Ccdc66 null mutation causes retinal degeneration and dysfunction.
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Ccdc66 null mutation causes retinal degeneration and dysfunction. / Gerding, Wanda M; Schreiber, Sabrina; Schulte-Middelmann, Tobias; de Castro Marques, Andreia; Atorf, Jenny; Akkad, Denis A; Dekomien, Gabriele; Kremers, Jan; Dermietzel, Rolf; Gal, Andreas; Rülicke, Thomas; Ibrahim, Saleh; Epplen, Jörg T; Petrasch-Parwez, Elisabeth.
In: HUM MOL GENET, Vol. 20, No. 18, 18, 2011, p. 3620-3631.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Ccdc66 null mutation causes retinal degeneration and dysfunction.
AU - Gerding, Wanda M
AU - Schreiber, Sabrina
AU - Schulte-Middelmann, Tobias
AU - de Castro Marques, Andreia
AU - Atorf, Jenny
AU - Akkad, Denis A
AU - Dekomien, Gabriele
AU - Kremers, Jan
AU - Dermietzel, Rolf
AU - Gal, Andreas
AU - Rülicke, Thomas
AU - Ibrahim, Saleh
AU - Epplen, Jörg T
AU - Petrasch-Parwez, Elisabeth
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - Animals
KW - Humans
KW - Male
KW - Female
KW - Disease Models, Animal
KW - Mice
KW - Mice, Knockout
KW - Gene Silencing
KW - Sequence Deletion
KW - Eye Proteins/genetics
KW - Retina/metabolism/pathology/physiopathology
KW - Retinal Degeneration/genetics/metabolism/pathology/physiopathology
KW - Retinitis Pigmentosa/genetics/metabolism/pathology/physiopathology
KW - Animals
KW - Humans
KW - Male
KW - Female
KW - Disease Models, Animal
KW - Mice
KW - Mice, Knockout
KW - Gene Silencing
KW - Sequence Deletion
KW - Eye Proteins/genetics
KW - Retina/metabolism/pathology/physiopathology
KW - Retinal Degeneration/genetics/metabolism/pathology/physiopathology
KW - Retinitis Pigmentosa/genetics/metabolism/pathology/physiopathology
M3 - SCORING: Journal article
VL - 20
SP - 3620
EP - 3631
JO - HUM MOL GENET
JF - HUM MOL GENET
SN - 0964-6906
IS - 18
M1 - 18
ER -
