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 response to 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 acquired molecular knowledge to the pre-clinical testing of a therapeutic intervention concept.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Skin, Fibroblast

DISEASE(S): Marinesco-sjogren Syndrome

SUBMITTER: Laxmikanth Kollipara

LAB HEAD: Dr. Andreas Roos

PROVIDER: PXD009272 | 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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Project description:SIL1 acts as a co-chaperone for the major ER-resident chaperone BiP and thus plays a role in many BiP-dependent cellular functions such as protein folding control and unfolded protein response. Whereas increase of BiP upon cellular stress conditions is a well-known phenomenon, elevation of SIL1 under stress conditions was thus far solely studied in yeast and different studies indicated an adverse effect of SIL1 increase. This is seemingly in contrast with the beneficial effect of SIL1 increase in surviving neurons in neurodegenerative disorders such as Amyotrophic Lateral Sclerosis and Alzheimer disease. In the present study, we systematically addressed these controversial findings. Using cell biological, morphological and biochemical methods, we could demonstrate that that SIL1 is increased in various mammalian cells and neuronal tissues upon induction of cellular stress. Investigation of heterozygous SIL1/Sil1 mutant cells and tissues supported this finding. Moreover, SIL1 protein was found to be stabilized during ER stress. Increased SIL1 initiates ER stress in a concentration-dependent manner which is in accordance with the described adverse effect of increased SIL1. However, our results also suggest that protective levels are achieved by the secretion of excessive SIL1 and GRP170 (no longer perturbing ER homeostasis) and that moderately increased SIL1 also ameliorates cellular fitness under stress conditions. Results of our immunoprecipitation studies indicate that under cellular stress conditions SIL1 might act in a BiP-independent manner. Unbiased proteomic studies revealed that elevated SIL1 levels alter the expression of several proteins including crucial players in neurodegeneration, especially in Alzheimer disease. This finding is in accordance with our observation of increased SIL1-immunoreactivity in surviving neurons of Alzheimer disease autopsy cases and supports the assumption that SIL1 plays a protective role in neurodegenerative disorders.

			Action	DRS
	F059946.dat	Other
	Fibroblasts_INPP5K_SampleIDs.xlsx	Xlsx
	Lumos00514.raw	Raw
	Lumos00515.raw	Raw
	Lumos00516.raw	Raw