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Identifying Pathogenic Genetic Background of Simplex or Multiplex Retinitis Pigmentosa Patients: A Large-Scale Mutation Screening Study
  1. Zi-Bing Jin (jinzb{at}cdb.riken.jp)
  1. RIKEN Center for Developmental Biology, Japan
    1. Michiko Mandai (mmandai{at}cdb.riken.jp)
    1. RIKEN Center for Developmental Biology, Japan
      1. Tomoko Yokota
      1. Kyoto University Hospital, Japan
        1. Kaori Higuchi
        1. Kyoto University Hospital, Japan
          1. Katsuyuki Ohmori
          1. Kyoto University Hospital, Japan
            1. Fumiko Ohtsuki
            1. Kyoto University Hospital, Japan
              1. Shunji Takakura
              1. Kyoto University Hospital, Japan
                1. Toshitaka Itabashi
                1. Osaki City Hospital, Japan
                  1. Yuko Wada
                  1. Wada-Yuko Eye Clinic, Japan
                    1. Masayuki Akimoto
                    1. Kyoto University Hospital, Japan
                      1. Satoro Ooto
                      1. Graduate School of Medicine, Kyoto University, Japan
                        1. Takuya Suzuki
                        1. Graduate School of Medicine, Kyoto University, Japan
                          1. Yasuhiko Hirami
                          1. Graduate School of Medicine, Kyoto University, Japan
                            1. Hanako Ikeda
                            1. Kyoto University Hospital, Japan
                              1. Naoaki Kawagoe
                              1. Graduate School of Medicine, Kyoto University, Japan
                                1. Akio Oishi
                                1. Graduate School of Medicine, Kyoto University, Japan
                                  1. Satoshi Ichiyama
                                  1. Kyoto University Hospital, Japan
                                    1. Masayo Takahashi
                                    1. RIKEN Center for Developmental Biology, Japan
                                      1. Nagahisa Yoshimura
                                      1. Graduate School of Medicine, Kyoto University, Japan
                                        1. Shinji Kosugi
                                        1. Graduate School of Medicine, Kyoto University, Japan

                                          Abstract

                                          Background and purpose: More than half of the retinitis pigmentosa (RP) cases are genetically simplex or multiplex. To date, 37 causative genes of RP have been identified; however, the elucidation of gene defects in simplex or multiplex RP patients/families remains problematic. The aim of our study was to identify the genetic causes of RP in patients with unknown or non-Mendelian inheritance.

                                          Methods and results: Since 2003, 52 simplex RP patients, 151 patients from 141 multiplex RP families, 6 sporadic patients with retinal degeneration were studied. A total of 108 exons of 30 RP-causing genes that harbored the reported mutations were screened by an efficient denaturing high-performance liquid chromatography (dHPLC)-based assay. Aberrant fragments were subsequently analyzed by automatic sequencing. Twenty-six mutations, including 2 frameshift mutations, one single amino acid deletion, and 23 missense mutations, were identified in 28 probands (14.07%). Eighteen mutations have not been reported to date. Three pairs of combined mutations in different genes were identified in 2 sporadic cases and 1 multiplex family, indicating the possibility of novel digenic patterns. Of the 23 missense mutations, 21 were predicted as deleterious mutations by computational methods using PolyPhen, SIFT, PANTHER, and PMut programs.

                                          Conclusion: We elucidated the mutation spectrum in Japanese RP patients and demonstrated the validity of the mutation detection system using dHPLC-sequencing for genetic diagnosis in RP patients independent of familial incidence, which may provide a model strategy for identifying genetic causes in other diseases linked to a wide range of genes.

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