PXD034993

PXD034993 is an original dataset announced via ProteomeXchange.

Title	A homozygous PPP1R21 splice variant associated with severe developmental delay, absence of speech and muscle weakness leads to activated proteasome function
Description	PPP1R21 acts as a co-factor for protein phosphatase 1 (PP1), an important serine/threonine phosphatase known to be essential for cell division, control of glycogen metabolism, protein synthesis and muscle contractility. Bi-allelic pathogenic variants in PPP1R21 were linked to a neurodevelopmental disorder with hypotonia, facial dysmorphism and brain abnormalities (NEDHFBA) with pediatric onset. Functional studies unravelled impaired vesicular transport as being part of PPP1R21-related pathophysiology. To decipher further pathophysiological processes leading to the clinical manifestation of NEDHFBA, we investigated the proteomic signature of fibroblasts derived from the first NEDHFBA patient harbouring a splice-site mutation within PPP1R21 and presenting with a milder phenotype. Proteomic findings and further functional studies demonstrate a profound activation of the ubiquitin-proteasome system with presence of protein aggregates and impact on cellular fitness and moreover suggest a cross-link between activation of the proteolytic system and cytoskeletal architecture as exemplified on paradigmatic proteins including actin, thus extending the pathophysiological spectrum of the disease. In addition, the proteomic signature of PPP1R21-mutant fibroblasts displayed a dysregulation of a variety of proteins of neurological relevance. This also includes the increase proteins which might act toward antagonization of cellular burden in terms of pro-survival, a molecular finding which might accord with the presentation of a milder phenotype of our NEDHFBA patient.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:46:02.059.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Andreas Hentschel
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-06-30 03:04:41	ID requested
1	2023-05-10 09:33:56	announced
⏵ 2	2023-11-14 08:46:06	announced	2023-11-14: Updated project metadata.

Hentschel A, Meyer N, Kohlschmidt N, Gro, ß C, Sickmann A, Schara-Schmidt U, F, ö, rster F, T, ö, pf A, Christiansen J, Horvath R, Vorgerd M, Thompson R, Polavarapu K, Lochm, ü, ller H, Preusse C, Hannappel L, Sch, ä, nzer A, Gr, ü, neboom A, Gangfu, ß A, Roos A, A Homozygous PPP1R21 Splice Variant Associated with Severe Developmental Delay, Absence of Speech, and Muscle Weakness Leads to Activated Proteasome Function. Mol Neurobiol, 60(5):2602-2618(2023) [pubmed]

submitter keyword: congenital,CHKB

Choline/ethanolamine kinase

Muscular dystrophy, megaconial type (MDCMC)

VAPB

Andreas Hentschel
contact affiliation	Proteomics, Leibniz-Institute for analytical sciences, Germany
contact email	andreas.hentschel@isas.de
lab head
Andreas Hentschel
contact affiliation	Leibniz Institut für Analytische Wissenschaften
contact email	andreas.hentschel@isas.de
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/2023/05/PXD034993

PRIDE project URI

• PRIDE
  1. PXD034993
     1. Label: PRIDE project
     2. Name: A homozygous PPP1R21 splice variant associated with severe developmental delay, absence of speech and muscle weakness leads to activated proteasome function