Retinal degeneration associated with RDH12 mutations results from decreased 11-cis retinal synthesis due to disruption of the visual cycle

Thompson, Debra A.; Janecke, Andreas; Lange, Jessica; Feathers, Kecia L.; Hübner, Christian A.; McHenry, Christina L.; Stockton, David W.; Rammesmayer, Gabriele; Lupski, James R.; Antiñolo, Guillermo; Ayuso, Carmen; Baiget, Montserrat; Gouras, Peter; Heckenlively, John R.; Hollander, Anneke den; Jacobson, Samuel G.; Lewis, Richard A.; Sieving, Paul A.; Wissinger, Bernd; Yzer, Suzanne; Zrenner, Eberhart; Utermann, Gerd; Gal, Andreas

doi:10.1093/hmg/ddl079

Cited by 17 publications

(46 citation statements)

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“…Three of the 11 patients carried diagnoses of macular dystrophy, and of these, two had disease that was essentially limited to the macula. Although both of these subjects had reduced visual acuity, the macular focus of disease was confirmed by visual fields, normal full-field ERG recordings, and retinal imaging, thus demonstrating a much milder phenotype than that seen in other individuals in this study or reported elsewhere (Janecke et al 2004;Perrault et al 2004;Thompson et al 2005;Schuster et al 2007;Sun et al 2007;Mackay et al 2011). Although Xin and colleagues reported a patient with macular findings and hyperautofluorescence along the vessels, the reported patient had reduced cone response amplitudes .…”

Section: Discussionsupporting

confidence: 68%

“…We identified 15 causal variants in this study, four of which were not previously reported-c.215A > G (p.Asp72Gly), c.362T > C (p.Ile121Thr), c.440A > C (p.Asn147Thr), and c.697G > A (p.Val233Ile). These novel mutations were located within regions previously shown to be critical to the enzymatic function of the RDH12 enzyme using functional studies (Thompson et al 2005;Sun et al 2007). Although variants in other IRD genes have been identified, they were not determined to be the primary cause for disease either because of lack of an additional recessive allele in the same gene or dominant variants that were too common in the population genetic databases (gnomAD) (Karczewski et al 2019) to be causal.…”

Section: Discussionmentioning

confidence: 99%

“…RDH8, localized in the photoreceptor outer segments, converts most of the all-trans-retinal necessary for the visual cycle, whereas RDH12, localized in the inner segments, is crucial for the reduction of alltrans-retinal in the inner segments preventing the buildup of toxic aldehydes. Accumulation of these aldehydes is thought to be the major cause of photoreceptor cell loss, as mutations in RDH12 and not RDH8 have been associated with disease (Thompson et al 2005;Maeda et al 2007;Marchette et al 2010;Chen et al 2012).…”

Section: Introductionmentioning

confidence: 99%

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Expanding the phenotypic spectrum in RDH12-associated retinal disease

Scott

Place

Ferenchak

et al. 2020

Cold Spring Harb Mol Case Stud

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Retinol dehydrogenase 12, RDH12, plays a pivotal role in the visual cycle to ensure the maintenance of normal vision. Alterations in activity of this protein result in photoreceptor death and decreased vision beginning at an early age and progressing to substantial vision loss later in life. Here we describe 11 patients with retinal degeneration that underwent next-generation sequencing (NGS) with a targeted panel of all currently known inherited retinal degeneration (IRD) genes and whole-exome sequencing to identify the genetic causality of their retinal disease. These patients display a range of phenotypic severity prompting clinical diagnoses of macular dystrophy, cone-rod dystrophy, retinitis pigmentosa, and early-onset severe retinal dystrophy all attributed to biallelic recessive mutations in RDH12. We report 15 causal alleles and expand the repertoire of known RDH12 mutations with four novel variants: c.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Expanding the phenotypic spectrum in RDH12-associated retinal disease

Scott

Place

Ferenchak

et al. 2020

Cold Spring Harb Mol Case Stud

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“…We found two recognizable consensus binding sites for CRX/OTX2 at this prospective promoter. Immediately downstream of these binding sites we found two separate variants in two unrelated individuals, RDH12 c.-162G>A (hg38, chr14:67722482G>A) and RDH12 c.-123C>T (hg38, chr14:67722520C>T) (reported in (Thompson et al, 2005)). Neither were previously characterized as deleterious, however c.-123C is conserved across simians and c.-162A is conserved down to monotremes.…”

Section: Resultsmentioning

confidence: 76%

Epigenomic Profiling and Single-Nucleus-RNA-Seq Reveal Cis-Regulatory Elements in Human Retina, Macula and RPE and Non-Coding Genetic Variation

Cherry

Yang

Harmin

et al. 2018

Preprint

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Cis-regulatory elements (CREs) orchestrate the dynamic and diverse transcriptional programs that assemble the human central nervous system (CNS) during development and maintain its function throughout life. Genetic variation within CREs plays a central role in phenotypic variation in complex traits including the risk of developing disease. However, the cellular complexity of the human brain has largely precluded the identification of functional regulatory variation within the human CNS. We took advantage of the retina, a well-characterized region of the CNS with reduced cellular heterogeneity, to establish a roadmap for characterizing regulatory variation in the human CNS. This comprehensive resource of tissue-specific regulatory elements, transcription factor binding, and gene expression programs in three regions of the human visual system (retina, macula, retinal pigment epithelium/choroid) reveals features of regulatory element evolution that shape tissue-specific gene expression programs and defines the regulatory elements with the potential to contribute to mendelian and complex disorders of human vision.

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“…At least 33 disease-associated mutations of RDH12 have been identified to date [1][2][3][4][5]. These include truncations (stop codons), frameshift mutations, and missense mutations.…”

Section: Introductionmentioning

confidence: 99%

Disease‐associated variants of microsomal retinol dehydrogenase 12 (RDH12) are degraded at mutant‐specific rates

2009

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a b s t r a c tMutations in retinol dehydrogenase 12 (RDH12) cause severe retinal degeneration. However, some of the disease-associated RDH12 mutants retain significant catalytic activity, indicating the existence of additional pathophysiological mechanisms. This study demonstrates that the catalytically active T49M and I51N mutants undergo accelerated degradation, which results in their reduced cellular levels. Inhibition of proteasome leads to significant accumulation of ubiquitylated T49M and I51N. Furthermore, the degree of ubiquitylation strongly correlates with the half-lives of the proteins. These results suggest that the accelerated degradation of RDH12 mutants by the ubiquitinproteasome system contributes to the pathophysiology and phenotypic variability associated with mutations in the RDH12 gene. Structured summary:MINT-7383581, MINT-7383598: RDH12 (uniprotkb:Q96NR8) physically interacts (MI:0915) with ubiquitin (uniprotkb:P62988) by anti tag coimmunoprecipitation (MI:0007)

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Retinal degeneration associated with RDH12 mutations results from decreased 11-cis retinal synthesis due to disruption of the visual cycle

Cited by 17 publications

References 0 publications

Expanding the phenotypic spectrum in RDH12-associated retinal disease

Expanding the phenotypic spectrum in RDH12-associated retinal disease

Epigenomic Profiling and Single-Nucleus-RNA-Seq Reveal Cis-Regulatory Elements in Human Retina, Macula and RPE and Non-Coding Genetic Variation

Disease‐associated variants of microsomal retinol dehydrogenase 12 (RDH12) are degraded at mutant‐specific rates

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