A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration.
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.
Department of Immunopathology, WPI Immunology Frontier Research Center, Osaka University, Suita City, Osaka 565-0871, Japan.
Satoshi
S
Nojima
Toshihiko
T
Toyofuku
Hiroyuki
H
Kamao
Chie
C
Ishigami
Jun
J
Kaneko
Tatsusada
T
Okuno
Hyota
H
Takamatsu
Daisuke
D
Ito
Sujin
S
Kang
Tetsuya
T
Kimura
Yuji
Y
Yoshida
Keiko
K
Morimoto
Yohei
Y
Maeda
Atsushi
A
Ogata
Masahito
M
Ikawa
Eiichi
E
Morii
Katsuyuki
K
Aozasa
Junichi
J
Takagi
Masayo
M
Takahashi
Atsushi
A
Kumanogoh
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D011992:Endosomes / Q000378:metabolism* / Q000528:radiation effects; D055879:Gene Knock-In Techniques; D018014:Gene Transfer Techniques; D005799:Genes, Dominant; D056426:Genetic Loci; D006801:Humans; D008027:Light; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008958:Models, Molecular; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology / Q000528:radiation effects; D017354:Point Mutation / Q000235:genetics*; D021381:Protein Transport / Q000528:radiation effects; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology* / Q000517:prevention & control; D055213:Retinal Pigment Epithelium / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D039961:Semaphorins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D013194:Staining and Labeling
C574096:SEMA4A protein, human; C534721:Sema4A protein, mouse; D039961:Semaphorins