IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v4y2013i1d10.1038_ncomms2420.html
   My bibliography  Save this article

A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration

Author

Listed:
  • Satoshi Nojima

    (WPI Immunology Frontier Research Center, Osaka University, Suita City
    Osaka University Graduate School of Medicine, Osaka University, Suita City)

  • Toshihiko Toyofuku

    (WPI Immunology Frontier Research Center, Osaka University, Suita City)

  • Hiroyuki Kamao

    (Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology
    Postgraduate School of Kawasaki Medical School, Kawasaki Medical School, Kurashiki City)

  • Chie Ishigami

    (Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology)

  • Jun Kaneko

    (Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology)

  • Tatsusada Okuno

    (WPI Immunology Frontier Research Center, Osaka University, Suita City
    Graduate School of Medicine, Osaka University, Suita City)

  • Hyota Takamatsu

    (WPI Immunology Frontier Research Center, Osaka University, Suita City)

  • Daisuke Ito

    (WPI Immunology Frontier Research Center, Osaka University, Suita City
    Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Suita City)

  • Sujin Kang

    (WPI Immunology Frontier Research Center, Osaka University, Suita City
    Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Suita City)

  • Tetsuya Kimura

    (WPI Immunology Frontier Research Center, Osaka University, Suita City
    Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Suita City)

  • Yuji Yoshida

    (WPI Immunology Frontier Research Center, Osaka University, Suita City
    Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Suita City)

  • Keiko Morimoto

    (WPI Immunology Frontier Research Center, Osaka University, Suita City
    Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Suita City)

  • Yohei Maeda

    (WPI Immunology Frontier Research Center, Osaka University, Suita City
    Graduate School of Medicine, Osaka University, Suita City)

  • Atsushi Ogata

    (WPI Immunology Frontier Research Center, Osaka University, Suita City
    Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Suita City)

  • Masahito Ikawa

    (Animal Resource Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Suita)

  • Eiichi Morii

    (Osaka University Graduate School of Medicine, Osaka University, Suita City)

  • Katsuyuki Aozasa

    (Osaka University Graduate School of Medicine, Osaka University, Suita City)

  • Junichi Takagi

    (Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, Suita City)

  • Masayo Takahashi

    (Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology)

  • Atsushi Kumanogoh

    (WPI Immunology Frontier Research Center, Osaka University, Suita City
    Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Suita City
    JST, CREST, Suita City)

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 Sema4AF350C 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 Sema4AF350C/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.

Suggested Citation

  • Satoshi Nojima & Toshihiko Toyofuku & Hiroyuki Kamao & Chie Ishigami & Jun Kaneko & Tatsusada Okuno & Hyota Takamatsu & Daisuke Ito & Sujin Kang & Tetsuya Kimura & Yuji Yoshida & Keiko Morimoto & Yohe, 2013. "A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration," Nature Communications, Nature, vol. 4(1), pages 1-10, June.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2420
    DOI: 10.1038/ncomms2420
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/ncomms2420
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/ncomms2420?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2420. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.