Ccdc66 null mutation causes retinal degeneration and dysfunction

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 ha...

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Published in:Human molecular genetics 2011-09, Vol.20 (18), p.3620-3631
Main Authors: GERDING, Wanda M, SCHREIBER, Sabrina, RÜLICKE, Thomas, IBRAHIM, Saleh, EPPLEN, Jörg T, PETRASCH-PARWEZ, Elisabeth, SCHULTE-MIDDELMANN, Tobias, DE CASTRO MARQUES, Andreia, ATORF, Jenny, AKKAD, Denis A, DEKOMIEN, Gabriele, KREMERS, Jan, DERMIETZEL, Rolf, GAL, Andreas
Format: Article
Language:English
Subjects:
Age
Animal models
Animals
Biological and medical sciences
Birth
Disease Models, Animal
Dysplasia
Electron microscopy
Eye Proteins - genetics
Female
Fundamental and applied biological sciences. Psychology
Gene Silencing
Genetics of eukaryotes. Biological and molecular evolution
Humans
Male
Medical sciences
Mice
Mice, Knockout
Molecular and cellular biology
Mutation
Ophthalmology
Photoreceptors
Retina
Retina - metabolism
Retina - pathology
Retina - physiopathology
retinal degeneration
Retinal Degeneration - genetics
Retinal Degeneration - metabolism
Retinal Degeneration - pathology
Retinal Degeneration - physiopathology
Retinitis pigmentosa
Retinitis Pigmentosa - genetics
Retinitis Pigmentosa - metabolism
Retinitis Pigmentosa - pathology
Retinitis Pigmentosa - physiopathology
Retinopathies
RNA
Rod outer segment membranes
Sequence Deletion
Sound
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Summary: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.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddr282