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

Lookup NU author(s): Dr Ana TopfORCiD, Professor Rita HorvathORCiD, Professor Hanns Lochmuller, Dr Andreas Roos



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2023, The Author(s). 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 pathomechanism. To decipher further the pathophysiological processes leading to the clinical manifestation of NEDHFBA, we investigated the proteomic signature of fibroblasts derived from the first NEDHFBA patient harboring a splice-site mutation in 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 (including filopodia) 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 includes increase proteins which might act toward antagonization of cellular stress burden in terms of pro-survival, a molecular finding which might accord with the presentation of a milder phenotype of our NEDHFBA patient.

Publication metadata

Author(s): Hentschel A, Meyer N, Kohlschmidt N, Gross C, Sickmann A, Schara-Schmidt U, Forster F, Topf A, Christiansen J, Horvath R, Vorgerd M, Thompson R, Polaparapu K, Lochmuller H, Preusse C, Hannappel L, Schanzer A, Gruneboom A, Gangfuss A, Roos A

Publication type: Article

Publication status: Published

Journal: Molecular Neurobiology

Year: 2023

Pages: Epub ahead of print

Online publication date: 24/01/2023

Acceptance date: 04/01/2023

Date deposited: 06/02/2023

ISSN (print): 0893-7648

ISSN (electronic): 1559-1182

Publisher: Springer


DOI: 10.1007/s12035-023-03219-9


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