1.1.1.300 A269Gfs*2 naturally occuring mutation, the mutant enzyme shows highly reduced activity 761045 1.1.1.300 C201R naturally occuring mutation in the active site, inactive mutant 761045 1.1.1.300 C300A the mutant shows no oxidation activity 739913 1.1.1.300 C300S the mutant shows reduced catalytic efficiency for the oxidation and reduction of all-trans-retinal compared to the wild-type enzyme 739913 1.1.1.300 E194S the mutant shows 15fold higher catalytic efficiency for the reduction of all-trans-retinal than the wild-type enzyme 739913 1.1.1.300 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 761137 1.1.1.300 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 761045 1.1.1.300 E266A the mutant shows no oxidation activity 739913 1.1.1.300 E457V the mutant shows 7.5fold higher catalytic efficiency for the reduction of all-trans-retinal than the wild-type enzyme 739913 1.1.1.300 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 761137 1.1.1.300 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 761818 1.1.1.300 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 761818 1.1.1.300 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 761045 1.1.1.300 I51N site-directed mutagenesis, significant activity in vitro. Dramatically reduced affinity for NADPH results in loss of function within cells 685381 1.1.1.300 I51N 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 722011 1.1.1.300 L99I site-directed mutagenesis, about 30% of wild-type activity 685381 1.1.1.300 M144G gain-of-function mutant, enables estrone to bind and be reduced as an additional substrate 712757 1.1.1.300 M146G mutation in isoform prRDH1, gain-of-function mutant, enables estrone to bind and be reduced as an additional substrate 712757 1.1.1.300 M147G mutation in isoform prRDH2, gain-of-function mutant, enables estrone to bind and be reduced as an additional substrate 712757 1.1.1.300 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 761045 1.1.1.300 additional information generation and analysis of RGR knockout mouse microsomes 763516 1.1.1.300 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 760957 1.1.1.300 additional information generation of enzyme knockout Rdh11-/- mice 761488 1.1.1.300 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 761323 1.1.1.300 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 762430 1.1.1.300 additional information generation of RDH11 knockout (KO) mice, phenotypes, overview 761488 1.1.1.300 additional information 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 -, 723236 1.1.1.300 additional information 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 761045 1.1.1.300 additional information lentiviral-mediated shRNA efficiently inhibits RDH10 expression. RDH10 knockdown impairs glioma cell proliferation in vitro 762073 1.1.1.300 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 762430 1.1.1.300 additional information transfection with retinol dehydrogenase 12 protects cells against nonanal-induced toxicity but is ineffective against 4-hydroxynonenal 685381 1.1.1.300 Q189X mutation found in an individual affected by autosomal recessive childhood-onset severe retinal dystrophy 656851 1.1.1.300 R25G/K26I The mutation allows the enzyme to flip its orientation in the membrane. The mutant is glycosylated in intact cells. 654687 1.1.1.300 R62X mutation found in an individual affected by autosomal recessive childhood-onset severe retinal dystrophy 656851 1.1.1.300 S175P site-directed mutagenesis, no catalytic activity. Protein is stable and abundantly expressed 685381 1.1.1.300 T49M inactive. Mutation is associated with Lebr congenital amaurosis. Mutant is not able to detoxify 4-hydroxynonenal in cells 712068 1.1.1.300 T49M mutation found in an individual affected by autosomal recessive childhood-onset severe retinal dystrophy 656851 1.1.1.300 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 761045 1.1.1.300 T49M site-directed mutagenesis, significant activity in vitro. Dramatically reduced affinity for NADPH results in loss of function within cells 685381 1.1.1.300 T49M 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 722011 1.1.1.300 Y226C 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 656851 1.1.1.300 Y226C naturally occuring mutation, autosomal recessive biallelic mutation causing severe retinal dystrophy 761045