Molecular genetics of cone-rod dystrophy in Chinese patients: New data from 61 probands and mutation overview of 163 probands

Huang, Li; Xiao, Xueshan; Li, Shiqiang; Jia, Xiaoyun; Wang, Panfeng; Sun, Wenmin; Xu, Yan; Wei, Xin; Guo, Xiangming; Zhang, Qingjiong

doi:10.1016/j.exer.2016.03.015

Cited by 56 publications

(54 citation statements)

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“…In vitro, RDH12 reportedly acts on retinoid substrates with a high affinity toward NADPH and is implicated in detoxification of unsaturated aldehydes produced from lipid peroxidation during oxidative stress (Belyaeva et al 2005; Marchette et al 2010). RDH12 mutations are associated with different types of retinal dystrophies (Gong et al 2015; Huang et al 2016; Zolnikova et al 2016) including Leber congenital amaurosis (LCA), a severe childhood-onset autosomal recessive retinal dystrophy characterized by early visual loss (Janecke et al 2004; Thompson et al 2005; Mackay et al 2011). …”

Section: Resultsmentioning

confidence: 99%

“…While its specific cellular substrate remains unknown, RDH12 displays enzymatic activity on both retinoid and sterol substrates in vitro (Keller and Adamski 2007). Mutations in RDH12 have been genetically linked to several different forms of retinal dystrophies including Stargardt disease (Zolnikova et al 2016), cone–rod dystrophy (Huang et al 2016), retinitis pigmentosa (Gong et al 2015), and Leber congenital amaurosis (LCA), which is the most severe form of childhood retinal dystrophy characterized by early visual loss (Janecke et al 2004; Thompson et al 2005; Mackay et al 2011). In addition, disease-associated mutations in RDH12 cofactor-binding domain correspond to accumulation of bioreactive retinoic acid, which can then induce apoptosis in many cells including photoreceptor cells (Lee et al 2007).…”

Section: Introductionmentioning

confidence: 99%

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Yeast ENV9 encodes a conserved lipid droplet (LD) short-chain dehydrogenase involved in LD morphology

et al. 2017

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Lipid droplets (LDs) have emerged as dynamic and interactive organelles with important roles in lipid metabolism and membrane biogenesis. Here, we report that Saccharomyces cerevisiae Env9 is a novel conserved oxidoreductase involved in LD morphology. Microscopic and biochemical studies confirm localization of tagged Env9 to LDs and implicate its C-terminal hydrophobic domain (aa241–265) in its membrane association and stability. Confocal studies reveal a role for Env9 in LD morphology. Env9 positively affects both formation of large LDs upon overexpression and LD proliferation under poor carbon source. In silico bioinformatic and modeling approaches establish that ENV9 is a widely conserved member of the short-chain dehydrogenase (SDR) superfamily. Bayesian phylogenetic studies strongly support ENV9 as an ortholog of human SDR retinol dehydrogenase 12 (RDH12). Dehydrogenase activity of Env9 was confirmed by in vitro oxidoreductase assays. RDH12 mutations have been linked to Leber Congenital Amaurosis. Similar site-directed point mutations in the predicted Env9 oxidoreductase active site (N146L) or cofactor-binding site (G23–24A) abolished its reductase activity in vitro, consistent with those reported in other retinol dehydrogenases. The same residues were essential for affecting LD size and number in vivo. Taken together, our results implicate oxidoreductase activity of Env9 in its cellular role in LD morphology.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Yeast ENV9 encodes a conserved lipid droplet (LD) short-chain dehydrogenase involved in LD morphology

et al. 2017

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“…For this reason, a more robust approach to clinical diagnosis that is best achieved with targeted panel testing of all known IRD genes as the standard of care is recommended (Neveling et al 2013;Consugar et al 2014). RDH12 mutations can cause a spectrum of retinal degenerations including LCA, CORD, autosomal recessive, autosomal dominant RP, and now macular dystrophy (MD) (Janecke et al 2004;Perrault et al 2004;Fingert et al 2008;Chacon-Camacho et al 2013;Huang et al 2016). For this reason, we suggest gene-specific nomenclature rather than a phenotypic-based approach that may be misleading due to some retinal diseases overlap with multiple genes.…”

Section: Discussionmentioning

confidence: 99%

“…RDH12-associated disease is thought to account for up to 4% of LCA cases (Perrault et al 2004). Subsequently, mutations in RDH12 have been found in patients with autosomal recessive (AR) retinitis pigmentosa (RP) as well as cone-rod dystrophies (CORDs) (Janecke et al 2004;Chacon-Camacho et al 2013;Huang et al 2016). Characteristics of disease caused by recessive biallelic mutations in RDH12 include early-onset progressive degeneration of both rods and cones with severely reduced or extinguished responses on electroretinogram (ERG) (Schuster et al 2007).…”

Section: Introductionmentioning

confidence: 99%

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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“…Of note, light sensitivity may be one major symptom in patients with variants in CACNA1F , CABP4 , and CACNA2D4 in addition to phenotypic variability sometimes leading to more progressive IRD and thus the term icCSNB may be misleading (reviewed in Zeitz et al, ). More than 150 different variants in CACNA1F and only a few in CABP4 and CACNA2D4 lead to icCSNB or similar phenotypes (reviewed and summarized in 2015 in Zeitz et al, ; additional publications since then, Ba‐Abbad et al, ; Hove et al, ; X. F. Huang et al, ; L. Huang et al, ; Patel et al, ; Sun et al, ; Xu et al, ; Zhao et al, ; Q. Zhou et al, ). The pathogenic variant spectrum comprises missense, nonsense, and splice‐site variants, small insertions and deletions, gross deletions, and complex rearrangements with most of the variants representing missense or nonsense variants (HGMD_Pro; Stenson et al, ; Zeitz et al, ).…”

Section: Introductionmentioning

confidence: 99%

Where are the missing gene defects in inherited retinal disorders? Intronic and synonymous variants contribute at least to 4% of CACNA1F ‐mediated inherited retinal disorders

et al. 2019

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Inherited retinal disorders (IRD) represent clinically and genetically heterogeneous diseases. To date, pathogenic variants have been identified in ~260 genes. Albeit that many genes are implicated in IRD, for 30–50% of the cases, the gene defect is unknown. These cases may be explained by novel gene defects, by overlooked structural variants, by variants in intronic, promoter or more distant regulatory regions, and represent synonymous variants of known genes contributing to the dysfunction of the respective proteins. Patients with one subgroup of IRD, namely incomplete congenital stationary night blindness (icCSNB), show a very specific phenotype. The major cause of this condition is the presence of a hemizygous pathogenic variant in CACNA1F. A comprehensive study applying direct Sanger sequencing of the gene‐coding regions, exome and genome sequencing applied to a large cohort of patients with a clinical diagnosis of icCSNB revealed indeed that seven of the 189 CACNA1F‐related cases have intronic and synonymous disease‐causing variants leading to missplicing as validated by minigene approaches. These findings highlight that gene‐locus sequencing may be a very efficient method in detecting disease‐causing variants in clinically well‐characterized patients with a diagnosis of IRD, like icCSNB.

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Molecular genetics of cone-rod dystrophy in Chinese patients: New data from 61 probands and mutation overview of 163 probands

Cited by 56 publications

References 47 publications

Yeast ENV9 encodes a conserved lipid droplet (LD) short-chain dehydrogenase involved in LD morphology

Yeast ENV9 encodes a conserved lipid droplet (LD) short-chain dehydrogenase involved in LD morphology

Expanding the phenotypic spectrum in RDH12-associated retinal disease

Where are the missing gene defects in inherited retinal disorders? Intronic and synonymous variants contribute at least to 4% of CACNA1F ‐mediated inherited retinal disorders

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