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Article Dans Une Revue Brain - A Journal of Neurology Année : 2021

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

Denisa Hathazi
  • Fonction : Auteur
Daniel Cox
  • Fonction : Auteur
Adele d'Amico
Giorgio Tasca
Richard Charlton
  • Fonction : Auteur
Jennifer Baumann
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Laxmikanth Kollipara
  • Fonction : Auteur
René P. Zahedi
Ingo Feldmann
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Annalaura Torella
Ronald D. Cohn
  • Fonction : Auteur
Emily Robinson
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Francesco Ricci
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Heinz Jungbluth
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Fabiana Fattori
Emily O'Connor
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Rita Horvath
Rita Barresi
Hanns Lochmüller
Andoni Urtizberea
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Laura E. Swan
Andreas Roos
  • Fonction : Auteur correspondant
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Résumé

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.

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Dates et versions

hal-03401813 , version 1 (25-10-2021)

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Citer

Denisa Hathazi, Daniel Cox, Adele d'Amico, Giorgio Tasca, Richard Charlton, et al.. INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH. Brain - A Journal of Neurology , 2021, 144 (8), pp.2427-2442. ⟨10.1093/brain/awab133⟩. ⟨hal-03401813⟩
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