biostudies-literatureHathazi DFrench Muscular Dystrophy AssociationAction Medical ResearchSenatskanzlei Wissenschaft und ForschungAtaxia UKCanada Research Chair in Neuromuscular Genomics and HealthEuropean Research CounciLily Foundation and the Evelyn TrustNational Research Agency, Investment for the FutureCanadian Institutes of Health ResearchCIHRDeutsche ForschungsgemeinschaftEuropean Research CouncilDeutsche Gesellschaft für MuskelkrankeMinisterium für Kultur und Wissenschaft des Landes Nordrhein-WestfalenMedical Research CouncilSorbonne Université- Faculté de MédecineThe Institut National de la Santé et de la Recherche MédicaleWellcome Investigator AwardCanada Foundation for InnovationMuscular Dystrophy UKDer Regierende Bürgermeister von BerlinWellcome TrustCanadian Institutes of Health Research and Muscular Dystrophy Canada2427-2442https://www.ebi.ac.uk/biostudies/studies/S-EPMC8418339biostudies-literatureUnknown144(8)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 Brain : a journal of neurologyINPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH.PMC8418339ANR-10-INBS-092146622429ZA 639/1–1FDN-167281MR/N027302/22446MR/N027302/1ZHORVATHCFI-JELF 38412950–232279109915/A/15/Z109915/Z/15/Z18GRO-PG36-0270309548MR/V009346/1MR/N010035/1201064/Z/16/ZMR/N025431/2G1000848MR/N025431/1D'Amico ASwan LZahedi RPBaumann JBoland ACharlton RFattori FFeldmann IO'Connor ETasca GRoos AJungbluth HNelson IBarresi RCohn RLochmuller HUrtizberea AHathazi DHorvath RTorella ACox DDeleuze JFRicci FCarlier RYBonne GRobinson EKollipara LJacquemont MLfalseINPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH.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 2021-01-01T00:00:00Z2021 Sep2026-05-09T04:12:48.135Z2024-11-08T17:02:10.104ZS-EPMC84183393379266410.1093/brain/awab133