| Summary: | The ciliopathies are a group of heterogeneous diseases with considerable variations in phenotypes for the different human ciliopathy conditions. Meckel-Gruber syndrome (MKS) and Joubert syndrome (JBTS) are allelic conditions even at the inter-individual level within families. In human patients mutations in the TMEM67 gene (also known as MKS3) cause both MKS and J8TS. TMEM67 encodes the orphan transmembrane receptor meckelin (TMEM67) that localizes to the ciliary transition zone. This study describes the Tmem6fm1(Dgen/H) knockout mouse model. Visceral organ malformations detected in Tmem67 mutant embryos and pups involved range of craniofacial malformations, laterality defects, pulmonary hypoplasia, polycystic kidneys, liver cysts and liver developmental disorders. Neither postaxial polydactyly nor preaxial polydactyly were detected in any mutant embryos or pups. Further characterization of this model showed extensive brain neuroanatomical malformations that recapitulate the brain phenotypic variability of the MKS and J8TS human ciliopathies. The cerebellum of all Tmem67 mutant animals in both phenotypic groups was hypoplastic with near consistency. This could be attributed to a combined midgestation reduction of canonical Wnt signalling and an early postnatal disturbed response to Shh stimulation. Morphologically, the forebrain was also reduced in the anteroposterior dimension. The ventral structure of the fully congenic forebrain was expanded at the expense of the dorsal structures. This indicated ventralization of the forebrain which could be attributed to increased Shh transcript levels in the forebrain . Tmem67 mutant animals could be categorized into two phenotypic groups. An "MKS-like" incipient congenic group (filial generations F6 to FIO) manifested very variable neurological features (including exencephaly, and frontal/occipital encephalocele) that were associated with loss of primary cilia and had high deregulated canonical Wnt/β-catenin signalling associated with hyper-activated Dishevelled-! (Dv1-1) localized to the basal body. Diminished levels of Shh Signalling were associated with dorsalization of the caudal neural tube. Conversely, a second fully congenic group (F>10) had less variable features pathognomonic for JBTS (including cerebellar hypoplasia), and retention of longer and bulbous cilia associated with mild neural tube ventralization. The "JBTS-like" group had de-regulated low levels of canonical Wnt signalling associated with loss of Dvl-1 localization to the basal body. These 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.
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