Tmem67-flox Mouse

TMEM67, also known as mecklin or MKS3, is a component of the multiprotein complex functioning as a gatekeeper at the transition zone (TZ) of primary cilia [2,4]. It is involved in ciliogenesis, cilium length regulation, and the gating function of the TZ that controls entry of membrane-associated proteins ARL13B and INPP5E into primary cilia [2]. Additionally, it participates in the canonical Wnt/β-catenin signalling pathway in the developing cerebellum via Hoxb5 [5].

In the Tmem67tm1(Dgen)/H knockout mouse, at mid-gestation, the cerebella were hypoplastic with aberrantly high canonical Wnt/β-catenin signalling, proliferation and apoptosis. Later, there were severe foliation defects and inferior lobe malformation in the cerebellar hemispheres, along with disrupted ciliogenesis and reduced Shh signalling responsiveness in the early postnatal cerebellum [5]. In humans, mutations in TMEM67 are associated with ciliopathies, such as Joubert syndrome, where individuals with pathogenic variants in TMEM67 have a significantly higher risk of liver fibrosis [1,3]. There are also associations with mild phenotypes of high gamma-glutamyl transpeptidase cholestasis and congenital hepatic fibrosis [4].

In conclusion, TMEM67 is essential for cilia-related functions and Wnt signalling in the developing cerebellum. Mouse knockout models have revealed its role in ciliopathy-associated phenotypes, especially those related to the cerebellum, liver, and potentially other organs affected in ciliopathies. These findings contribute to understanding the molecular mechanisms underlying ciliopathies and related diseases.