title: Biochemical Basis for Dominant Inheritance, Variable Penetrance, and Maternal Effects in RBP4 Congenital Eye Disease.
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.
authors.affiliation: Departments of Human Genetics and Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Chou
authors.affiliation: Department of Ophthalmology, Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Nelson
authors.affiliation: Departments of Human Genetics and Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Tarlé
authors.affiliation: Department of Ophthalmology, Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: Pribila
authors.affiliation: Division of Genetics, Einstein Medical Center, Philadelphia, PA 19141, USA.
authors.forename: Tanya
authors.initials: T
authors.lastname: Bardakjian
authors.affiliation: Department of Cell Biology and Human Anatomy, Congenital Eye Disease Study Group, University of California, Davis School of Medicine, Davis, CA 95616, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Woods
authors.affiliation: Division of Genetics, Einstein Medical Center, Philadelphia, PA 19141, USA.
authors.forename: Adele
authors.initials: A
authors.lastname: Schneider
authors.affiliation: 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: tmglaser@ucdavis.edu.
authors.forename: Tom
authors.initials: T
authors.lastname: Glaser
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004252:DNA Mutational Analysis; D015785:Eye Diseases, Hereditary / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D008431:Maternal-Fetal Exchange; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D019683:Penetrance; D011247:Pregnancy; D054839:Retinol-Binding Proteins, Plasma / Q000737:chemistry / Q000235:genetics*; D016415:Sequence Alignment; D014802:Vitamin A Deficiency / Q000378:metabolism
chemical_list: C101326:RBP4 protein, human; D054839:Retinol-Binding Proteins, Plasma