No abstract

Joubert syndrome (JBTS) and Meckel-Gruber syndrome (MKS) are rare recessive disorders caused by defects of cilia, and they share overlapping clinical features and allelic loci. Mutations of MKS1 contribute approximately 7% to all MKS cases and are found in some JBTS patients. Here, we describe a JBTS patient with two novel mutations of MKS1. Whole exome sequencing (WES) revealed c.191-1G > A and c.1058delG compound heterozygous variants. The patient presented with typical cerebellar vermis hypoplasia, hypotonia, and developmental delay, but without other renal/hepatic involvement or polydactyly. Functional studies showed that the c.1058delG mutation disrupts the B9 domain of MKS1, attenuates the interactions with B9D2, and impairs its ciliary localization at the transition zone (TZ), indicating that the B9 domain of MKS1 is essential for the integrity of the B9 protein complex and localization of MKS1 at the TZ. This work expands the mutation spectrum of MKS1 and elucidates the clinical heterogeneity of MKS1-related ciliopathies.

IFT74 is identified as a Joubert syndrome-associated gene in a Chinese cohort. The variants disrupt intraflagellar transport and ciliary signaling.

Cilia assembly and centriole duplication are closely coordinated with cell cycle progression, and inhibition of cilia disassembly impedes cell cycle progression. The centrosomal protein trichoplein (TCHP) has been shown to promote cell cycle progression in the G 1 -S phase by disassembling cilia. In this study, we showed that deletion of TCHP not only prevented the progression to the S phase but also resulted in cell cycle exit and entrance into G 0 phase. Surprisingly, we found that loss of TCHP-induced G 0 arrest could not be reversed by blocking the assembly of cilia.In cells without IFT20 or CEP164, two genes encoding key factors for ciliogenesis, depletion of TCHP still led to G 0 arrest. Mechanistically, we also found that TCHP depletion-induced cell cycle arrest was not mediated through a centrosome surveillance mechanism, but inhibition of Rb or concomitant inhibition of both Rb and p53 signaling pathways was required to reverse the cell cycle phenotype. In conclusion, our study provides new insights into the function of TCHP in cell cycle progression.