PMID: 25910211 DOI: 10.1016/j.cell.2015.03.006
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.

Figures