Identification of autosomal recessive novel genes and retinal phenotypes in members of the solute carrier (SLC) superfamily

Millo, Talya; Rivera, Antonio; Obolensky, Alexey; Marks-Ohana, Devora; Xu, Min; Li, Yumei; Wilhelm, Enosh; Gopalakrishnan, Prakadeeswari; Gross, Menachem; Rosin, Boris; Hanany, Mor; Webster, Andrew R.; Tracewska, Anna M; Koenekoop, Robert K.; Chen, Rui; Arno, Gavin; Schueler‐Furman, Ora; Roosing, Susanne; Banin, Eyal; Sharon, Dror

doi:10.1016/j.gim.2022.03.020

Cited by 7 publications

(5 citation statements)

References 33 publications

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“… 14 ) , EYS, MY O 7A, PEX6, PQCL2 (described in Millo et al. 15 ), PROM1, and RPE65 (described in Panneman et al. 30 ) .…”

Section: Resultsmentioning

confidence: 99%

“… Pathogenic c.2131-695A>C p.(?) VUS Possibly solved arRP34 6 USH2A c.2276G>T p.(Cys759Phe) Pathogenic c.2276G>T p.(Cys759Phe) Pathogenic Solved arRP36 USH2A c.2276G>T p.(Cys759Phe) Pathogenic c.4397-3890A>G p.Ala1465_Ala1466ins ∗ 5 Likely pathogenic Solvedˆ arRP37 15 RPE65 c.886dup p.(Arg296Lysfs ∗ 7) Pathogenic c.675C>A p.(Asp215Valfs ∗ 4) Pathogenic Solvedˆ arRP41 6 USH2A c.2276G>T p.(Cys759Phe) Pathogenic c.2276G>T p.(Cys759Phe) Pathogenic Solved arRP42 6 USH2A c.2276G>T p.(Cys759Phe) Pathogenic c.2276G>T p.(Cys759Phe) Pathogenic Solved DFNB2 USH2A c.653T>A p.(Val218Glu) Pathogenic c.4627+25436_4987+659del p.(?) Likely pathogenic Solvedˆ USH5 USH2A c.1267G>T p.(Gly423 ∗ ) Likely pathogenic c.14791+5G>T p.Tyr4862Alafs ∗ 22 Likely pathogenic Solved USH7 USH2A c.13245_13246del p.(Gly4416Valfs ∗ 2) Likely pathogenic c.652-23899_2809+1417dup p.(?)…”

Section: Methodsmentioning

confidence: 99%

“… Pathogenic c.2994- 3 030_14343+488dup p.(?) Pathogenic Solved USH32 USH2A c.14408T>C p.(Ile4803Thr) VUS c.4885+375A>G 15 p.Ser1629Valfs ∗ 52 Likely pathogenic Possibly solved USH33 USH2A c.14791+2T>C p.(?) Likely pathogenic c.9335_9371+8063delinsGAA GACACTCC p.(?)…”

Section: Methodsmentioning

confidence: 99%

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Whole genome sequencing for USH2A-associated disease reveals several pathogenic deep-intronic variants that are amenable to splice correction

Reurink¹,

Weisschuh²,

Garanto³

et al. 2023

Human Genetics and Genomics Advances

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“… 14 ) , EYS, MY O 7A, PEX6, PQCL2 (described in Millo et al. 15 ), PROM1, and RPE65 (described in Panneman et al. 30 ) .…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Whole genome sequencing for USH2A-associated disease reveals several pathogenic deep-intronic variants that are amenable to splice correction

Reurink¹,

Weisschuh²,

Garanto³

et al. 2023

Human Genetics and Genomics Advances

Self Cite

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“…OLA1 has been shown to be associated with hereditary breast and ovarian cancers as well as with a poor prognosis of HCC [ 28 , 29 ]. Polymorphisms were also found in other canonical cancer-related genes, including SLC37A3 , BAZ1A , SRP54 , MYH1 and ABCC1 [ 30 , 31 , 32 , 33 ], but were not directly involved in MASLD pathogenesis. As shown in Table 3 , we also identified a SNP (synonymous variant) in ORAI1 (ORAI calcium release-activated calcium modulator 1), which encodes a membrane calcium channel subunit activated by the calcium sensor STIM1 when calcium stores are depleted [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Whole-Exome Sequencing (WES) Reveals Novel Sex-Specific Gene Variants in Non-Alcoholic Steatohepatitis (MASH)

Wei,

Wu,

Daoud

2024

Genes

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Non-alcoholic steatohepatitis (NASH, also known as MASH) is a severe form of non-alcoholic fatty liver disease (NAFLD, also known as MASLD). Emerging data indicate that the progression of the disease to MASH is higher in postmenopausal women and that genetic susceptibility increases the risk of MASH-related cirrhosis. This study aimed to investigate the association between genetic polymorphisms in MASH and sexual dimorphism. We applied whole-exome sequencing (WES) to identify gene variants in 8 age-adjusted matched pairs of livers from both male and female patients. Sequencing alignment, variant calling, and annotation were performed using standard methods. Polymerase chain reaction (PCR) coupled with Sanger sequencing and immunoblot analysis were used to validate specific gene variants. cBioPortal and Gene Set Enrichment Analysis (GSEA) were used for actionable target analysis. We identified 148,881 gene variants, representing 57,121 and 50,150 variants in the female and male cohorts, respectively, of which 251 were highly significant and MASH sex-specific (p < 0.0286). Polymorphisms in CAPN14, SLC37A3, BAZ1A, SRP54, MYH11, ABCC1, and RNFT1 were highly expressed in male liver samples. In female samples, Polymorphisms in RGSL1, SLC17A2, HFE, NLRC5, ACTN4, SBF1, and ALPK2 were identified. A heterozygous variant 1151G>T located on 18q21.32 for ALPK2 (rs3809983) was validated by Sanger sequencing and expressed only in female samples. Immunoblot analysis confirmed that the protein level of β-catenin in female samples was 2-fold higher than normal, whereas ALPK2 expression was 0.5-fold lower than normal. No changes in the protein levels of either ALPK2 or β-catenin were observed in male samples. Our study suggests that the perturbation of canonical Wnt/β-catenin signaling observed in postmenopausal women with MASH could be the result of polymorphisms in ALPK2.

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“…Numerous studies in the past five years have demonstrated a potential involvement of multiple genes in RP pathogenesis through genome sequencing [ 136 , 137 , 138 ]. For example, analyzing sequence variants of the solute carrier (SLC) genes in Israeli and Palestinian inherited retinal disease cases, two novel targets were identified: SLC66A1 and SLC39A12 [ 139 ]. Other variants of SLC genes were shown to be involved in RP; SLC7A14 knockout mice show retinal degeneration and altered visual function, suggesting a role for this gene in retinal development [ 140 ].…”

Section: Gene Therapymentioning

confidence: 99%

Retinitis Pigmentosa: Novel Therapeutic Targets and Drug Development

Kulbay

Toameh

et al. 2023

Pharmaceutics

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Retinitis pigmentosa (RP) is a heterogeneous group of hereditary diseases characterized by progressive degeneration of retinal photoreceptors leading to progressive visual decline. It is the most common type of inherited retinal dystrophy and has a high burden on both patients and society. This condition causes gradual loss of vision, with its typical manifestations including nyctalopia, concentric visual field loss, and ultimately bilateral central vision loss. It is one of the leading causes of visual disability and blindness in people under 60 years old and affects over 1.5 million people worldwide. There is currently no curative treatment for people with RP, and only a small group of patients with confirmed RPE65 mutations are eligible to receive the only gene therapy on the market: voretigene neparvovec. The current therapeutic armamentarium is limited to retinoids, vitamin A supplements, protection from sunlight, visual aids, and medical and surgical interventions to treat ophthalmic comorbidities, which only aim to slow down the progression of the disease. Considering such a limited therapeutic landscape, there is an urgent need for developing new and individualized therapeutic modalities targeting retinal degeneration. Although the heterogeneity of gene mutations involved in RP makes its target treatment development difficult, recent fundamental studies showed promising progress in elucidation of the photoreceptor degeneration mechanism. The discovery of novel molecule therapeutics that can selectively target specific receptors or specific pathways will serve as a solid foundation for advanced drug development. This article is a review of recent progress in novel treatment of RP focusing on preclinical stage fundamental research on molecular targets, which will serve as a starting point for advanced drug development. We will review the alterations in the molecular pathways involved in the development of RP, mainly those regarding endoplasmic reticulum (ER) stress and apoptotic pathways, maintenance of the redox balance, and genomic stability. We will then discuss the therapeutic approaches under development, such as gene and cell therapy, as well as the recent literature identifying novel potential drug targets for RP.

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Identification of autosomal recessive novel genes and retinal phenotypes in members of the solute carrier (SLC) superfamily

Cited by 7 publications

References 33 publications

Whole genome sequencing for USH2A-associated disease reveals several pathogenic deep-intronic variants that are amenable to splice correction

Whole genome sequencing for USH2A-associated disease reveals several pathogenic deep-intronic variants that are amenable to splice correction

Whole-Exome Sequencing (WES) Reveals Novel Sex-Specific Gene Variants in Non-Alcoholic Steatohepatitis (MASH)

Retinitis Pigmentosa: Novel Therapeutic Targets and Drug Development

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