Homozygous WASHC4 variant in two sisters causes a syndromic phenotype defined by dysmorphisms, intellectual disability, profound developmental disorder, and skeletal muscle involvement.
KIAA1033
WASHC4
coherent anti-Stokes Raman scattering microscopy
dysmorphisms
fibroblast proteomics
intellectual disability
muscle autophagy
valosin-containing protein
Journal
The Journal of pathology
ISSN: 1096-9896
Titre abrégé: J Pathol
Pays: England
ID NLM: 0204634
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
revised:
01
09
2021
received:
12
03
2021
accepted:
29
09
2021
pubmed:
3
10
2021
medline:
4
1
2022
entrez:
2
10
2021
Statut:
ppublish
Résumé
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.
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
93-107Subventions
Organisme : Wellcome Trust Pathfinder Scheme
ID : 201064/Z/16/Z
Organisme : Medical Research Council
ID : MR/N010035/1
Pays : United Kingdom
Organisme : NHGRI NIH HHS
ID : UM1 HG008900
Pays : United States
Organisme : Medical Research Council
ID : G1000848
Pays : United Kingdom
Organisme : Medical Research Council (UK)
ID : MR/N025431/1
Organisme : Wellcome Investigator Award
ID : 109915/Z/15/Z
Organisme : Medical Research Council
ID : MR/V009346/1
Pays : United Kingdom
Organisme : CIHR
ID : FDN-167281
Pays : Canada
Organisme : NHGRI NIH HHS
ID : R01 HG009141
Pays : United States
Organisme : Medical Research Council
ID : MR/N025431/2
Pays : United Kingdom
Organisme : Newton Fund UK/Turkey
ID : MR/N027302/1
Organisme : European Research Council
ID : 309548
Pays : International
Informations de copyright
© 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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