Progressive Cone and Cone-Rod Dystrophies: Phenotypes and Underlying Molecular Genetic Basis

Michaelides, Michel; Hardcastle, Alison J.; Hunt, David M.; Moore, Anthony T.

doi:10.1016/j.survophthal.2006.02.007

Cited by 198 publications

(160 citation statements)

References 193 publications

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“…Inherited retinal degenerative disorders are pathologically and genetically heterogeneous (Hartong et al, 2006;Michaelides et al, 2006) and are characterized by the premature and progressive death of rod and cone photoreceptors. Several genes are involved in retinal diseases in humans and in animal models (Michaelides et al, 2006;Knust, 2007;Karan et al, 2008), and, of these, the rhodopsin gene is most frequently mutated.…”

Section: Introductionmentioning

confidence: 99%

“…Several genes are involved in retinal diseases in humans and in animal models (Michaelides et al, 2006;Knust, 2007;Karan et al, 2008), and, of these, the rhodopsin gene is most frequently mutated. Approximately 25% of the autosomal dominant retinitis pigmentosa cases in humans result from various mutations of the rhodopsin gene; thus, understanding rhodopsin regulation will further our knowledge of retinal disease pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Autophagy-Dependent Rhodopsin Degradation Prevents Retinal Degeneration inDrosophila

Midorikawa

Yamamoto-Hino²,

Awano³

et al. 2010

J. Neurosci.

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Recent studies have demonstrated protective roles for autophagy in various neurodegenerative disorders, including the polyglutamine diseases; however, the role of autophagy in retinal degeneration has remained unclear. Accumulation of activated rhodopsin in some Drosophila mutants leads to retinal degeneration, and although it is known that activated rhodopsin is degraded in endosomal pathways in normal photoreceptor cells, the contribution of autophagy to rhodopsin regulation has remained elusive. This study reveals that activated rhodopsin is degraded by autophagy in collaboration with endosomal pathways to prevent retinal degeneration. Lightdependent retinal degeneration in the Drosophila visual system is caused by the knockdown or mutation of autophagy-essential components, such as autophagy-related protein 7 and 8 (atg-7/atg-8), or genes essential for PE (phosphatidylethanolamine) biogenesis and autophagosome formation, including Phosphatidylserine decarboxylase (Psd) and CDP-ethanolamine:diacylglycerol ethanolaminephosphotransferase (Ept). The knockdown of atg-7/8 or Psd/Ept produced an increase in the amount of rhodopsin localized to Rab7-positive late endosomes. This rhodopsin accumulation, followed by retinal degeneration, was suppressed by overexpression of Rab7, which accelerated the endosomal degradation pathway. These results indicate a degree of cross talk between the autophagic and endosomal/lysosomal pathways. Importantly, a reduction in rhodopsin levels rescued Psd knockdown-induced retinal degeneration. Additionally, the Psd knockdown-induced retinal degeneration phenotype was enhanced by Ppt1 inactivation, which causes infantile neuronal ceroid lipofuscinosis, implying that autophagy plays a significant role in its pathogenesis. Collectively, the current data reveal that autophagy suppresses light-dependent retinal degeneration in collaboration with the endosomal degradation pathway and that rhodopsin is a key substrate for autophagic degradation in this context.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Autophagy-Dependent Rhodopsin Degradation Prevents Retinal Degeneration inDrosophila

Midorikawa

Yamamoto-Hino²,

Awano³

et al. 2010

J. Neurosci.

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“…Inherited progressive cone rod dystrophies (CRD) are characterized by progressive loss of cone photoreceptor function followed by progressive loss of rod photoreceptor function and are often accompanied by retinal degeneration (Hamel, 2007;Merin, 2005;Michaelides, et al, 2006). In contrast, in inherited progressive cone OFFICIAL JOURNAL www.hgvs.org dystrophies (CD) only cone function is impaired and retinal degeneration is often minimal and confined to the central retina.…”

Section: Introductionmentioning

confidence: 99%

Mutations in theGUCA1Agene involved in hereditary cone dystrophies impair calcium-mediated regulation of guanylate cyclase

Kitiratschky

Behnen

Kellner³

et al. 2009

Hum. Mutat.

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ABSTRACT:The GUCA1A gene encodes the guanylate cyclase activating protein 1 (GCAP1) of mammalian rod and cone photoreceptor cells, which is involved in the Ca 2+ -dependent negative feedback regulation of membrane bound guanylate cyclases in the retina. Mutations in the GUCA1A gene have been associated with different forms of cone dystrophies leading to impaired cone vision and retinal degeneration. Here we report the identification of three novel and one previously detected GUCA1A mutations: c.265G>A (p.Glu89Lys), c.300T>A (p.Asp100Glu), c.476G>T (p.Gly159Val) and c.451C>T (p.Leu151Phe). The clinical data of the patients carrying these mutations were compared with the functional consequences of the mutant GCAP1 forms. For this purpose we purified the heterologously expressed GCAP1 forms and investigated whether the mutations affected the Ca 2+ -triggered conformational changes and the apparent interaction affinity with the membrane bound guanylate cyclase. Furthermore, we analyzed Ca 2+ -dependent regulatory modes of wildtype and mutant GCAP1 forms. Although all novel mutants were able to act as a Ca 2+ -sensor protein, they differed in their Ca 2+ -dependent activation profiles leading to a persistent stimulation of guanylate cyclase activities at physiological intracellular Ca 2+ concentration.

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“…25 The visual prognosis in CRD is poor and the precise prognosis regarding the progression remains difficult, because even intrafamilial variability can often be observed.…”

Section: Therapymentioning

confidence: 99%

Clinical Utility Gene Card for: autosomal recessive cone-rod dystrophy

et al. 2015

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Progressive Cone and Cone-Rod Dystrophies: Phenotypes and Underlying Molecular Genetic Basis

Cited by 198 publications

References 193 publications

Autophagy-Dependent Rhodopsin Degradation Prevents Retinal Degeneration inDrosophila

Autophagy-Dependent Rhodopsin Degradation Prevents Retinal Degeneration inDrosophila

Mutations in theGUCA1Agene involved in hereditary cone dystrophies impair calcium-mediated regulation of guanylate cyclase

Clinical Utility Gene Card for: autosomal recessive cone-rod dystrophy

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