CCT2 Mutations Evoke Leber Congenital Amaurosis due to Chaperone Complex Instability.

ABSTRACT: Leber congenital amaurosis (LCA) is a hereditary early-onset retinal dystrophy that is accompanied by severe macular degeneration. 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, CCT?. The zebrafish mutants of CCT? are known to exhibit the eye phenotype while its mutation and association with human disease have been unknown. The CCT proteins (CCT ?-?) forms ring complex for its chaperon function. The LCA mutants of CCT?, T400P and R516H, are biochemically instable and the affinity for the adjacent subunit, CCT?, was affected distinctly in both mutants. The patient-derived induced pluripotent stem cells (iPSCs), carrying these CCT? mutants, were less proliferative than the control iPSCs. Decreased proliferation under Cct2 knockdown in 661W cells was significantly rescued by wild-type CCT? expression. However, the expression of T400P and R516H didn't exhibit the significant effect. In mouse retina, both CCT? and CCT? are expressed in the retinal ganglion cells and connecting cilium of photoreceptor cells. The Cct2 knockdown decreased its major client protein, transducing ?1 (G?1). Here we report the novel LCA mutations in CCT? and the impact of chaperon disability by these mutations in cellular biology.

SUBMITTER: Minegishi Y 

PROVIDER: S-EPMC5028737 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature