Spata7 is a retinal ciliopathy gene critical for correct RPGRIP1 localization and protein trafficking in the retina.
Leber congenital amaurosis (LCA) and juvenile retinitis pigmentosa (RP) are severe hereditary diseases that causes visual impairment in infants and children. SPATA7 has recently been identified as the LCA3 and juvenile RP gene in humans, whose function in the retina remains elusive. Here, we show that SPATA7 localizes at the primary cilium of cells and at the connecting cilium (CC) of photoreceptor cells, indicating that SPATA7 is a ciliary protein. In addition, SPATA7 directly interacts with the retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1), a key connecting cilium protein that has also been linked to LCA. In the retina of Spata7 null mutant mice, a substantial reduction of RPGRIP1 levels at the CC of photoreceptor cells is observed, suggesting that SPATA7 is required for the stable assembly and localization of the ciliary RPGRIP1 protein complex. Furthermore, our results pinpoint a role of this complex in protein trafficking across the CC to the outer segments, as we identified that rhodopsin accumulates in the inner segments and around the nucleus of photoreceptors. This accumulation then likely triggers the apoptosis of rod photoreceptors that was observed. Loss of Spata7 function in mice indeed results in a juvenile RP-like phenotype, characterized by progressive degeneration of photoreceptor cells and a strongly decreased light response. Together, these results indicate that SPATA7 functions as a key member of a retinal ciliopathy-associated protein complex, and that apoptosis of rod photoreceptor cells triggered by protein mislocalization is likely the mechanism of disease progression in LCA3/ juvenile RP patients.
HGSC, Department of Molecular and Human Genetics.
Aiden
A
Eblimit
Department of Human Genetics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6525, The Netherlands.
Thanh-Minh T
TM
Nguyen
HGSC, Department of Molecular and Human Genetics.
Yiyun
Y
Chen
Jules Stein Eye Institute, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA.
Julian
J
Esteve-Rudd
Department of Pathology and Immunology.
Hua
H
Zhong
Department of Human Genetics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6525, The Netherlands.
Stef
S
Letteboer
Department of Human Genetics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6525, The Netherlands.
Jeroen
J
Van Reeuwijk
Department of Neuroscience and Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030, USA.
David L
DL
Simons
Department of Ophthalmology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Qian
Q
Ding
Department of Human Genetics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6525, The Netherlands.
Ka Man
KM
Wu
HGSC, Department of Molecular and Human Genetics.
Yumei
Y
Li
Department of Human Genetics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6525, The Netherlands.
Sylvia
S
Van Beersum
Department of Neuroscience and.
Yalda
Y
Moayedi
HGSC, Department of Molecular and Human Genetics.
Huidan
H
Xu
HGSC, Department of Molecular and Human Genetics.
Patrick
P
Pickard
HGSC, Department of Molecular and Human Genetics.
Keqing
K
Wang
Department of Ophthalmology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Lin
L
Gan
Department of Neuroscience and Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030, USA.
Samuel M
SM
Wu
Jules Stein Eye Institute, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA.
David S
DS
Williams
Department of Molecular and Human Genetics, Department of Pathology and Immunology, Department of Neuroscience and Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030, USA, ruichen@bcm.edu roepman@radboudumc.nl gmardon@bcm.edu.
Graeme
G
Mardon
Department of Human Genetics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6525, The Netherlands, ruichen@bcm.edu roepman@radboudumc.nl gmardon@bcm.edu.
Ronald
R
Roepman
HGSC, Department of Molecular and Human Genetics, ruichen@bcm.edu roepman@radboudumc.nl gmardon@bcm.edu.
Rui
R
Chen
D000818:Animals; D017209:Apoptosis; D002417:Cattle; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D055212:Photoreceptor Connecting Cilium / Q000378:metabolism / Q000473:pathology*; D021381:Protein Transport; D011506:Proteins / Q000378:metabolism*; D017949:Retinal Cone Photoreceptor Cells / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism / Q000473:pathology*; D012243:Rhodopsin / Q000378:metabolism
D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D011506:Proteins; C415903:RPGRIP1 protein, human; C482323:SPATA7 protein, human; D012243:Rhodopsin