title: Ccdc66 null mutation causes retinal degeneration and dysfunction.
abstract: Retinitis pigmentosa (RP) is a group of human retinal disorders, with more than 100 genes involved in retinal degeneration. Canine and murine models are useful for investigating human RP based on known, naturally occurring mutations. In Schapendoes dogs, for example, a mutation in the CCDC66 gene has been shown to cause autosomal recessively inherited, generalized progressive retinal atrophy (gPRA), the canine counterpart to RP. Here, a novel mouse model with a disrupted Ccdc66 gene was investigated to reveal the function of protein CCDC66 and the pathogenesis of this form of gPRA. Homozygous Ccdc66 mutant mice lack retinal Ccdc66 RNA and protein expression. Light and electron microscopy reveal an initial degeneration of photoreceptors already at 13 days of age, followed by a slow, progressive retinal degeneration over months. Retinal dysfunction causes reduced scotopic a-wave amplitudes, declining from 1 to 7 months of age as well as an early reduction of the photopic b-wave at 1 month, improving slightly at 7 months, as evidenced by electroretinography. In the retina of the wild-type (WT) mouse, protein CCDC66 is present at highest levels after birth, followed by a decline until adulthood, suggesting a crucial role in early development. Protein CCDC66 is expressed predominantly in the developing rod outer segments as confirmed by subcellular analyses. These findings illustrate that the lack of protein CCDC66 causes early, slow progressive rod-cone dysplasia in the novel Ccdc66 mutant mouse model, thus providing a sound foundation for the development of therapeutic strategies.
authors.affiliation: Department of Human Genetics, Ruhr-University,44780 Bochum, Germany.
authors.forename: Wanda M
authors.initials: WM
authors.lastname: Gerding
authors.forename: Sabrina
authors.initials: S
authors.lastname: Schreiber
authors.forename: Tobias
authors.initials: T
authors.lastname: Schulte-Middelmann
authors.forename: Andreia
authors.initials: A
authors.lastname: de Castro Marques
authors.forename: Jenny
authors.initials: J
authors.lastname: Atorf
authors.forename: Denis A
authors.initials: DA
authors.lastname: Akkad
authors.forename: Gabriele
authors.initials: G
authors.lastname: Dekomien
authors.forename: Jan
authors.initials: J
authors.lastname: Kremers
authors.forename: Rolf
authors.initials: R
authors.lastname: Dermietzel
authors.forename: Andreas
authors.initials: A
authors.lastname: Gal
authors.forename: Thomas
authors.initials: T
authors.lastname: Rülicke
authors.forename: Saleh
authors.initials: S
authors.lastname: Ibrahim
authors.forename: Jörg T
authors.initials: JT
authors.lastname: Epplen
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Petrasch-Parwez
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012160:Retina / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D012162:Retinal Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D017384:Sequence Deletion
chemical_list: C569280:Ccdc66 protein, mouse; D005136:Eye Proteins