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Homozygous WASHC4 variant in two sisters causes a syndromic phenotype defined by dysmorphisms, intellectual disability, profound developmental disorder, and skeletal muscle involvement

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.

Publication metadata

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


DOI: 10.1002/path.5812

PubMed id: 34599609


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Funder referenceFunder name
... (MR/N025431/1), the Wellcome Trust Pathfinder Scheme (201064/Z/16/Z), the Newton Fund (UK/Turkey, MR/N027302/1), the Lily Foundation, and the Evelyn Trust.
and in part by National Human Genome Research Institute grant R01 HG009141.
AT is supported by the Horizon 2020 research and innovation program via grant 779257 ‘Solve-RD’.
European Reference Network for Neuromuscular Diseases – Project ID No 870177.
framework of the NME-GPS project by the European Regional Development Fund (ERDF).
HL receives support from the Canadian Institutes of Health Research (Foundation Grant FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst
Lung and Blood Institute grant UM1 HG008900,
French Muscular Dystrophy Association (AFM-Téléthon) (#21466) to AR.
Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279).
Leibniz Research Cluster (grant number 031A360E)
RH was supported by the European Research Council (309548), a Wellcome Investigator Award (109915/Z/15/Z), the Medical Research Council (UK) ...