title: 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.
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.
authors.affiliation: Ciliopathy Research Group, Section of Ophthalmology and Neurosciences, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK.
authors.forename: Zakia A
authors.initials: ZA
authors.lastname: Abdelhamed
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Wheway
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Szymanska
authors.forename: Subaashini
authors.initials: S
authors.lastname: Natarajan
authors.forename: Carmel
authors.initials: C
authors.lastname: Toomes
authors.forename: Chris
authors.initials: C
authors.lastname: Inglehearn
authors.forename: Colin A
authors.initials: CA
authors.lastname: Johnson
mesh_terms: D000015:Abnormalities, Multiple; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D019521:Body Patterning / Q000235:genetics; D002526:Cerebellar Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002531:Cerebellum / Q000002:abnormalities; D002923:Cilia / Q000473:pathology; D002925:Ciliary Motility Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D000072261:Dishevelled Proteins; D004677:Encephalocele / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005124:Eye Abnormalities / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049409:Luciferases, Firefly / Q000096:biosynthesis / Q000235:genetics; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009436:Neural Tube Defects / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism; D007690:Polycystic Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D021381:Protein Transport; D012160:Retina / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D012174:Retinitis Pigmentosa; D060449:Wnt Signaling Pathway
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000606578:DVL1 protein, human; D000072261:Dishevelled Proteins; C000606579:Dvl1 protein, mouse; D053823:Hedgehog Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; C465570:Shh protein, mouse; C583064:TMEM67 protein, mouse; D049409:Luciferases, Firefly