Leber congenital amaurosis (LCA) is a hereditary early-onset congenital retinopathy that develops concomitantly with severe macular degeneration 1.

Here we report the novel LCA mutations in CCTβ and the impact of chaperon disability by these mutations in cellular biology. The Cct2 knockdown decreased its major client protein, transducing β1 (Gβ1). In mouse retina, both CCTβ and CCTγ are expressed in the retinal ganglion cells and connecting cilium of photoreceptor cells. However, the expression of T400P and R516H didn’t exhibit the significant effect. Decreased proliferation under Cct2 knockdown in 661W cells was significantly rescued by wild-type CCTβ expression. The patient-derived induced pluripotent stem cells (iPSCs), carrying these CCTβ mutants, were less proliferative than the control iPSCs. The LCA mutants of CCTβ, T400P and R516H, are biochemically instable and the affinity for the adjacent subunit, CCTγ, was affected distinctly in both mutants. The CCT proteins (CCT α-θ) forms ring complex for its chaperon function.

The zebrafish mutants of CCTβ are known to exhibit the eye phenotype while its mutation and association with human disease have been unknown. In this study, novel compound heterozygous mutations were identified as LCA-causative in chaperonin-containing TCP-1, subunit 2 (CCT2), a gene that encodes the molecular chaperone protein, CCTβ. Leber congenital amaurosis (LCA) is a hereditary early-onset retinal dystrophy that is accompanied by severe macular degeneration.

Chaperone synonym