Serine biosynthesis defect due to haploinsufficiency of PHGDH causes retinal disease

Eade, Kevin; Gantner, Marin L.; Hostyk, Joseph; Nagasaki, Takayuki; Giles, Sarah; Fallon, Regis; Harkins‐Perry, Sarah; Baldini, M; Lim, Esther W.; Scheppke, Lea; Dorrell, Michael I.; Cai, Charles L.; Baugh, Evan H.; Wolock, Charles J.; Wallace, Martina; Berlow, Rebecca B.; Goldstein, David B.; Metallo, Christian M.; Friedlander, Martin; Allikmets, Rando

doi:10.1038/s42255-021-00361-3

Cited by 43 publications

(55 citation statements)

References 51 publications

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“…While the upregulation of these pathways in KO progenitor cells may reflect the higher proliferative index in KO organoids, the downregulation of these pathways in Müller glia could have a long-term impact on the survival of these cells and on the metabolic support they provide to photoreceptors (Hurley et al, 2015;Shen et al, 2021). These findings could have significance to understanding 5q14.3-associated phenotypes including MacTel, which is known to be a metabolic disease linked to the dysregulation of serine synthesis through central carbon metabolism (Bonelli et al, 2020;Eade et al, 2021;Gantner et al, 2019). Furthermore, we also observe downregulated genes that are involved in vascular signaling, such as FLT1, SEMA3A, COL18A1, and VEGFA, in KO Müller glia.…”

Section: Discussionsupporting

confidence: 55%

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Multi-omic Analysis of Developing Human Retina and Organoids Reveals Cell-Specific Cis-Regulatory Elements and Mechanisms of Non-Coding Genetic Disease Risk

Thomas

Timms

Giles

et al. 2021

Preprint

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Cis-regulatory elements (CREs) play a critical role in the development, maintenance, and disease-states of all human cell types. In the human retina, CREs have been implicated in a variety of inherited retinal disorders. To characterize cell-class-specific CREs in the human retina and elucidate their potential functions in development and disease, we performed single-nucleus (sn)ATAC-seq and snRNA-seq on the developing and adult human retina and on human retinal organoids. These analyses allowed us to identify cell-class-specific CREs, enriched transcription factor binding motifs, putative target genes, and to examine how these features change over development. By comparing DNA accessibility between the human retina and retinal organoids we found that CREs in organoids are highly correlated at the single-cell level, validating the use of organoids as a model for studying disease-associated CREs. As a proof of concept, we studied the function of a disease-associated CRE at 5q14.3 in organoids, identifying its principal target gene as the miR-9-2 primary transcript and demonstrating a dual role for this CRE in regulating neurogenesis and gene regulatory programs in mature glia. This study provides a rich resource for characterizing cell-class-specific CREs in the human retina and showcases retinal organoids as a model in which to study the function of retinal CREs that influence retinal development and disease.

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Section: Discussionsupporting

confidence: 55%

“…as cell line 1, and the female line was designated as cell line 2. These lines have been utilized and validated in previous studies (Eade et al, 2021;Gantner et al, 2019).…”

Section: Supplemental Tablesmentioning

confidence: 99%

Multi-omic Analysis of Developing Human Retina and Organoids Reveals Cell-Specific Cis-Regulatory Elements and Mechanisms of Non-Coding Genetic Disease Risk

Thomas

Timms

Giles

et al. 2021

Preprint

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“…In the mouse model of OIR, serine and onecarbon metabolism were found to mediate HIF response in retinopathy through liver-eye serine crosstalk (79). In macular telangiectasia type 2 (MacTel) , a rare degenerative eye disease with abnormal intraretinal angiogenesis, defective serine biosynthesis and PHDGH haploinsufficiency were genetically linked with disease onset and associated with toxic ceramide accumulation in circulation and in retinal pigment epithelium cells (80,81). Whether SLC38A5 may regulate serine transportation to influence retinal angiogenesis and retinal diseases will need additional investigation.…”

Section: Discussionmentioning

confidence: 99%

Amino acid transporter SLC38A5 regulates developmental and pathological retinal angiogenesis

Wang

Yemanyi

Huang

et al. 2021

Preprint

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Amino acid metabolism in vascular endothelium is important for sprouting angiogenesis. SLC38A5(solute carrier family 38 member 5), an amino acid (AA) transporter, shuttles neutral AAs across cell membrane, including glutamine, which may serve as metabolic fuel for proliferating endothelial cells (ECs) to promote angiogenesis. Here we found that SLC38A5 is highly enriched in normal retinal vascular endothelium, and more specifically in pathological sprouting neovessels. SLC38A5 is suppressed in retinal blood vessels from Lrp5-/-and Ndpy/- mice, both genetic models of defective retinal vascular development with Wnt signaling mutations. Additionally, Slc38a5 transcription is directly regulated by Wnt/β-catenin signaling. Genetic deficiency of SLC38A5 in mice substantially delays retinal vascular development and suppresses pathological neovascularization in oxygen-induced retinopathy modeling ischemic proliferative retinopathies. Inhibition of SLC38A5 in retinal vascular ECs impairs EC proliferation and angiogenic function, suppresses glutamine uptake, and dampens vascular endothelial growth factor receptor 2 (VEGFR2). Together these findings suggest that SLC38A5 is a new metabolic regulator of retinal angiogenesis by controlling AA nutrient uptake and homeostasis in ECs.

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“…Serine metabolism via phosphoglycerate dehydrogenase (PHGDH), a key enzyme in the serine synthesis pathway, is important for retinal cell survival, including in EC [80,120]. Loss of Phgdh in ECs cause defects in retinal angiogenesis and promotes EC apoptosis via heme deficiency, which induces mitochondrial respiration defects and oxidative stress [121].…”

Section: Amino Acidsmentioning

confidence: 99%

Metabolism in Retinopathy of Prematurity

Tomita

Usui‐Ouchi

Nilsson

et al. 2021

Life

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Retinopathy of prematurity is defined as retinal abnormalities that occur during development as a consequence of disturbed oxygen conditions and nutrient supply after preterm birth. Both neuronal maturation and retinal vascularization are impaired, leading to the compensatory but uncontrolled retinal neovessel growth. Current therapeutic interventions target the hypoxia-induced neovessels but negatively impact retinal neurons and normal vessels. Emerging evidence suggests that metabolic disturbance is a significant and underexplored risk factor in the disease pathogenesis. Hyperglycemia and dyslipidemia correlate with the retinal neurovascular dysfunction in infants born prematurely. Nutritional and hormonal supplementation relieve metabolic stress and improve retinal maturation. Here we focus on the mechanisms through which metabolism is involved in preterm-birth-related retinal disorder from clinical and experimental investigations. We will review and discuss potential therapeutic targets through the restoration of metabolic responses to prevent disease development and progression.

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Serine biosynthesis defect due to haploinsufficiency of PHGDH causes retinal disease

Cited by 43 publications

References 51 publications

Multi-omic Analysis of Developing Human Retina and Organoids Reveals Cell-Specific Cis-Regulatory Elements and Mechanisms of Non-Coding Genetic Disease Risk

Multi-omic Analysis of Developing Human Retina and Organoids Reveals Cell-Specific Cis-Regulatory Elements and Mechanisms of Non-Coding Genetic Disease Risk

Amino acid transporter SLC38A5 regulates developmental and pathological retinal angiogenesis

Metabolism in Retinopathy of Prematurity

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