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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

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dc.contributor.author Gangfuß, Andrea
dc.contributor.author Czech, Artur
dc.contributor.author Hentschel, Andreas
dc.contributor.author Münchberg, Ute
dc.contributor.author Horvath, Rita
dc.contributor.author Töpf, Ana
dc.contributor.author O'Heir, Emily
dc.contributor.author Lochmüller, Hanns
dc.contributor.author Stehling, Florian
dc.contributor.author Kiewert, Cordula
dc.contributor.author Sickmann, Albert
dc.contributor.author Kuechler, Alma
dc.contributor.author Kaiser, Frank J.
dc.contributor.author Kölbel, Heike
dc.contributor.author Christiansen, Jon
dc.contributor.author Schara-Schmidt, Ulrike
dc.contributor.author Roos, Andreas
dc.date.accessioned 2022-01-31T12:39:25Z
dc.date.available 2022-01-31T12:39:25Z
dc.date.issued 2022
dc.identifier.citation Gangfuss A, Czech A, Hentschel A, Münchberg U, Horvath R, Töpf A et al. Homozygous WASHC4 variant in two sisters causes a syndromic phenotype defined by dysmorphisms, intellectual disability, profound developmental disorder, and skeletal muscle involvement. J Pathol. 2022 Jan; 256(1): 93-107. DOI: 10.1002/path.5812
dc.identifier.issn 1096-9896
dc.identifier.uri http://hdl.handle.net/10230/52375
dc.description.abstract 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 Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
dc.description.sponsorship This study was supported by four authors of this publication who are members of the European Reference Network for Neuromuscular Diseases – Project ID No 870177. This study was supported also by the ‘Ministerium für Kultur und Wissenschaft des Landes Nordrhein-Westfalen’, the ‘Regierenden Bürgermeister von Berlin – Senatskanzlei Wissenschaft und Forschung’, and the ‘Bundesministerium für Bildung und Forschung’, also in form of the Leibniz Research Cluster (grant number 031A360E). This work was also supported by a grant from the French Muscular Dystrophy Association (AFM-Téléthon) (#21466) to AR. RH was supported by the European Research Council (309548), a Wellcome Investigator Award (109915/Z/15/Z), the Medical Research Council (UK) (MR/N025431/1), the Wellcome Trust Pathfinder Scheme (201064/Z/16/Z) and the Newton Fund (UK/Turkey, MR/N027302/1). 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 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). Parts of this study were financed within the framework of the NME-GPS project by the European Regional Development Fund (ERDF). AT is supported by the Horizon 2020 research and innovation program via grant 779257 ‘Solve-RD’. Sequencing and analysis were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and were funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute grant UM1 HG008900, and in part by National Human Genome Research Institute grant R01 HG009141
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Wiley
dc.rights © 2021 Andrea Ganfuss et al. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.other Fenotip
dc.subject.other Malformacions
dc.subject.other Deficiència mental
dc.subject.other Trastorns del desenvolupament
dc.subject.other Autofàgia
dc.title Homozygous WASHC4 variant in two sisters causes a syndromic phenotype defined by dysmorphisms, intellectual disability, profound developmental disorder, and skeletal muscle involvement
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1002/path.5812
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/779257
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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