INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH



Hathazi, Denisa, Cox, Dan, D'Amico, Adele, Tasca, Giorgio, Charlton, Richard, Carlier, Robert-Yves, Baumann, Jennifer, Kollipara, Laxmikanth, Zahedi, René P, Feldmann, Ingo
et al (show 18 more authors) (2021) INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH. Brain, 144 (8). pp. 2427-2442.

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Abstract

<jats:title>Abstract</jats:title> <jats:p>Marinesco-Sjögren syndrome (MSS) is a rare human disorder caused by biallelic mutations in SIL1 characterized by cataracts in infancy, myopathy and ataxia, symptoms that 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 MSS and the INPP5K-phenotype. We applied unbiased proteomic profiling on cells derived from MSS- and INPP5K-patients and identified alterations in D-3-phosphoglycerate dehydrogenase as a common molecular feature. D-3-phosphoglycerate dehydrogenase modulates the production of L-serine and mutations in this enzyme were previously associated with a neurological phenotype, which clinically overlaps with MSS and INPP5K-disease. As, L-serine administration represents a promising therapeutic strategy for D-3-phosphoglycerate dehydrogenase 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.</jats:p>

Item Type: Article
Uncontrolled Keywords: SIL1, BiP, PHGDH, INPP5K, L-serine
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 09 Apr 2021 08:25
Last Modified: 08 Feb 2023 14:46
DOI: 10.1093/brain/awab133
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3118336