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Ciliopathy‐associated IQCB1/NPHP5 protein is required for mouse photoreceptor outer segment formation
Author(s) -
Ronquillo Cecinio C.,
HankeGogokhia Christin,
Revelo Monica P.,
Frederick Jeanne M.,
Jiang Li,
Baehr Wolfgang
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201600511r
Subject(s) - ciliopathy , ciliogenesis , cilium , biology , microbiology and biotechnology , retina , joubert syndrome , retinal degeneration , anatomy , phenotype , genetics , gene , neuroscience
Null mutations in the human IQCB1/NPHP5 (nephrocystin‐5) gene that encodes NPHP5 are the most frequent cause of Senior‐Løken syndrome, a ciliopathy that is characterized by Leber congenital amaurosis and nephronophthisis. We generated germline Nphp5 ‐knockout mice by placing a b‐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.—Ronquillo, C. C., Hanke‐Gogokhia, C., Revelo, M. P., Frederick, J. M., Jiang, L., Baehr, W. Ciliopathy‐associated IQCB1/NPHP5 protein is required for mouse photoreceptor outer segment formation. FASEB J. 30, 3400–3412 (2016). www.fasebj.org