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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.
- Source :
-
Human molecular genetics [Hum Mol Genet] 2013 Apr 01; Vol. 22 (7), pp. 1358-72. Date of Electronic Publication: 2013 Jan 02. - Publication Year :
- 2013
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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.
- Subjects :
- Abnormalities, Multiple
Adaptor Proteins, Signal Transducing metabolism
Animals
Body Patterning genetics
Cerebellar Diseases genetics
Cerebellar Diseases pathology
Cerebellum abnormalities
Cilia pathology
Ciliary Motility Disorders genetics
Ciliary Motility Disorders pathology
Disease Models, Animal
Dishevelled Proteins
Encephalocele genetics
Encephalocele pathology
Eye Abnormalities genetics
Eye Abnormalities pathology
Gene Expression Regulation
Genes, Reporter
HEK293 Cells
Humans
Kidney Diseases, Cystic genetics
Kidney Diseases, Cystic pathology
Luciferases, Firefly biosynthesis
Luciferases, Firefly genetics
Membrane Proteins deficiency
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Neural Tube Defects genetics
Neural Tube Defects metabolism
Neural Tube Defects pathology
Phenotype
Phosphoproteins metabolism
Polycystic Kidney Diseases genetics
Polycystic Kidney Diseases pathology
Protein Transport
Retina abnormalities
Retina metabolism
Retina pathology
Retinitis Pigmentosa
Cerebellar Diseases metabolism
Ciliary Motility Disorders metabolism
Encephalocele metabolism
Eye Abnormalities metabolism
Hedgehog Proteins metabolism
Kidney Diseases, Cystic metabolism
Membrane Proteins genetics
Polycystic Kidney Diseases metabolism
Wnt Signaling Pathway
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2083
- Volume :
- 22
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Human molecular genetics
- Publication Type :
- Academic Journal
- Accession number :
- 23283079
- Full Text :
- https://doi.org/10.1093/hmg/dds546