A point mutation in Semaphorin 4A associated with retinal degenerative diseases

2013 Fiscal Year Final Research Report

• Project/Area Number: 23790444
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Experimental pathology
• Research Institution: Osaka University
• Principal Investigator: NOJIMA Satoshi 大阪大学, 医学(系)研究科(研究院), 助教 (40528791)
• Co-Investigator(Renkei-kenkyūsha): 熊ノ郷 淳 大阪大学, 大学院 医学系研究科, 呼吸器・免疫アレルギー内科学教授 (10294125)
• Project Period (FY): 2011 – 2013
• Keywords: セマフォリン / 点突然変異 / 網膜ホメオスタシス / 網膜変性疾患

Research Abstract

Semaphorin 4A(Sema4A) has an essential role in photoreceptor survival. In humans, mutations in Sema4A are thought to contribute to retinal degenerative diseases. Here we generate a series of knock-in mouse lines with corresponding mutations (D345H, F350C or R713Q) in the Sema4A gene and find that Sema4A F350C causes retinal degeneration phenotypes. The F350C mutation results in abnormal localization of the Sema4A protein, leading to impaired endosomal sorting of molecules indispensable for photoreceptor survival. Additionally, protein structural modelling reveals that the side chain of the 350th amino acid is critical to retain the proper protein conformation. Furthermore, Sema4A gene transfer successfully prevents photoreceptor degeneration in Sema4A F350C/F350C and Sema4A-/- mice. Thus, our findings not only indicate the importance of the Sema4A protein conformation in human and mouse retina homeostasis but also identify a novel therapeutic target for retinal degenerative diseases.

Research Products

• [Journal Article] A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration (2013)
  • Author(s): Nojima S, Toyofuku T, Kamao H, Ishigami C, Kaneko J, Okuno T, Takamatsu H, Ito D, Kang S, Kimura T, Yoshida Y, Morimoto K, Maeda Y, Ogata A, Ikawa M, Morii E, Aozasa K, Takagi J, Takahashi M, Kumanogoh A
  • Journal Title: Nature Communication Volume: 4 Pages: 1406
  • DOI: 10.1038/ncomms2420
• [Journal Article] Endosomal sorting by Semaphorin 4A in retinal pigment epithelium supports photoreceptor survival (2012)
  • Author(s): Toyofuku T, Nojima S, Ishikawa T, Takamatsu H, Tsujimura T, Uemura A, Matsuda J, Seki T, Kumanogoh A
  • Journal Title: Genes&Development Volume: 26(8) Pages: 816-829
• [Presentation] A point mutation in Semaphorin 4A, associated with defective endosomal sorting for chronic oxidative stress, causes retinal degenerative diseases (2013)
  • Organizer: JST-CREST International Symposium
  • Place of Presentation: 一橋記念講堂
  • Year and Date: 20130212-13
• [Presentation] A point mutation in Semaphorin 4A, associated with defective endosomal sorting for chronic oxidative stress, causes retinal degenerative diseases (2012)
  • Organizer: 第22回日本サイトメトリー学会学術集会
  • Place of Presentation: 千里ライフサイエンスセンター
  • Year and Date: 20120629-30
• [Presentation] Semaphorin4Aにおける点突然変異と網膜色素変性症 (2012)
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 京王プラザホテル
  • Year and Date: 20120426-28
• [Presentation] Semaphorin4Aにおける点突然変異と網膜色素変性症 (2012)
  • Organizer: 第49回日本臨床分子医学会学術集会
  • Place of Presentation: 京都・みやこめっせ
  • Year and Date: 20120413-14
• [Remarks] 日刊工業新聞,2013年01月『網膜色素変性症治療に道』
• [Remarks] 大阪大学免疫学フロンティアセンター公式ホームページ, 2013年01月『新たな網膜変性疾患の病態機序を発見(熊ノ郷 教授がNat Communに掲載)』
• [Remarks] Nature Communications注目の論文, natureasia.com, 2013年01月『エンドソームでの選別異常に関連し網膜変性の原因となるSemaphorin 4A中の点突然変異とSema4Aを用いた網膜疾患治療への応用』
• [Remarks] マイナビニュース,2013年02月『阪大、「網膜色素変性症」の新たな発症メカニズムを発見』