title: Identification of Novel Mutations in the LRR-Cap Domain of C21orf2 in Japanese Patients With Retinitis Pigmentosa and Cone-Rod Dystrophy.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: National Institute of Sensory Organs Tokyo Medical Center, National Hospital Organization, Tokyo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Suga
authors.affiliation: Department of Ophthalmology, Teikyo University School of Medicine, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Mizota
authors.affiliation: Department of Pediatrics, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Ophthalmology, Kinki University Faculty of Medicine, Osakasayama City, Osaka, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Kuniyoshi
authors.affiliation: Japan Software Management, Yokohama, Japan.
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Yoshitake
authors.affiliation: National Institute of Sensory Organs Tokyo Medical Center, National Hospital Organization, Tokyo, Japan.
authors.forename: William
authors.initials: W
authors.lastname: Sultan
authors.affiliation: Department of Orthopaedic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Yamazaki
authors.affiliation: Department of Ophthalmology, Kinki University Faculty of Medicine, Osakasayama City, Osaka, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Shimomura
authors.affiliation: CIB-DDBJ, National Institute of Genetics, Mishima, Shizuoka, Japan.
authors.forename: Kazuho
authors.initials: K
authors.lastname: Ikeo
authors.affiliation: National Institute of Sensory Organs Tokyo Medical Center, National Hospital Organization, Tokyo, Japan.
authors.forename: Kazushige
authors.initials: K
authors.lastname: Tsunoda
authors.affiliation: National Institute of Sensory Organs Tokyo Medical Center, National Hospital Organization, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwata
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002675:Child, Preschool; D000071700:Cone-Rod Dystrophies / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D003598:Cytoskeletal Proteins; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008297:Male; D051379:Mice; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D015995:Prevalence; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C111475:CFAP410 protein, human; D003598:Cytoskeletal Proteins; D011506:Proteins; D004247:DNA