Title:
Discovery and characterization of novel genes responsible for hereditary retinal diseases

 

Speaker:
Takeshi Iwata
National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan

 

Abstract:
Thirty ophthalmology departments and institutions in Japan were united as a Japan Eye Genetics Consortium (JEGC, http://jegc.jp) to obtain information of gene mutations responsible for hereditary retinal diseases. The disease includes retinitis pigmentosa, Leber’s congenital amaurosis, Stargardt disease, macular dystrophy, congenital stationary night blindness, achromatopsia, hereditary open angle glaucoma and others. Patient’s phenotypic information from 872 pedigrees were collected through secure online database and blood/saliva samples were also collected for DNA extraction. Exon capture (Agilent, SureSelect ver. 6) and DNA sequencing (Illumina, HiSeq4000) at average of 100 reads were performed. The sequence analysis was performed at Tokyo Medical Center (Tokyo, Japan). Approximately 14% of the pedigree was identified with known mutations, 17% with novel mutation in known genes, and surprisingly 8% of the pedigree resulted with mutation in novel gene. Each novel disease-causing gene is cloned and characterized for functional abnormality in patient derived iPS cells or in knock-in mouse eye. Collected genotype-phenotype information is now under construction AMED for public database. The novel mutations identified in Japanese patients were added to the collection of LUMINEX multiplex PCR detection kit (MBL, Co., Ltd.) for future gene mutation detection service in Asia. To identify multiple families with same gene mutations, Asian Eye Genetics Consortium (AEGC, http://asianeyegenetics.org) was established in 2014 to promote collaborative research program to exchange eye genetic information and researcher in this region with common disease interest. Over 130 members from 17 countries has now joined the consortium to expand the research to entire Asia.

 

References:
Minegishi Y, Nakayama M, Iejima D, Iwata T. Significance of Optineurin Mutations in Glaucoma and Other Diseases. Prog Ret Eye Res 2016;S1350-9462(16)30061-1.

 

Minegishi Y, Sheng X, Yoshitake K, Sergeev Y, Iejima D, Shibagaki Y, Monma N, Ikeo K, Furuno M, Zhuang W, Liu Y, Rong W, Hattori A, Iwata T. CCT2 Mutations Evoke Leber Congenital Amaurosis due to Chaperone Complex Instability. Sci Rep 2016;6:33742..

 

Iejima D, Itabashi T, Kawamura Y, Noda T, Yuasa S, Fukuda K, Oka C, Iwata T. High-Temperature Requirement A Serine Peptidase 1 Gene is Transcriptionally Regulated by Insertion/Deletion Nucleotides Located at the 3 Prime End of Age-Related Maculopathy Susceptibility 2 Gene in Patients with Age-Related Macular Degeneration. The Journal of Biological Chemistry 2015;290:2784-97

 

Minegishi Y, Iejima D, Kobayashi H, Chi Z-L, Kawase K, Yamamoto T, Seki T, Yuasa S, Fukuda K, Iwata T. Enhanced optineurin E50K-TBK1 interaction evokes protein insolubility and initiates familial primary open-angle glaucoma. Human Molecular Genetics 2013;22:3559-67

 

Akahori M, Tsunoda K, Miyake Y, Fukuda Y, Ishiura H, Tsuji S, Hatase T, Nakamura M, Ohde H, Itabashi T, Okamoto H, Takada Y, and Iwata T. Dominant mutations in RP1L1 gene are responsible for occult macular dystrophy. The American Journal of Human Genetics 2010;87:424-429

 

Chi Z-L, Akahori, A, Obazawa M, Minami M, Noda T, Nakaya N, Tomarev S, Kawase K, Yamamoto T, Noda S, Sasaoka M, Shimazaki A, Takada Y, and Iwata T. Overexpression of optineurin E50K disrupts Rab8 interaction and leads to a progressive retinal degeneration in mice. Human Molecular Genetics 2010;19:2605-2615