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Serine biosynthesis defect due to haploinsufficiency of PHGDH causes retinal disease
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Serine biosynthesis defect due to haploinsufficiency of PHGDH causes retinal disease
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Journal Article
Serine biosynthesis defect due to haploinsufficiency of PHGDH causes retinal disease
2021
Overview
Macular telangiectasia type 2 (MacTel) is a progressive, late-onset retinal degenerative disease linked to decreased serum levels of serine that elevate circulating levels of a toxic ceramide species, deoxysphingolipids (deoxySLs); however, causal genetic variants that reduce serine levels in patients have not been identified. Here we identify rare, functional variants in the gene encoding the rate-limiting serine biosynthetic enzyme, phosphoglycerate dehydrogenase (PHGDH), as the single locus accounting for a significant fraction of MacTel. Under a dominant collapsing analysis model of a genome-wide enrichment analysis of rare variants predicted to impact protein function in 793 MacTel cases and 17,610 matched controls, the
PHGDH
gene achieves genome-wide significance (
P
= 1.2 × 10
−13
) with variants explaining ~3.2% of affected individuals. We further show that the resulting functional defects in PHGDH cause decreased serine biosynthesis and accumulation of deoxySLs in retinal pigmented epithelial cells.
PHGDH
is a significant locus for MacTel that explains the typical disease phenotype and suggests a number of potential treatment options.
Rare variants in the gene encoding PHGDH, the rate-limiting enzyme in de novo serine biosynthesis, are identified as responsible for serine deficiency associated with the macular degenerative disease MacTel.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 45/22
/ 45/23
/ 45/29
/ 45/43
/ 45/70
/ 45/77
/ 631/208
/ Amyotrophic lateral sclerosis
/ Biomedical and Life Sciences
/ Disease
/ Enzymes
/ Genes
/ Genomes
/ Humans
/ Mutation
/ Phosphoglycerate dehydrogenase
/ Phosphoglycerate Dehydrogenase - genetics
/ Proteins
/ Retina
/ Retinal Pigment Epithelium - metabolism
/ Retinal Telangiectasis - genetics
/ Serine
