Abstract
SUMMARYMaternally skewed transmission of traits has been associated with genomic imprinting and oocyte-derived mRNA. We report canine congenital eye malformations, caused by an amino acid deletion (K12del) near the N terminus of retinol-binding protein (RBP4). The disease is only expressed when both dam and offspring are deletion homozygotes. RBP carries vitamin A (retinol) from hepatic stores to peripheral tissues, including the placenta and developing eye, where it is required to synthesize retinoic acid. Gestational vitamin A deficiency is a known risk factor for ocular birth defects. The K12del mutation disrupts RBP folding in vivo, decreasing its secretion from hepatocytes to serum. The maternal penetrance effect arises from an impairment in the sequential transfer of retinol across the placenta, via RBP encoded by maternal and fetal genomes. Our results demonstrate a mode of recessive maternal inheritance, with a physiological basis, and they extend previous observations on dominant-negative RBP4 alleles in humans.
Highlights
The microphthalmia, anophthalmia, and coloboma (MAC) spectrum of congenital eye malformations are important causes of childhood blindness (Hornby et al, 2000)
Apart from gene mutations, various environmental risk factors have been reported for human MAC disease, most notably vitamin A deficiency (VAD) (Hornby et al, 2002)
We demonstrate that deletion of a single amino acid from the canine serum RBP causes severe congenital eye malformations in Irish soft-coated wheaten terriers (ISCWTs) using segregation, clinical, and molecular data
Summary
The microphthalmia, anophthalmia, and coloboma (MAC) spectrum of congenital eye malformations are important causes of childhood blindness (Hornby et al, 2000). Anophthalmia refers to the complete absence and microphthalmia to reduced size of the ocular globe. Colobomas are notch-like defects in the iris, chorioretina, and/or optic nerve head that result from incomplete closure of the axial optic fissure during development (Onwochei et al, 2000). With defects limited to the eye, but in one-third of patients the eye malformations occur as part of a syndrome (Verma and Fitzpatrick, 2007). Apart from gene mutations, various environmental risk factors have been reported for human MAC disease, most notably vitamin A deficiency (VAD) (Hornby et al, 2002). The eye is most sensitive among organs to reduced RA levels during embryogenesis
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