Dataset Information

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

ABSTRACT: In this study, we describe new patients suffering from INPP5K mutations and hereby expand the mutational and clinical spectrum of the underlying disease. Pathogenicity of a new INPP5K missense mutation has been functionally confirmed. In addition, we systematically addressed the need to identify common molecular key players to link phenotypically similar rare diseases. For this purpose, utilizing cells derived from INPP5K and SIL1 patients, we performed proteomic profiling and identified PHGDH, as a protein significantly altered in abundance in the in vitro systems of both diseases. Prompted by the striking molecular link between MSS, INPP5K- and PHGDH-phenotypes and the fact that PHGDH-patients notoriously respond to L-serine treatment, respective zebrafish models have been generated and responseto L-serine treatment has been addressed in vivo. Apart from the biochemical link between MSS, INPP5K-and PHGDH-phenotypes, affection of CDK9, a protein modulating the activity of CTDP1 biochemically links the INPP5K-phenotype to CCFDN. Thus, our study not only allowed to build molecular bridges between four phenotypically overlapping rare diseases but more importantly allowed to transfer the acquiredmolecular knowledge to the pre-clinical testing of a therapeutic intervention concept.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Skin, Fibroblast

DISEASE(S): Marinesco-sjogren Syndrome

SUBMITTER: Laxmikanth Kollipara

LAB HEAD: Dr. Andreas Roos

PROVIDER: PXD009297 | Pride | 2021-04-06

REPOSITORIES: Pride

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

Hathazi Denisa D Cox Dan D D'Amico Adele A Tasca Giorgio G Charlton Richard R Carlier Robert-Yves RY Baumann Jennifer J Kollipara Laxmikanth L Zahedi René P RP Feldmann Ingo I Deleuze Jean-Francois JF Torella Annalaura A Cohn Ronald R Robinson Emily E Ricci Francesco F Jungbluth Heinz H Fattori Fabiana F Boland Anne A O'Connor Emily E Horvath Rita R Barresi Rita R Lochmüller Hanns H Urtizberea Andoni A Jacquemont Marie-Line ML Nelson Isabelle I Swan Laura L Bonne Gisèle G Roos Andreas A

Brain : a journal of neurology 20210901 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 di ...[more]

PMID: 33792664

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			Action	DRS
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	MSS_Fibroblasts_iTRAQ4plex.pep.xml	Pepxml
	VELOS02_01795.raw	Raw
	VELOS02_01796.raw	Raw
	VELOS02_01810.raw	Raw