Stargardt disease-associated mutation spectrum of a Russian Federation cohort

Зольникова, И. В.; Стрельников, В. В.; Skvortsova, Natalia A.; Танас, А. С.; Barh, Debmalya; Рогатина, Е В; Egorova, I. V.; Levina, D.V.; Demenkova, O. N; Prikaziuk, Egor G.; Ivanova, Mariya

doi:10.1016/j.ejmg.2016.12.002

Cited by 16 publications

(15 citation statements)

References 32 publications

(35 reference statements)

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“…In previous studies, the incidents of STGD-associated variants in ABCA4 were 70.5% in the Russian Federation, 70.8% in Korea, 67% in Portugal, and 60.5% in Spain (Fumagalli et al, 2001;Maia-Lopes et al, 2009;Riveiro-Alvarez et al, 2009;Sung, Choi, Shim, & Song, 2019;Zolnikova et al, 2017). In previous studies, the incidents of STGD-associated variants in ABCA4 were 70.5% in the Russian Federation, 70.8% in Korea, 67% in Portugal, and 60.5% in Spain (Fumagalli et al, 2001;Maia-Lopes et al, 2009;Riveiro-Alvarez et al, 2009;Sung, Choi, Shim, & Song, 2019;Zolnikova et al, 2017).…”

Section: Discussionmentioning

confidence: 91%

Application of targeted exome and whole‐exome sequencing for Chinese families with Stargardt disease

Dan

Huang

Xing

et al. 2019

Annals of Human Genetics

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Objective: The aim of this study was to investigate pathogenic variants and molecular etiologies of Stargardt disease (STGD) in a cohort of Chinese families. Materials and Methods:A cohort of 12 unrelated STGD families diagnosed on the basis of clinical manifestations underwent analysis by targeted exome or whole-exome sequencing. Bioinformatics analysis, Sanger sequencing, and cosegregation analysis of available family members were used to validate sequencing data and confirm the presence of disease-causing genes.Results: Using targeted exome and whole-exome sequencing, we found that eight families had disease-causing variants in the ABCA4 gene, one family had only one heterozygous variant in the ABCA4 gene, and the remaining three families have not been identified with any disease-causing variants for STGD. We identified 15 variants in the ABCA4 gene; of these, five variants have not been previously described for STGD. Conclusion:The findings in this study expand the data regarding the frequency and spectrum of variants in the ABCA4 gene, thus potentially enriching our understanding of the molecular basis of STGD. Moreover, they constitute clues for future STGD diagnosis and therapy.

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Section: Discussionmentioning

confidence: 91%

Application of targeted exome and whole‐exome sequencing for Chinese families with Stargardt disease

Dan

Huang

Xing

et al. 2019

Annals of Human Genetics

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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%

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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“…For example, variants in other genes that code for proteins within the same biochemical pathway as the primary gene may affect expression of disease (Badano et al 2003;Coppieters et al 2010). As such, ABCA4, coding for a retinal-specific ATP-binding transporter that participates in the visual cycle, is a prime candidate (Zolnikova et al 2017). Two patients in our study were found to carry rare variants in ABCA4: c.5640T > A, p.Phe1880Leu (OGI3076-4666) and c.2088T > G, p.Ile696Met (OGI3077-4669).…”

Section: Discussionmentioning

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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Stargardt disease-associated mutation spectrum of a Russian Federation cohort

Cited by 16 publications

References 32 publications

Application of targeted exome and whole‐exome sequencing for Chinese families with Stargardt disease

Application of targeted exome and whole‐exome sequencing for Chinese families with Stargardt disease

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

Expanding the phenotypic spectrum in RDH12-associated retinal disease

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