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

Denisa Hathazi, Dan Cox, Adele D'Amico, Giorgio Tasca, Richard Charlton, Robert Yves Carlier, Jennifer Baumann, Laxmikanth Kollipara, René P. Zahedi, Ingo Feldmann, Jean Francois Deleuze, Annalaura Torella, Ronald Cohn, Emily Robinson, Francesco Ricci, Heinz Jungbluth, Fabiana Fattori, Anne Boland, Emily O'Connor, Rita HorvathRita Barresi, Hanns Lochmüller, Andoni Urtizberea, Marie Line Jacquemont, Isabelle Nelson, Laura Swan, Gisèle Bonne, Andreas Roos

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)2427-2442
Number of pages16
Issue number8
Publication statusPublished - 1 Aug 2021


  • BiP
  • INPP5K
  • L-serine
  • SIL1


Dive into the research topics of 'INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH'. Together they form a unique fingerprint.

Cite this