New syndrome with retinitis pigmentosa is caused by nonsense mutations in retinol dehydrogenase RDH11

Xie, Yajing; Lee, Winston; Cai, Charles L.; Gambin, Tomasz; Nõupuu, Kalev; Sujirakul, Tharikarn; Ayuso, Carmen; Jhangiani, Shalini N.; Muzny, Donna M.; Boerwinkle, Eric; Gibbs, Richard A.; Greenstein, Vivienne C.; Lupski, James R.; Tsang, Stephen H.; Allikmets, Rando

doi:10.1093/hmg/ddu291

Cited by 31 publications

(18 citation statements)

References 32 publications

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“…RDH11, a dual-substrate specificity RDH, is one such enzyme that contributes to 11- cis -RAL reduction in the RPE (Haeseleer et al 2002, Kim et al 2005). Recently, RDH11 mutations have been identified as a cause of syndromic RP, indicating that this enzyme could also have a role in controlling RA levels during development (Xie et al 2014). RDH10 also is expressed in the RPE (Wu et al 2002), where it contributes to 11- cis -ROL oxidation (Farjo et al 2009).…”

Section: Retinol Dehydrogenases: Reversible Redox Chemistry Of Retmentioning

confidence: 99%

Retinoids and Retinal Diseases

Kiser

Palczewski

2016

Annu. Rev. Vis. Sci.

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Recent progress in molecular understanding of the retinoid cycle in mammalian retina stems from painstaking biochemical reconstitution studies supported by natural or engineered animal models with known genetic lesions and studies of humans with specific genetic blinding diseases. Structural and membrane biology have been used to detect critical retinal enzymes and proteins and their substrates and ligands, placing them in a cellular context. These studies have been supplemented by analytical chemistry methods that have identified small molecules by their spectral characteristics, often in conjunction with the evaluation of models of animal retinal disease. It is from this background that rational therapeutic interventions to correct genetic defects or environmental insults are identified. Thus, most presently accepted modulators of the retinoid cycle already have demonstrated promising results in animal models of retinal degeneration. These encouraging signs indicate that some human blinding diseases can be alleviated by pharmacological interventions.

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Section: Retinol Dehydrogenases: Reversible Redox Chemistry Of Retmentioning

confidence: 99%

Retinoids and Retinal Diseases

Kiser

Palczewski

2016

Annu. Rev. Vis. Sci.

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“…From those genes, we found a few of them have known functions consistent with the expression pattern and human phenotype. For example, RDH11 is highly expressed in Müller Glia cell which plays an important function in retinal cycle and mutations in RDH11 lead to RP 80 . GRM6 and TRPM1 are bipolar DEGs and their mutations could cause a recessive congenital stationary night blindness (CSNB), and CSNB is known to be caused by abnormal photoreceptor-bipolar signaling 81–87 .…”

Section: Resultsmentioning

confidence: 99%

Single-nuclei RNA-seq on human retinal tissue provides improved transcriptome profiling

Liang

Dharmat

Owen

et al. 2018

Preprint

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26Gene expression profiling is an effective way to provide insights into cell function. 27 However, for heterogeneous tissues, bulk RNA-Seq can only provide the average gene 28 expression profile for all cells from the tissue, making the interpretation of the sequencing 29 result challenging. Single-cell RNA-seq, on the other hand, generates transcriptomic 30 profiles of individual cell and cell types, making it a powerful method to decode the 31 heterogeneity in complex tissues. 32 The retina is a heterogeneous tissue composed of multiple cell types with distinct 33 functions. Here we report the first single-nuclei RNA-seq transcriptomic study on human 34 neural retinal tissue to identify transcriptome profile for individual cell types. Six retina 35 samples from three healthy donors were profiled and RNA-seq data with high quality was 36 obtained for 4730 single nuclei. All seven major cell types were observed from the dataset 37 and signature genes for each cell type were identified by differential gene express 38 analysis. The gene expression of the macular and peripheral retina was compared at the 39 cell type level, showing significant improvement from previous bulk RNA-seq studies. 40Furthermore, our dataset showed improved power in prioritizing genes associated with 41 human retinal diseases compared to both mouse single-cell RNA-seq and human bulk 42 RNA-seq results. In conclusion, we demonstrated that feasibility of obtaining single cell 43 transcriptome from human frozen tissues to provide additional insights that is missed by 44 either the human bulk RNA-seq or the animal models. 45 46 48 cell type and state, and investigating human diseases 1-3 . Transcriptome can be more 49 powerful when combined with other 'omics' data to build prediction models on human 50 diseases 4 . For example, by combining transcriptomic data and proteomic data, a list of 51 candidate disease genes can be predicted with high specificity 5 . However, until recently, 52 vast majority transcriptome profiles are generated from profiling tissue samples 53 containing thousands to millions of cells. Thus, gene expression information of individual 54 cells would be lost. For tissues with high cellular heterogeneity, knowing the transcriptome 55 profiles of each cell type would be important for both identification of novel cell types and 56 understanding the functional organization of the tissue. Cell sorting would be required to 57 obtain transcriptome of a single cell type; not only was it not always practical, but also the 58 heterogeneities of many tissues were not fully revealed. This gap was met by the 59 development of the high throughput single-cell RNA-seq technology 6-8 . 60 61 Transcriptomic studies on the single cell level was first performed decades ago 9,10 , while 62 the first single-cell transcriptome study based on Next-Generation Sequencing was 63 reported ten years ago 11 . Since then, technologies have been dramatically improved in 64 scale and sensitivity. Development in single-cell isolation, such as microf...

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“…A compound heterozygous nonsense mutation c.C199T:p.R67 and c.c322T:p.R108 in RDH11 has been reported in a syndromic retinitis pigmentosa [46]. The syndromic features in the patient include facial dysmorphologies, psychomotor developmental delays since childhood, learning disability and short stature.…”

Section: Retinol Dehydrogenases (Rdhs) In the Rpementioning

confidence: 99%

Retinol Dehydrogenases Regulate Vitamin A Metabolism for Visual Function

Sahu

Maeda

2016

Nutrients

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The visual system produces visual chromophore, 11-cis-retinal from dietary vitamin A, all-trans-retinol making this vitamin essential for retinal health and function. These metabolic events are mediated by a sequential biochemical process called the visual cycle. Retinol dehydrogenases (RDHs) are responsible for two reactions in the visual cycle performed in retinal pigmented epithelial (RPE) cells, photoreceptor cells and Müller cells in the retina. RDHs in the RPE function as 11-cis-RDHs, which oxidize 11-cis-retinol to 11-cis-retinal in vivo. RDHs in rod photoreceptor cells in the retina work as all-trans-RDHs, which reduce all-trans-retinal to all-trans-retinol. Dysfunction of RDHs can cause inherited retinal diseases in humans. To facilitate further understanding of human diseases, mouse models of RDHs-related diseases have been carefully examined and have revealed the physiological contribution of specific RDHs to visual cycle function and overall retinal health. Herein we describe the function of RDHs in the RPE and the retina, particularly in rod photoreceptor cells, their regulatory properties for retinoid homeostasis and future therapeutic strategy for treatment of retinal diseases.

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New syndrome with retinitis pigmentosa is caused by nonsense mutations in retinol dehydrogenase RDH11

Cited by 31 publications

References 32 publications

Retinoids and Retinal Diseases

Retinoids and Retinal Diseases

Single-nuclei RNA-seq on human retinal tissue provides improved transcriptome profiling

Retinol Dehydrogenases Regulate Vitamin A Metabolism for Visual Function

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