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Gangfuß A, Czech A, Hentschel 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. 2021;256(1):93-107doi: 10.1002/path.5812.
Gangfuß, A., Czech, A., Hentschel, A., Münchberg, U., Horvath, R., Töpf, A., O'Heir, E., Lochmüller, H., Stehling, F., Kiewert, C., Sickmann, A., Kuechler, A., Kaiser, F. J., Kölbel, H., Christiansen, J., Schara-Schmidt, U., & Roos, A. (2022). Homozygous WASHC4 variant in two sisters causes a syndromic phenotype defined by dysmorphisms, intellectual disability, profound developmental disorder, and skeletal muscle involvement. The Journal of pathology, 256(1), 93-107. https://doi.org/10.1002/path.5812
Gangfuß, Andrea, et al. "Homozygous WASHC4 variant in two sisters causes a syndromic phenotype defined by dysmorphisms, intellectual disability, profound developmental disorder, and skeletal muscle involvement." The Journal of pathology vol. 256,1 (2022): 93-107. doi: https://doi.org/10.1002/path.5812
Gangfuß A, Czech A, Hentschel A, Münchberg U, Horvath R, Töpf A, O'Heir E, Lochmüller H, Stehling F, Kiewert C, Sickmann A, Kuechler A, Kaiser FJ, Kölbel H, Christiansen J, Schara-Schmidt U, Roos A. 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. Epub 2021 Nov 18. PMID: 34599609.
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J Pathol. 2022 Jan;256(1):93-107. doi: 10.1002/path.5812. Epub 2021 Nov 18.

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

The Journal of pathology

Andrea Gangfuß, Artur Czech, Andreas Hentschel, Ute Münchberg, Rita Horvath, Ana Töpf, Emily O'Heir, Hanns Lochmüller, Florian Stehling, Cordula Kiewert, Albert Sickmann, Alma Kuechler, Frank J Kaiser, Heike Kölbel, Jon Christiansen, Ulrike Schara-Schmidt, Andreas Roos

Affiliations

  1. Department of Pediatric Neurology, Centre for Neuromuscular Disorders, Centre for Translational Neuro- and Behavioral Sciences, University Duisburg-Essen, Essen, Germany.
  2. Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany.
  3. Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
  4. The John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
  5. Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  6. Department of Neuropediatrics and Muscle Disorders, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany.
  7. Centro Nacional de Análisis Genómico (CNAG-CRG), Center for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
  8. Children's Hospital of Eastern Ontario Research Institute; Division of Neurology, Department of Medicine, The Ottawa Hospital; and Brain and Mind Research Institute, University of Ottawa, Ottawa, Canada.
  9. Children's Hospital, Department of Pneumology, University Hospital Essen, Essen, Germany.
  10. Children's Hospital, Department of Endocrinology, University Hospital Essen, Essen, Germany.
  11. Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
  12. Essener Zentrum für seltene Erkrankungen (EZSE), University Hospital Essen, University Duisburg-Essen, Essen, Germany.

PMID: 34599609 DOI: 10.1002/path.5812

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.

© 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Keywords: KIAA1033; WASHC4; coherent anti-Stokes Raman scattering microscopy; dysmorphisms; fibroblast proteomics; intellectual disability; muscle autophagy; valosin-containing protein

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