A spontaneous mutation in ADIPOR1 causes retinal degeneration in mice

Abstract

AbstractAdiponectin receptor 1 (ADIPOR1) is a transmembrane protein necessary for normal anatomy and physiology in the retina. In a recent study of complement factor H knockout mice (Cfh−/−), our lab discovered a flecked retina phenotype and retinal thinning by fundus imaging and optical coherence tomography (OCT), respectively. The phenotype was observed in a subset (50%) ofCfh−/−mice. The thinning observedin vivois due to an early degeneration of rod photoreceptors. This phenotype has not been reported in published studies ofCfh−/−mice. AdipoR1 knockout mice (AdipoR1−/−) and mice deficient in Membrane Frizzled Related Protein (MFRP) exhibit this phenotype, suggesting an involvement in the emergence of the retinal degeneration observed in a subset ofCfh−/−mice.CfhandAdipoR1are located in close proximity on mouse Chromosome 1 (Chr1) and a complementation cross betweenCfhandAdipoR1mice with retinal degeneration produced 100% progeny with retinal degeneration. Sequencing of theCfh−/− mice revealed a c.841 C > T mutation inAdipoR1. Furthermore, oneCfhwildtype (of Cfh+/+) and 2 heterozygous (ofCfh+/−) mice exhibited retinal degeneration and were homozygous for the point mutation. The c.841 C > T mutation results in a proline to serine conversion at position 281 (P281S) in ADIPOR1. This residue is critical for ADIPOR1 open and closed conformations in the membrane.In silicomodeling of candidate ADIPOR1 ligands, 11-cis-retinaldehyde and docosahexaenoic acid (DHA), that are deficient in AdipoR1−/−, suggests that ADIPOR1 is involved in trafficking retinoids and fatty acids and their combined deficiency in the ADIPOR1 mutant retinas might explain the retinal degeneration phenotype.