Dataset Information

A homozygous PPP1R21 splice variant associated with severe developmental delay, absence of speech and muscle weakness leads to activated proteasome function

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Leukocyte, Fibroblast

SUBMITTER: Andreas Hentschel

LAB HEAD: Andreas Hentschel

PROVIDER: PXD034993 | Pride | 2023-05-10

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20200212_122904_Fib-Analysis-PPP21R1.xlsx	Xlsx
	20220623_073822_NME_Fibro_PPP21R1_Ctrl.sne	Other
	Lumos08681_18_F-CO-56.raw	Raw
	Lumos08682_18_F-CO-56.raw	Raw
	Lumos08683_18_F-CO-56.raw	Raw

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Publications

A Homozygous PPP1R21 Splice Variant Associated with Severe Developmental Delay, Absence of Speech, and Muscle Weakness Leads to Activated Proteasome Function.

Hentschel Andreas A Meyer Nancy N Kohlschmidt Nicolai N Groß Claudia C Sickmann Albert A Schara-Schmidt Ulrike U Förster Fabian F Töpf Ana A Christiansen Jon J Horvath Rita R Vorgerd Matthias M Thompson Rachel R Polavarapu Kiran K Lochmüller Hanns H Preusse Corinna C Hannappel Luis L Schänzer Anne A Grüneboom Anika A Gangfuß Andrea A Roos Andreas A

Molecular neurobiology 20230124 5

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 unraveled impaired vesicular transport as being part of PPP1R21-related pathomech ...[more]

PMID: 36692708

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