PXD065493

PXD065493 is an original dataset announced via ProteomeXchange.

Title	Biallelic variants in the ribosomal protein RPS6KC1 cause a complex neurodevelopmental disorder
Description	The ribosomal protein S6 kinase family members play essential biological functions in disease, from cancer to intellectual disability. Little is known about RPS6KC1, aside from its lack of phosphorylation capacity and its roles in sphingosine-1-phosphate signaling and peroxiredoxin-3 transport to mitochondria. Through whole-exome sequencing, we identified biallelic RPS6KC1 variants in 13 individuals from 8 independent families. Phenotypic manifestations included neurodevelopmental delay, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome (OMIM #303600) caused by RPS6KA3 mutations. Functional studies on peripheral blood mononuclear cells (PBMCs) from the different individuals indicated a diminished expression and phosphorylation of RPS6, impacting ribosomal protein synthesis, and a decrease in the known interactors PRDX3 and SPHK1, accompanied by marked repression of the mTOR/PI3K pathway. We detected a dysregulation of phosphoinositides and sphingoid bases levels on plasma samples from the different individuals. Further studies in HAP1 RPS6KC1 knockdown cells suggested that RPS6KC1 may regulate PRDX3 and SPHK1 activities by facilitating their endosome anchoring. In Drosophila melanogaster, RPS6KC1 knockdown resulted in locomotor dysfunction, defective neuromuscular junctions, reduced lifespan, and decreased mTOR activity. Overexpression of mTOR in this model improved motor function and lifespan. These findings underscore the crucial roles of RPS6KC1 in neurodevelopment by controlling ribosomal protein synthesis, lipid signaling, and the mTOR pathway.
HostingRepository	PRIDE
AnnounceDate	2025-09-25
AnnouncementXML	Submission_2025-09-25_01:42:57.163.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Joan Josep Bech-Serra
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Eclipse; Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2025-06-26 01:27:13	ID requested
⏵ 1	2025-09-25 01:42:57	announced

Dataset with its publication pending

submitter keyword: DIA, TMT, sphingosine, PI(3)P, RPS6KC1,Neurodevelopmental delay, RSK family, mTOR, label free

Aurora Pujol
contact affiliation	1)Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Catalonia, Spain 2) Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain 3)Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Catalonia, Spain
contact email	apujol@idibell.cat
lab head
Joan Josep Bech-Serra
contact affiliation	Proteomics Unit - Josep Carreras Leukaemia Research Institute
contact email	jbech@carrerasresearch.org
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/09/PXD065493

PRIDE project URI

• PRIDE
  1. PXD065493
     1. Label: PRIDE project
     2. Name: Biallelic variants in the ribosomal protein RPS6KC1 cause a complex neurodevelopmental disorder