Zakia A. Abdelhamed
Variable expressivity of ciliopathy neurological phenotypes that encompass Meckel - Gruber syndrome and Joubert syndrome is caused by complex de-regulated ciliogenesis, Shh and wnt signalling defects
Abdelhamed, Zakia A.; Wheway, Gabrielle; Szymanska, Katarzyna; Natarajan, Subaashini; Toomes, Carmel; Inglehearn, Chris; Johnson, Colin A.
Authors
Gabrielle Wheway Gabrielle.Wheway@uwe.ac.uk
Occasional Associate Lecturer - CHSS - DAS
Katarzyna Szymanska
Subaashini Natarajan
Carmel Toomes
Chris Inglehearn
Colin A. Johnson
Abstract
The ciliopathies are a group of heterogeneous diseases with considerable variations in phenotype for allelic conditions such as Meckel-Gruber syndrome (MKS) and Joubert syndrome (JBTS) even at the inter-individual level within families. In humans, mutations in TMEM67 (also known as MKS3) cause both MKS and JBTS, with TMEM67 encoding the orphan receptor meckelin (TMEM67) that localizes to the ciliary transition zone. We now describe the Tmem67tm1(Dgen/H) knockout mouse model that recapitulates the brain phenotypic variability of these human ciliopathies, with categorization of Tmem67 mutant animals into two phenotypic groups. An MKS-like incipient congenic group (F6 to F10) manifested very variable neurological features (including exencephaly, and frontal/occipital encephalocele) that were associated with the loss of primary cilia, diminished Shh signalling and dorsalization of the caudal neural tube. The 'MKS-like' group also had high de-regulated canonical Wnt/β-catenin signalling associated with hyper-activated Dishevelled-1 (Dvl-1) localized to the basal body. Conversely, a second fully congenic group (F > 10) had less variable features pathognomonic for JBTS (including cerebellar hypoplasia), and retention of abnormal bulbous cilia associated with mild neural tube ventralization. The 'JBTS-like' group had de-regulated low levels of canonical Wnt signalling associated with the loss of Dvl-1 localization to the basal body. Our results suggest that modifier alleles partially determine the variation between MKS and JBTS, implicating the interaction between Dvl-1 and meckelin, or other components of the ciliary transition zone. The Tmem67tm1(Dgen/H) line is unique in modelling the variable expressivity of phenotypes in these two ciliopathies. © The Author 2013. Published by Oxford University Press. All rights reserved.
Journal Article Type | Article |
---|---|
Acceptance Date | Dec 20, 2012 |
Publication Date | Apr 1, 2013 |
Deposit Date | Jun 7, 2016 |
Journal | Human Molecular Genetics |
Print ISSN | 0964-6906 |
Electronic ISSN | 1460-2083 |
Publisher | Oxford University Press (OUP) |
Peer Reviewed | Peer Reviewed |
Volume | 22 |
Issue | 7 |
Pages | 1358-1372 |
DOI | https://doi.org/10.1093/hmg/dds546 |
Public URL | https://uwe-repository.worktribe.com/output/936497 |
Publisher URL | http://dx.doi.org/10.1093/hmg/dds546 |
Contract Date | Jun 7, 2016 |
You might also like
The role of primary cilia in the development and disease of the retina
(2013)
Journal Article
Atmin is a transcriptional regulator of both lung morphogenesis and ciliogenesis
(2014)
Journal Article
Downloadable Citations
About UWE Bristol Research Repository
Administrator e-mail: repository@uwe.ac.uk
This application uses the following open-source libraries:
SheetJS Community Edition
Apache License Version 2.0 (http://www.apache.org/licenses/)
PDF.js
Apache License Version 2.0 (http://www.apache.org/licenses/)
Font Awesome
SIL OFL 1.1 (http://scripts.sil.org/OFL)
MIT License (http://opensource.org/licenses/mit-license.html)
CC BY 3.0 ( http://creativecommons.org/licenses/by/3.0/)
Powered by Worktribe © 2024
Advanced Search