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Lookup NU author(s): Dr Ana TopfORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Recessive variants in WASHC4 are linked to intellectual disability complicated by poor language skills, short stature, and dysmorphic features. The protein encoded by WASHC4 is part of the Wiskott–Aldrich syndrome protein and SCAR homolog family, co-localizes with actin in cells, and promotes Arp2/3-dependent actin polymerization in vitro. Functional studies in a zebrafish model suggested that WASHC4 knockdown may also affect skeletal muscles by perturbing protein clearance. However, skeletal muscle involvement has not been reported so far in patients, and precise biochemical studies allowing a deeper understanding of the molecular etiology of the disease are still lacking. Here, we report two siblings with a homozygous WASHC4 variant expanding the clinical spectrum of the disease and provide a phenotypical comparison with cases reported in the literature. Proteomic profiling of fibroblasts of the WASHC4-deficient patient revealed dysregulation of proteins relevant for the maintenance of the neuromuscular axis. Immunostaining on a muscle biopsy derived from the same patient confirmed dysregulation of proteins relevant for proper muscle function, thus highlighting an affliction of muscle cells upon loss of functional WASHC4. The results of histological and coherent anti-Stokes Raman scattering microscopic studies support the concept of a functional role of the WASHC4 protein in humans by altering protein processing and clearance. The proteomic analysis confirmed key molecular players in vitro and highlighted, for the first time, the involvement of skeletal muscle in patients. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Author(s): Gangfuss A, Czech A, Hentschel A, Munchberg U, Horvath R, Topf A, O'Heir E, Lochmuller H, Stehling F, Kiewert C, Sickmann A, Kuechler A, Kaiser FJ, Kolbel H, Christiansen J, Schara-Schmidt U, Roos A
Publication type: Article
Publication status: Published
Journal: Journal of Pathology
Year: 2022
Volume: 256
Issue: 1
Pages: 93-107
Print publication date: 01/01/2022
Online publication date: 02/10/2021
Acceptance date: 29/09/2021
Date deposited: 04/01/2022
ISSN (print): 0022-3417
ISSN (electronic): 1096-9896
Publisher: John Wiley and Sons Ltd
URL: https://doi.org/10.1002/path.5812
DOI: 10.1002/path.5812
PubMed id: 34599609
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