RRC ID 70339
Author Hathazi D, Cox D, D'Amico A, Tasca G, Charlton R, Carlier RY, Baumann J, Kollipara L, Zahedi RP, Feldmann I, Deleuze JF, Torella A, Cohn R, Robinson E, Ricci F, Jungbluth H, Fattori F, Boland A, O'Connor E, Horvath R, Barresi R, Lochmüller H, Urtizberea A, Jacquemont ML, Nelson I, Swan L, Bonne G, Roos A.
Title INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH.
Journal Brain
Abstract Marinesco-Sjögren syndrome is a rare human disorder caused by biallelic mutations in SIL1 characterized by cataracts in infancy, myopathy and ataxia, symptoms which are also associated with a novel disorder caused by mutations in INPP5K. While these phenotypic similarities may suggest commonalties at a molecular level, an overlapping pathomechanism has not been established yet. In this study, we present six new INPP5K patients and expand the current mutational and phenotypical spectrum of the disease showing the clinical overlap between Marinesco-Sjögren syndrome and the INPP5K phenotype. We applied unbiased proteomic profiling on cells derived from Marinesco-Sjögren syndrome and INPP5K patients and identified alterations in d-3-PHGDH as a common molecular feature. d-3-PHGDH modulates the production of l-serine and mutations in this enzyme were previously associated with a neurological phenotype, which clinically overlaps with Marinesco-Sjögren syndrome and INPP5K disease. As l-serine administration represents a promising therapeutic strategy for d-3-PHGDH patients, we tested the effect of l-serine in generated sil1, phgdh and inpp5k a+b zebrafish models, which showed an improvement in their neuronal phenotype. Thus, our study defines a core phenotypical feature underpinning a key common molecular mechanism in three rare diseases and reveals a common and novel therapeutic target for these patients.
Volume 144(8)
Pages 2427-2442
Published 2021-9-4
DOI 10.1093/brain/awab133
PII 6207983
PMID 33792664
PMC PMC8418339
MeSH Adolescent Adult Animals Child Female Guanine Nucleotide Exchange Factors / genetics* Humans Inositol Polyphosphate 5-Phosphatases / genetics* Male Middle Aged Muscle, Skeletal / pathology Mutation* Phenotype* Phosphoglycerate Dehydrogenase / genetics* Proteomics Spinocerebellar Degenerations / genetics* Spinocerebellar Degenerations / pathology Zebrafish
IF 11.337
Zebrafish Tg(CM-isl1:GFP)rw0