PUBLICATION
The novel zebrafish model pretzel demonstrates a central role for SH3PXD2B in defective collagen remodelling and fibrosis in Frank-Ter Haar syndrome
- Authors
- de Vos, I.J.H.M., Wong, A.S.W., Taslim, J., Ong, S.L.M., Syder, N.C., Goggi, J.L., Carney, T.J., van Steensel, M.A.M.
- ID
- ZDB-PUB-201126-3
- Date
- 2020
- Source
- Biology Open 9(12): (Journal)
- Registered Authors
- Carney, Tom
- Keywords
- ECM remodelling, FTHS, Fibrosis, SH3PXD2B
- MeSH Terms
-
- Adaptor Proteins, Signal Transducing/genetics*
- Adaptor Proteins, Signal Transducing/metabolism
- Animals
- Collagen/metabolism*
- Craniofacial Abnormalities/etiology*
- Craniofacial Abnormalities/metabolism*
- Craniofacial Abnormalities/pathology
- Dermis/metabolism
- Dermis/pathology
- Developmental Disabilities/etiology
- Developmental Disabilities/metabolism
- Developmental Disabilities/pathology
- Disease Models, Animal
- Drosophila Proteins/genetics*
- Drosophila Proteins/metabolism
- Extracellular Matrix/metabolism
- Fibrosis
- Gene Editing
- Heart Defects, Congenital/etiology*
- Heart Defects, Congenital/metabolism*
- Heart Defects, Congenital/pathology
- Immunohistochemistry
- Mutation
- Osteochondrodysplasias/congenital*
- Osteochondrodysplasias/etiology
- Osteochondrodysplasias/metabolism
- Osteochondrodysplasias/pathology
- Phenotype
- Zebrafish
- PubMed
- 33234702 Full text @ Biol. Open
Citation
de Vos, I.J.H.M., Wong, A.S.W., Taslim, J., Ong, S.L.M., Syder, N.C., Goggi, J.L., Carney, T.J., van Steensel, M.A.M. (2020) The novel zebrafish model pretzel demonstrates a central role for SH3PXD2B in defective collagen remodelling and fibrosis in Frank-Ter Haar syndrome. Biology Open. 9(12):.
Abstract
Frank-Ter Haar syndrome (FTHS, MIM #249420) is a rare skeletal dysplasia within the Defective Collagen Remodelling Spectrum (DECORS), which is characterised by craniofacial abnormalities, skeletal malformations and fibrotic soft tissues changes including dermal fibrosis and joint contractures. FTHS is caused by homozygous or compound heterozygous loss-of-function mutation or deletion of SH3PXD2B (Src homology 3 and Phox homology domain-containing protein 2B; MIM #613293). SH3PXD2B encodes an adaptor protein with the same name, which is required for full functionality of podosomes, specialised membrane structures involved in extracellular matrix (ECM) remodelling. The pathogenesis of DECORS is still incompletely understood and, as a result, therapeutic options are limited. We previously generated an mmp14a/b knockout zebrafish and demonstrated that it primarily mimics the DECORS-related bone abnormalities. Here, we present a novel sh3pxd2b mutant zebrafish, pretzel, which primarily reflects the DECORS-related dermal fibrosis and contractures. In addition to relatively mild skeletal abnormalities, pretzel mutants develop dermal and musculoskeletal fibrosis, contraction of which seems to underlie grotesque deformations that include kyphoscoliosis, abdominal constriction and lateral folding. The discrepancy in phenotypes between mmp14a/b and sh3pxd2b mutants suggests that in fish, as opposed to humans, there are differences in spatiotemporal dependence of ECM remodelling on either sh3pxd2b or mmp14a/b The pretzel model presented here can be used to further delineate the underlying mechanism of the fibrosis observed in DECORS, as well as screening and subsequent development of novel drugs targeting DECORS-related fibrosis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping