Joubert syndrome is an inherited disorder that affects the area of the brain that controls balance and coordination; it is characterized by symptoms such as loss of muscle tone, developmental delay, and mental retardation. Mutations in several genes have been associated with Joubert syndrome. The mutations in one of these, AHI1, are known to generate truncated forms of the AHI1 protein but how this contributes to the development of disease has not been determined. However, Xiao-Jiang Li and colleagues have now provided insight into this issue by showing that mouse Ahi1 interacts with the protein Hap1, which is critical for neonatal development.
In the study, it was found that Ahi1 binds tightly to Hap1 and that they form a stable complex in the mouse brain. Further analysis indicated that the two proteins stabilize each other and that truncated mouse Ahi1 that resembled the truncated AHI1 protein observed in individuals with Joubert syndrome was unable to stabilize mouse Hap1. The ability of Hap1 and Ahi1 to stabilize each other was important for maintaining levels of the protein TrkB, which is critical for the generation of nerves and brain development. These data have provided insight into the mechanisms underlying disease in individuals with Joubert syndrome associated with AHI1 mutations and might provide new targets for the development of novel therapeutic approaches.