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

Satoshi Nojima, Toshihiko Toyofuku (), Hiroyuki Kamao, Chie Ishigami, Jun Kaneko, Tatsusada Okuno, Hyota Takamatsu, Daisuke Ito, Sujin Kang, Tetsuya Kimura, Yuji Yoshida, Keiko Morimoto, Yohei Maeda, Atsushi Ogata, Masahito Ikawa, Eiichi Morii, Katsuyuki Aozasa, Junichi Takagi, Masayo Takahashi and Atsushi Kumanogoh ()
Additional contact information
Satoshi Nojima: WPI Immunology Frontier Research Center, 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
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
Hyota Takamatsu: WPI Immunology Frontier Research Center, Osaka University, Suita City
Daisuke Ito: WPI Immunology Frontier Research Center, Osaka University, Suita City
Sujin Kang: WPI Immunology Frontier Research Center, Osaka University, Suita City
Tetsuya Kimura: WPI Immunology Frontier Research Center, Osaka University, Suita City
Yuji Yoshida: WPI Immunology Frontier Research Center, Osaka University, Suita City
Keiko Morimoto: WPI Immunology Frontier Research Center, Osaka University, Suita City
Yohei Maeda: WPI Immunology Frontier Research Center, Osaka University, Suita City
Atsushi Ogata: WPI Immunology Frontier Research Center, 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

Nature Communications, 2013, vol. 4, issue 1, 1-10

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms2420

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