Ciliopathy-associated IQCB1/NPHP5 protein is required for mouse photoreceptor outer segment formation
- Null mutations in the human IQCB1/NPHP5 (nephrocystin-5) gene that encodes NPHP5 are the most frequent cause of Senior-LOken syndrome, a ciliopathy that is characterized by Leber congenital amaurosis and nephronophthisis. We generated germline Nphp5-knockout mice by placing a -Geo gene trap in intron 4, thereby truncating NPHP5 at Leu87 and removing all known functional domains. At eye opening, Nphp5(-/-) mice exhibited absence of scotopic and photopic electroretinogram responses, a phenotype that resembles Leber congenital amaurosis. Outer segment transmembrane protein accumulation in Nphp5(-/-) endoplasmic reticulum was evident as early as postnatal day (P)6. EGFP-CETN2, a centrosome and transition zone marker, identified basal bodies in Nphp5(-/-) photoreceptors, but without fully developed transition zones. Ultrastructure of P6 and 10 Nphp5(-/-) photoreceptors revealed aberrant transition zones of reduced diameter. Nphp5(-/-) photoreceptor degeneration was complete at 1 mo of age but was delayed significantly inNull mutations in the human IQCB1/NPHP5 (nephrocystin-5) gene that encodes NPHP5 are the most frequent cause of Senior-LOken syndrome, a ciliopathy that is characterized by Leber congenital amaurosis and nephronophthisis. We generated germline Nphp5-knockout mice by placing a -Geo gene trap in intron 4, thereby truncating NPHP5 at Leu87 and removing all known functional domains. At eye opening, Nphp5(-/-) mice exhibited absence of scotopic and photopic electroretinogram responses, a phenotype that resembles Leber congenital amaurosis. Outer segment transmembrane protein accumulation in Nphp5(-/-) endoplasmic reticulum was evident as early as postnatal day (P)6. EGFP-CETN2, a centrosome and transition zone marker, identified basal bodies in Nphp5(-/-) photoreceptors, but without fully developed transition zones. Ultrastructure of P6 and 10 Nphp5(-/-) photoreceptors revealed aberrant transition zones of reduced diameter. Nphp5(-/-) photoreceptor degeneration was complete at 1 mo of age but was delayed significantly in Nphp5(-/-);Nrl(-/-) (cone only) retina. Nphp5(-/-) mouse embryonic fibroblast developed normal cilia, and Nphp5(-/-) kidney histology at 1 yr of age showed no significant pathology. Results establish that nephrocystin-5 is essential for photoreceptor outer segment formation but is dispensable for kidney and mouse embryonic fibroblast ciliary formation.…
Author details: | Cecinio C. Ronquillo, Christin Hanke-Gogokhia, Monica P. Revelo, Jeanne M. Frederick, Li JiangORCiD, Wolfgang BaehrORCiD |
---|---|
DOI: | https://doi.org/10.1096/fj.201600511R |
ISSN: | 0892-6638 |
ISSN: | 1530-6860 |
Pubmed ID: | https://pubmed.ncbi.nlm.nih.gov/27328943 |
Title of parent work (English): | The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology |
Publisher: | Federation of American Societies for Experimental Biology |
Place of publishing: | Bethesda |
Publication type: | Article |
Language: | English |
Year of first publication: | 2016 |
Publication year: | 2016 |
Release date: | 2020/03/22 |
Tag: | Leber congenital amaurosis; Senior-LOken syndrome; nephrocystins; nephronophthisis |
Volume: | 30 |
Number of pages: | 13 |
First page: | 3400 |
Last Page: | 3412 |
Funding institution: | U.S. National Institutes of Health (NIH), National Eye Institute (NEI) National Research Service Award Grant [1F31EY021972-01A1]; NIH NEI [EY08123, EY019298, EY014800-039003]; Research to Prevent Blindness; Retina Research Foundation (Houston, TX, USA); Foundation for Retina Research; Nelson Trust Award |
Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie |
Peer review: | Referiert |