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):

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