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C300A
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the mutant shows no oxidation activity
C300S
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the mutant shows reduced catalytic efficiency for the oxidation and reduction of all-trans-retinal compared to the wild-type enzyme
E194S
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the mutant shows 15fold higher catalytic efficiency for the reduction of all-trans-retinal than the wild-type enzyme
E266A
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the mutant shows no oxidation activity
E457V
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the mutant shows 7.5fold higher catalytic efficiency for the reduction of all-trans-retinal than the wild-type enzyme
M146G
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mutation in isoform prRDH1, gain-of-function mutant, enables estrone to bind and be reduced as an additional substrate
M147G
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mutation in isoform prRDH2, gain-of-function mutant, enables estrone to bind and be reduced as an additional substrate
A269Gfs*2
naturally occuring mutation, the mutant enzyme shows highly reduced activity
C201R
naturally occuring mutation in the active site, inactive mutant
E260R
naturally occuring mutation, a single base pair deletion resulting in a frameshift and premature termination, mutants display a milder late onset (average age of diagnosis is 28.5 years) retinitis pigmentosa (RP) phenotype, with intraretinal bone spicule pigmentation and attenuation of retinal arterioles, phenotypes, overview
E260Rfs*18
naturally occuring mutation, autosomal dominant RDH12 variant, the heterozygous single base pair deletion c.776delG results in a frameshift and premature termination at codon 277, in 19 affected members of a large 6 generation family
F254Lfs*24
naturally occuring mutation c.759del, the mutation results in a frameshift and premature termination identified in two unrelated individuals with familial autosomal dominant retinitis pigmentosa (RP), phenotypes, overview
G43A/G47A/G49A
site-directed mutagenesis, the cofactor binding mutants, RDH10 G43A/G47A/G49A-HA and DHRS3 G49A/G51A-FLAG, retain the capacity to form complexes with wild-type protein partners
G49A/G51A
site-directed mutagenesis, the cofactor binding mutants, RDH10 G43A/G47A/G49A-HA and DHRS3 G49A/G51A-FLAG, retain the capacity to form complexes with wild-type protein partners
L99I
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site-directed mutagenesis, about 30% of wild-type activity
M144G
gain-of-function mutant, enables estrone to bind and be reduced as an additional substrate
Q189X
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mutation found in an individual affected by autosomal recessive childhood-onset severe retinal dystrophy
R25G/K26I
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The mutation allows the enzyme to flip its orientation in the membrane. The mutant is glycosylated in intact cells.
R62X
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mutation found in an individual affected by autosomal recessive childhood-onset severe retinal dystrophy
S175P
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site-directed mutagenesis, no catalytic activity. Protein is stable and abundantly expressed
T49M
inactive. Mutation is associated with Lebr congenital amaurosis. Mutant is not able to detoxify 4-hydroxynonenal in cells
I51N
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site-directed mutagenesis, significant activity in vitro. Dramatically reduced affinity for NADPH results in loss of function within cells
I51N
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site-directed mutagenesis, the catalytically active I51N variant of RDH12 undergoes accelerated degradation through the ubiquitin-proteosome system, which results in reduced level of the protein in the cell. The RDH12 mutant has lost its retinaldehyde reductase activity. Inhibitors of proteosome activity, e.g. MG132, or dimethyl sulfoxide can partially restore the activity
I51N
naturally occuring mutation, when transiently transfected in HEK-293 cells, the mutant degrades at a faster rate than the wild-type protein with significantly lower half-lif, the mutant loses its ability to protect against 4-HNE induced apoptosis
T49M
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mutation found in an individual affected by autosomal recessive childhood-onset severe retinal dystrophy
T49M
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site-directed mutagenesis, significant activity in vitro. Dramatically reduced affinity for NADPH results in loss of function within cells
T49M
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site-directed mutagenesis, the catalytically active T49M variant of RDH12 undergoes accelerated degradation through the ubiquitin-proteosome system, which results in reduced level of the protein in the cell.The RDH12 mutant has lost its retinaldehyde reductase activity. Inhibitors of proteosome activity, e.g. MG132, or dimethyl sulfoxide can partially restore the activity
T49M
naturally occuring mutation, the mutant enzyme shows highly reduced activity, when transiently transfected in HEK-293 cells, the mutant degrades at a faster rate than the wild-type protein with significantly lower half-life, the mutant loses its ability to protect against 4-HNE induced apoptosis
Y226C
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mutation present in all individuals affected by autosomal recessive childhood-onset severe retinal dystrophy from three Austrian kindreds, enzyme expressed in COS-7 cells shows diminished activity
Y226C
naturally occuring mutation, autosomal recessive biallelic mutation causing severe retinal dystrophy
additional information
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transfection with retinol dehydrogenase 12 protects cells against nonanal-induced toxicity but is ineffective against 4-hydroxynonenal
additional information
according to the human gene mutation database (HGMD, April 2019), 80 RDH12 mutations have been reported, 51 of which are missense and 12 are nonsense mutations, the mutations span the entire gene, including the conserved regions, with no specific hotspots. In COS-7 cells transiently transfected with various RDH12 missense mutants, 11 out of 14 variants show significantly reduced enzyme activity, 5-18% of wild-type levels. They also show decreased expression levels, most likely as a result of protein instability
additional information
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according to the human gene mutation database (HGMD, April 2019), 80 RDH12 mutations have been reported, 51 of which are missense and 12 are nonsense mutations, the mutations span the entire gene, including the conserved regions, with no specific hotspots. In COS-7 cells transiently transfected with various RDH12 missense mutants, 11 out of 14 variants show significantly reduced enzyme activity, 5-18% of wild-type levels. They also show decreased expression levels, most likely as a result of protein instability
additional information
lentiviral-mediated shRNA efficiently inhibits RDH10 expression. RDH10 knockdown impairs glioma cell proliferation in vitro
additional information
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lentiviral-mediated shRNA efficiently inhibits RDH10 expression. RDH10 knockdown impairs glioma cell proliferation in vitro
additional information
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generation of Rdh13 knockout mice. No obvious difference in phenotype or function between Rdh13 knockout and wild-type mice. But in Rdh13-/- mice subjected to intense light exposure, the photoreceptor outer-plus-inner-segment and outer nuclear layer are dramatically shorter, and the amplitudes of a- and b-waves under scotopic conditions are significantly attenuated. Increased expression levels of CytC, CytC-responsive apoptosis proteinase activating factor-1 and caspases 3, and other mitochondria apoptosis-related genes, e.g. nuclear factor-kappa B P65 and B-cell lymphoma 2-associated X protein, are observed in Rdh13-/- mice
additional information
generation of embryonic stage-specific inactivation of retinol dehydrogenase 10 (Rdh10). Stage-specific inactivation of retinol metabolism in Rdh10delta/flox mutant embryos serves as a model for vitamin A/retinoid-deficient cleft palate. Conditional inactivation of Rdh10 causes cleft palate. Nuclear fluorescence imaging of Rdh10flox + control and Rdh10delta/flox mutant embryos at E16.5 reveals complete cleft of the secondary palate in 36% of mutant embryos. For insight into the tissue architecture in cleft palates of Rdh10delta/flox mutant embryos, hematoxylin and eosin staining of paraffin sections is performed. At E13.5, the palate shelf morphology of Rdh10delta/flox mutant embryos resembled that of Rdh10flox/+ control littermates, with palate shelves aligned vertically on either side of the tongue. Using the ubiquitously expressed Cre-ERT2, the genotype of embryos with a floxed allele changes following administration of tamoxifen. Embryos with a pre-tamoxifen genotype of Rdh10flox/+ become Rdh10delta/+ post-tamoxifen. Embryos with a pretamoxifen genotype of Rdh10delta/flox or Rdh10flox/flox become Rdh10delta/delta post-tamoxifen treatment. Cleft palate was not observed in any Rdh10flox/+ control embryos. Rdh10delta/flox mutants have abnormally positioned tongues that obstruct palate shelf elevation, mutant morphologies, overview. No defect in the intrinsic tongue muscles is detected in mutant embryos relative to control littermates. The morphogenesis of tongue musculature is grossly normal in retinoid-deficient embryos, suggesting the abnormal tongue shape does not result from aberrant muscle morphogenesis. Spontaneous fetal mouth movement in utero is restricted in Rdh10delta/flox mutant embryos. Rdh10delta/flox mutant embryos have defects in motor nerves of the posterior pharyngeal arches. Retinoid-deficient embryos develop defects in the pharyngeal skeleton. Retinoid-deficient embryos develop defects in the pharyngeal skeleton
additional information
generation of enzyme Rdh8-/- knockout mice. Cyclic-light-reared Rdh8-/- mice accumulates A2E and RPE lipofuscin approximately 1.5times and approximately 2times faster, respectively, than dark-reared mice. Moving Rdh8-/- mice from cyclic-light to darkness results in bis-retinoid A2E levels less than expected to have accumulated before the move. A2E levels are significantly higher in cyclic-light compared to dark-reared animals at 2, 3, and 6 months of age. In Rdh8-/- mice, the potential contribution of elevated all-trans-retinal to bis-retinoid formation can be maximized
additional information
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generation of enzyme Rdh8-/- knockout mice. Cyclic-light-reared Rdh8-/- mice accumulates A2E and RPE lipofuscin approximately 1.5times and approximately 2times faster, respectively, than dark-reared mice. Moving Rdh8-/- mice from cyclic-light to darkness results in bis-retinoid A2E levels less than expected to have accumulated before the move. A2E levels are significantly higher in cyclic-light compared to dark-reared animals at 2, 3, and 6 months of age. In Rdh8-/- mice, the potential contribution of elevated all-trans-retinal to bis-retinoid formation can be maximized
additional information
generation of RDH11 knockout (KO) mice, phenotypes, overview
additional information
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generation of Rdh8-/- Rdh12-/- double knockout mice. The Rdh12-/- mouse model is generated by replacement of exons 1-3 of the Rdh12 gene with a neomycin cassette. Rdh12-/- mice display normal retinal morphology at 6 weeks of age. There is no significant difference in rhodopsin levels, indicating efficient regeneration of the chromophore. No difference in all-trans RDH activity in dissected retinae or isolated rod outer segments (ROS) between wild-type and Rdh12-/- mice is observed
additional information
RDH10 enzyme knockout and overexpression in retina cell. Rdh10 mRNA levels are substantially reduced in retinas obtained from Pdgfra-Cre Rdh10flox/flox mice through a knockout in Müller cells. Similarly, the expression of Rdh10 is also dramatically reduced in Six3-Cre Rdh10flox/flox retinas, demonstrating its suppression in the entire retina. In contrast, Rdh10 mRNA levels are notably increased in transgenic Rdh10+ mice. The deletion of RDH10 in cones does not affect the overall number of cone cells or their function, and cone dark adaptation in vivo is unaffected by cone-specific deletion of RDH10
additional information
generation and analysis of RGR knockout mouse microsomes
additional information
generation of enzyme knockout Rdh11-/- mice
additional information
generation of mice lacking RDH10 either in cone photoreceptors, Müller cells, or the entire retina. In vivo electroretinography and transretinal recordings reveal normal cone photoresponses in all RDH10-deficient mouse lines. Notably, their cone-driven dark adaptation both in vivo and in isolated retina is unaffected, indicating that RDH10 is not required for the function of the retina visual cycle. Generation of transgenic mice expressing RDH10 ectopically in rod cells. Rod dark adaptation is unaffected by the expression of RDH10 and transgenic rods are unable to use cis-retinol for pigment regeneration. Lack of phenotype of mice lacking RDH10 in the entire retina
additional information
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generation of Rdh13 knockout mice. No obvious difference in phenotype or function between Rdh13 knockout and wild-type mice. But in Rdh13-/- mice subjected to intense light exposure, the photoreceptor outer-plus-inner-segment and outer nuclear layer are dramatically shorter, and the amplitudes of a- and b-waves under scotopic conditions are significantly attenuated. Increased expression levels of CytC, CytC-responsive apoptosis proteinase activating factor-1 and caspases 3, and other mitochondria apoptosis-related genes, e.g. nuclear factor-kappa B P65 and B-cell lymphoma 2-associated X protein, are observed in Rdh13-/- mice
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