TALPID3 controls centrosome and cell polarity and the human ortholog KIAA0586 is mutated in Joubert syndrome (JBTS23)

摘要

Joubert syndrome is a rare and severe neurodevelopmental disease in which two parts of the brain called the cerebellar vermis and brainstem do not develop properly. The disease is caused by defects in the formation of small projections from the surface of cells, called cilia, which are essential for signalling processes inside cells. Mutations in at least 25 genes are known to cause Joubert syndrome, and all encode proteins that create or maintain cilia. However, these mutations account for only half of the cases that have been studied, which indicates that mutations in other genes may also cause Joubert syndrome. Here, Stephen et al. used genetic techniques called ‘homozygosity mapping’ and ‘whole-exome sequencing’ to search for other mutations that might cause the disease. They found that mutations in a gene encoding a protein called KIAA0586 also cause Joubert syndrome in humans. One of these mutations (c.428delG) is unexpectedly common in the healthy human population. It might be a major contributor to Joubert syndrome, and the manifestation of Joubert syndrome in individuals with this mutation might depend on the presence and nature of other mutations in KIAA0586 and in other genes. The TALPID3 protein in chickens and other ‘model’ animals is the equivalent of human KIAA0586. A loss of TALPID3 protein in animals has been shown to stop cilia from forming. This protein is found in a structure called the basal body, which is part of a larger structure called the centrosome that anchors cilia to the cell. Here, Stephen et al. show that this is also true in mouse and human eye cells. Further experiments using chicken embryos show that a loss of the TALPID3 protein alters the location of centrosomes inside cells. TALPID3 is also required for cells and organs to develop the correct polarity, that is, directional differences in their structure and shape. The centrosomes of chicken brain cells that lacked TALPID3 were poorly positioned at the cell surface and abnormally long, which is likely responsible for the cilia failing to form. Stephen et al.'s findings suggest that KIAA0586 is also important for human development through its ability to control the centrosome. Defects in TALPID3 have a more severe effect on animal models than many of the identified KIAA0586 mutations have on humans. Therefore, the next step in this research is to find a more suitable animal in which to study the role of this protein, which may inform efforts to develop treatments for Joubert syndrome.