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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

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
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
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 Tmem67(tm1(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 Tmem67(tm1(Dgen/H)) line is unique in modelling the variable expressivity of phenotypes in these two ciliopathies.
0964-6906
1358-1372
Abdelhamed, Z.
b4ff1341-981a-4c9b-8e4a-f7ae4e5d7c9d
Wheway, G.
2e547e5d-b921-4243-a071-2208fd4cc090
Szymanska, K.
c2757637-5dba-453e-9fc6-718089332294
Natarajan, S.
0eb6b648-d7c9-4589-ab2c-a317e402f959
Toomes, C.
d956aaa4-457f-4cd5-951b-7b9449b83309
Inglehearn, C.
21dedb2c-9fa2-4c7d-b68b-74545036bd08
Johnson, C.A.
221db283-bc51-4c0e-bdc9-36b4c499e55a
Abdelhamed, Z.
b4ff1341-981a-4c9b-8e4a-f7ae4e5d7c9d
Wheway, G.
2e547e5d-b921-4243-a071-2208fd4cc090
Szymanska, K.
c2757637-5dba-453e-9fc6-718089332294
Natarajan, S.
0eb6b648-d7c9-4589-ab2c-a317e402f959
Toomes, C.
d956aaa4-457f-4cd5-951b-7b9449b83309
Inglehearn, C.
21dedb2c-9fa2-4c7d-b68b-74545036bd08
Johnson, C.A.
221db283-bc51-4c0e-bdc9-36b4c499e55a

Abdelhamed, Z., Wheway, G., Szymanska, K., Natarajan, S., Toomes, C., Inglehearn, C. and Johnson, C.A. (2013) 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. Human Molecular Genetics, 22 (7), 1358-1372. (doi:10.1093/hmg/dds546).

Record type: Article

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 Tmem67(tm1(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 Tmem67(tm1(Dgen/H)) line is unique in modelling the variable expressivity of phenotypes in these two ciliopathies.

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Accepted/In Press date: 20 December 2012
e-pub ahead of print date: 2 January 2013
Published date: 1 April 2013

Identifiers

Local EPrints ID: 423520
URI: https://eprints.soton.ac.uk/id/eprint/423520
ISSN: 0964-6906
PURE UUID: c3a80cb2-5b2a-4c06-8d7c-946562e83279
ORCID for G. Wheway: ORCID iD orcid.org/0000-0002-0494-0783

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Date deposited: 25 Sep 2018 16:30
Last modified: 14 Mar 2019 01:21

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Contributors

Author: Z. Abdelhamed
Author: G. Wheway ORCID iD
Author: K. Szymanska
Author: S. Natarajan
Author: C. Toomes
Author: C. Inglehearn
Author: C.A. Johnson

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