A mutation in Bicdl1 (BICD family-like cargo adaptor 1) leads to mild outer retina thinning and late retinal...

Both photoreceptors and the retinal pigment epithelium (RPE) are highly metabolically active cell types that require extensive molecular transport and adequate energy production to maintain their function. We tested the hypothesis that cargo adaptor protein Bicdl1 has a non-redundant role in retinal health.

Using an unbiased forward genetics approach, we identified an association between outer retinal thinning and a point mutation in Bicdl1. We generated Bicdl1 KI (knock-in) mice carrying the same point mutation identified in the mutagenesis pipeline and characterized the resulting retinal phenotype using optical coherence tomography (OCT), fundus photography, histology, immunofluorescence, electroretinography, electron microscopy (EM), and transcriptomics.

Analysis of OCT images and histology sections demonstrated a mild decrease in outer retinal thickness and rod outer segment thickness. We found an increased number of fundus spots in retinal photographs and an increased number of Iba1⁺/Tmem119⁺ cells on RPE flat mounts of Bicdl1 KI mice. Electroretinography in aging mice showed a mild impairment in visual function, reflected by a reduction in a-wave amplitudes. EM revealed fewer RPE mitochondria in Bicdl1 KI mice. To elucidate the mechanistic basis of the observed retinal degeneration, transcriptomic studies were conducted, which suggested an association between low Bicdl1 expression and increased oxidative phosphorylation in photoreceptors.

Despite the expression of many cargo adaptor proteins and dynein activators in the retina, we identified a novel non-redundant role of Bicdl1 in retinal homeostasis. Pathway analysis of transcriptomic data suggested that Bicdl1 deficiency may affect energy metabolism.