Show simple item record

dc.contributor.authorGangfuß, Andrea
dc.contributor.authorCzech, Artur
dc.contributor.authorHentschel, Andreas
dc.contributor.authorMünchberg, Ute
dc.contributor.authorHorvath, Rita
dc.contributor.authorTöpf, Ana
dc.contributor.authorO'Heir, Emily
dc.contributor.authorLochmüller, Hanns
dc.contributor.authorStehling, Florian
dc.contributor.authorKiewert, Cordula
dc.contributor.authorSickmann, Albert
dc.contributor.authorKuechler, Alma
dc.contributor.authorKaiser, Frank J
dc.contributor.authorKölbel, Heike
dc.contributor.authorChristiansen, Jon
dc.contributor.authorSchara-Schmidt, Ulrike
dc.contributor.authorRoos, Andreas
dc.date.accessioned2022-01-04T14:32:33Z
dc.date.available2022-01-04T14:32:33Z
dc.date.issued2022-01
dc.date.submitted2021-03-12
dc.identifier.issn0022-3417
dc.identifier.otherpath5812
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/331897
dc.descriptionFunder: European Regional Development Fund; Id: http://dx.doi.org/10.13039/501100008530
dc.description.abstractRecessive 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.languageen
dc.publisherWiley
dc.subjectOriginal Paper
dc.subjectOriginal Papers
dc.subjectKIAA1033
dc.subjectWASHC4
dc.subjectintellectual disability
dc.subjectdysmorphisms
dc.subjectfibroblast proteomics
dc.subjectmuscle autophagy
dc.subjectvalosin‐containing protein
dc.subjectcoherent anti‐Stokes Raman scattering microscopy
dc.titleHomozygous WASHC4 variant in two sisters causes a syndromic phenotype defined by dysmorphisms, intellectual disability, profound developmental disorder, and skeletal muscle involvement.
dc.typeArticle
dc.date.updated2022-01-04T14:32:32Z
prism.endingPage107
prism.issueIdentifier1
prism.publicationNameJ Pathol
prism.startingPage93
prism.volume256
dc.identifier.doi10.17863/CAM.79347
dcterms.dateAccepted2021-09-29
rioxxterms.versionofrecord10.1002/path.5812
rioxxterms.versionAO
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.contributor.orcidGangfuß, Andrea [0000-0002-9975-0092]
dc.contributor.orcidHorvath, Rita [0000-0002-9841-170X]
dc.contributor.orcidO'Heir, Emily [0000-0001-7669-8239]
dc.identifier.eissn1096-9896
pubs.funder-project-idWellcome Trust (109915_A_15_Z)
pubs.funder-project-idMedical Research Council (MR/N025431/2)
pubs.funder-project-idMRC (MR/V009346/1)
cam.issuedOnline2021-11-18


Files in this item

Thumbnail
Thumbnail

This item appears in the following Collection(s)

Show simple item record