Ciliopathy in PCS (MVA) syndrome

The spindle assembly checkpoint (SAC) is a surveillance mechanism of faithful chromosome segregation during mitosis. Budding uninhibited by benzimidazole-related-1 (BubR1) plays a central role in the SAC through inhibition of anaphase promoting complex/cyclosome (APC/C) activity until all chromosomes have established proper attachment to the mitotic spindle. Loss-of-function mutations in the BUB1B gene, encoding BubR1, cause a rare autosomal recessive disorder: premature chromatid separation (PCS) syndrome (Mendelian Inheritance in Man [MIM] 176430), which is also known as mosaic variegated aneuploidy (MVA) syndrome (MIM 257300) [1]. PCS (MVA) syndrome can also be caused by an intergenic mutation 44-kb upstream of the BUB1B gene, which suppresses the transcription level of BUB1B [2]. PCS (MVA) syndrome is cytogenetically characterized by PCS in > 50% of metaphase cells as well as the presence of mosaic aneuploidy [2]. Patients with the syndrome show an increased genetic predisposition to Wilms tumor and rhabdomyosarcoma, which may be attributed to the loss of SAC function. Patients also present with cataracts, uncontrollable chronic seizures, Dandy-Walker complex, polycystic kidneys and obesity. These clinical symptoms imply an additional function of BubR1 other than SAC in the context of morphogenesis. The primary cilium is a hair-like, microtubule-based, nonmotile organelle formed on the surface of quiescent mammalian cells. It receives extracellular information and transmits signals required for cell proliferation, tissue development, and tissue homeostasis. Ciliary dysfunction is causally linked to the group of human disorders known as ciliopathies, which include Bardet-Biedl syndrome, nephronophthisis, Meckel-Gruber syndrome, Joubert syndrome, and Oral-facial-digit syndrome. To date, more than 50 loci associated with ciliopathy have been reported. In addition to these, Baker and Beales proposed that at least 193 diseases in the Online Mendelian Inheritance in Men database (OMIM, www.ncbi.nlm.nih.gov/sites/entrez?db = OMIM) can potentially be categorized as ciliopathies [3]. Patients with a ciliopathy show a series of clinical features including polycystic kidneys, polydactyly, obesity, situs inversus, and neuronal and other developmental abnormalities. Overlap of the clinical spectrum of PCS (MVA) syndrome with those of the ciliopathies has led us to explore whether BubR1 is required for primary cilium formation. We found that skin fibroblasts from PCS (MVA) patients exhibit impaired ciliogenesis, thus PCS (MVA) syndrome is a ciliopathy [4]. Interestingly, BubR1-knockdown medaka fish also showed ciliopathy-like phenotypes, such as defective cerebellar development and disrupted left-right asymmetry of the embryo. These results indicated that the role of BubR1 in primary cilium formation is conserved among vertebrates [4]. However, little is …