A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration
Open accessAbstract
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. Semaphorin 4A is implicated in photoreceptor survival. Nojima and colleagues generate transgenic mice with different mutations in the Sema4A gene and find that point mutation of F350 causes severe degeneration in photoreceptor cells, which can be rescued by virus-mediated gene therapy.
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Sema4A mutant proteins associated with human disease are mislocalized in the RPE, leading to defective endosomal sorting of prosaposins and CRALBP, which makes photoreceptors susceptible to degeneration.
“Sema4A mutant proteins that are associated with human disease are mislocalized in the RPE, leading to defective endosomal sorting of prosaposins and CRALBP, which makes the photoreceptors susceptible to degeneration (Nojima et al., 2013).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Nojima et al., 2013
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- Authors
- 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.
- Affiliations
- Immunology Frontier Research Center, The University of Osaka (JP)
- Kawasaki Medical School (JP)
- RIKEN (JP)
- Research Institute for Microbial Diseases, The University of Osaka (JP)
- The University of Osaka (JP)
- Institute for Protein Research, The University of Osaka (JP)
- Japan Science and Technology Agency (JP)
- Corresponding author
- Toyofuku, Toshihiko
- Kumanogoh, Atsushi
- ORCID
- Venue
- Nature Communications
- Published
- 2013-01-29
- Volume
- 4
- Issue
- 1
- Pages
- 1406-1406
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC3562463
- OpenAlex
- W2026441607
- Cited by
- 27
- References
- 34
- Citations by year
- 2024: 5 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 2 · 2017: 2 · 2016: 3 · 2015: 2 · 2014: 5 · 2013: 4
- FWCI
- 2.09
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (22247010, 24111001, 24651260, 23790444, 20670006, 23390069)
- Core Research for Evolutional Science and Technology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- SEMA4A, retinal degeneration, photoreceptor survival, point mutations, endosomal sorting, protein conformation, knock-in mice, gene therapy
- MeSH terms
- Animals, Chlorocebus aethiops, Genes, Dominant, Humans, Light, Mice, Inbred C57BL, Mice, Mutant Strains, Models, Molecular, Endosomes, Retinal Degeneration, Staining and Labeling, Point Mutation, Gene Transfer Techniques, COS Cells, Photoreceptor Cells, Vertebrate, Protein Transport, Semaphorins, Mice, Retinal Pigment Epithelium, Gene Knock-In Techniques, Genetic Loci
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