title: 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, CCTβ. The zebrafish mutants of CCTβ are known to exhibit the eye phenotype while its mutation and association with human disease have been unknown. The CCT proteins (CCT α-θ) forms ring complex for its chaperon function. 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 patient-derived induced pluripotent stem cells (iPSCs), carrying these CCTβ mutants, were less proliferative than the control iPSCs. Decreased proliferation under Cct2 knockdown in 661W cells was significantly rescued by wild-type CCTβ expression. However, the expression of T400P and R516H didn't exhibit the significant effect. In mouse retina, both CCTβ and CCTγ are expressed in the retinal ganglion cells and connecting cilium of photoreceptor cells. The Cct2 knockdown decreased its major client protein, transducing β1 (Gβ1). Here we report the novel LCA mutations in CCTβ and the impact of chaperon disability by these mutations in cellular biology.
authors.affiliation: Division of Molecular and Cellular Biology, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Minegishi
authors.affiliation: Ningxia Eye Hospital, Ningxia People's Hospital, Ningxia, China.
authors.forename: XunLun
authors.initials: X
authors.lastname: Sheng
authors.affiliation: Laboratory of DNA Data Analysis, National Institute of Genetics, Shizuoka, Japan.
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Yoshitake
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Sergeev
authors.affiliation: Division of Molecular and Cellular Biology, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Iejima
authors.affiliation: Division of Biochemistry, School of Pharmaceutical Science, Kitasato University, Tokyo, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Shibagaki
authors.affiliation: Laboratory of DNA Data Analysis, National Institute of Genetics, Shizuoka, Japan.
authors.forename: Norikazu
authors.initials: N
authors.lastname: Monma
authors.affiliation: Laboratory of DNA Data Analysis, National Institute of Genetics, Shizuoka, Japan.
authors.forename: Kazuho
authors.initials: K
authors.lastname: Ikeo
authors.affiliation: RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Life Science Accelerator Technology Group, Transcriptome Technology Team, Yokohama, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Furuno
authors.affiliation: Ningxia Eye Hospital, Ningxia People's Hospital, Ningxia, China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhuang
authors.affiliation: Ningxia Eye Hospital, Ningxia People's Hospital, Ningxia, China.
authors.forename: Yani
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Ningxia Eye Hospital, Ningxia People's Hospital, Ningxia, China.
authors.forename: Weining
authors.initials: W
authors.lastname: Rong
authors.affiliation: Division of Biochemistry, School of Pharmaceutical Science, Kitasato University, Tokyo, Japan.
authors.forename: Seisuke
authors.initials: S
authors.lastname: Hattori
authors.affiliation: Division of Molecular and Cellular Biology, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwata
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics*; D056404:Chaperonin Containing TCP-1 / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology; D057130:Leber Congenital Amaurosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D055550:Protein Stability; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C533298:CCT2 protein, human; D029961:Zebrafish Proteins; D056404:Chaperonin Containing TCP-1