Compound heterozygous mutations in a mouse model of Leber congenital amaurosis reveal the role of CCT2 in photoreceptor maintenance.
Takeshi IwataYuriko MinegishiMegumi YamamotoKoji UedaTakeshi IwataPublished in: Communications biology (2024)
TRiC/CCT is a chaperonin complex required for the folding of cytoplasmic proteins. Although mutations in each subunit of TRiC/CCT are associated with various human neurodegenerative diseases, their impact in mammalian models has not yet been examined. A compound heterozygous mutation in CCT2 (p.[Thr400Pro]; p.[Arg516His]) is causal for Leber congenital amaurosis. Here, we generate mice carrying each mutation and show that Arg516His (R516H) homozygosity causes photoreceptor degeneration accompanied by a significant depletion of TRiC/CCT substrate proteins in the retina. In contrast, Thr400Pro (T400P) homozygosity results in embryonic lethality, and the compound heterozygous mutant (T400P/R516H) mouse showed aberrant cone cell lamination and died 2 weeks after birth. Finally, CCDC181 is identified as a interacting protein for CCTβ protein, and its localization to photoreceptor connecting cilia is compromised in the mutant mouse. Our results demonstrate the distinct impact of each mutation in vivo and suggest a requirement for CCTβ in ciliary maintenance.
Keyphrases
- early onset
- mouse model
- endothelial cells
- single cell
- magnetic resonance
- wild type
- gene expression
- amino acid
- single molecule
- protein protein
- metabolic syndrome
- pregnant women
- binding protein
- computed tomography
- molecular dynamics simulations
- adipose tissue
- insulin resistance
- cell therapy
- diabetic retinopathy
- high fat diet induced