RRC ID 47222
著者 Suga A, Mizota A, Kato M, Kuniyoshi K, Yoshitake K, Sultan W, Yamazaki M, Shimomura Y, Ikeo K, Tsunoda K, Iwata T.
タイトル Identification of Novel Mutations in the LRR-Cap Domain of C21orf2 in Japanese Patients With Retinitis Pigmentosa and Cone-Rod Dystrophy.
ジャーナル Invest Ophthalmol Vis Sci
Abstract PURPOSE:C21orf2 encodes a ciliary protein related to syndromic and nonsyndromic retinal degeneration. The purpose of this study was to identify novel mutations of C21orf2 associated with syndromic autosomal recessive retinitis pigmentosa (arRP) and autosomal recessive cone-rod dystrophy (arCRD) by using whole exome sequencing of a Japanese cohort.
METHODS:Whole exome sequencing was performed on DNA from affected and healthy members from 147 families with retinal degenerations. Identified nonsense and missense mutations were further restricted by using the reported single nucleotide variation frequencies and inherited patterns. The effect of the mutations was examined by in vitro assays.
RESULTS:Novel mutations in C21orf2 were found in Japanese patients with arRP with skeletal defects or arCRD. Compound heterozygous mutations, from one family (p.V111M and p.Y107H), and a homozygous mutation, from another family (p.Y107C), were all located in the leucine-rich repeat C-terminal domain required for protein stabilization. C21orf2 was expressed in the retina through the developing to the mature stage, and the protein localized to the photoreceptor cilia in the adult retina. In vitro expression showed reduced levels and affected localizations of mutated protein products compared to the wild type.
CONCLUSIONS:The identified C21orf2 mutations decreased protein stability and affected cytoplasmic localization of C21orf2. Since C21orf2 was required for ciliogenesis, our data suggested that reduced levels of functional C21orf2 induced photoreceptor degradation through abnormal cilia formation, leading to arRP or arCRD in the retina.
巻・号 57(10)
ページ 4255-63
公開日 2016-8-1
DOI 10.1167/iovs.16-19450
PII 2546332
PMID 27548899
MeSH Animals Blotting, Western Cells, Cultured Child, Preschool Cone-Rod Dystrophies / epidemiology Cone-Rod Dystrophies / genetics* Cone-Rod Dystrophies / metabolism Cytoskeletal Proteins DNA / genetics* DNA Mutational Analysis Exome Female Genes, Recessive Homozygote Humans Japan / epidemiology Male Mice Middle Aged Mutation, Missense* Pedigree Prevalence Proteins / genetics* Proteins / metabolism Retinitis Pigmentosa / epidemiology Retinitis Pigmentosa / genetics* Retinitis Pigmentosa / metabolism Reverse Transcriptase Polymerase Chain Reaction
IF 3.47
引用数 9
WOS 分野 OPHTHALMOLOGY
リソース情報
遺伝子材料 Genome Network Project Human cDNA IRAL058O23 (HGY103559).