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- W3137028944 abstract "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." @default.
- W3137028944 created "2021-03-29" @default.
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- W3137028944 date "2021-03-22" @default.
- W3137028944 modified "2023-10-17" @default.
- W3137028944 title "Serine biosynthesis defect due to haploinsufficiency of PHGDH causes retinal disease" @default.
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- W3137028944 doi "https://doi.org/10.1038/s42255-021-00361-3" @default.
- W3137028944 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/8084205" @default.
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