Patient Mutations in Doublecortin Define a Repeated Tubulin-binding Domain*

Doublecortin (DCX) missense mutations are found in two clusters in patients with defective cortical neuronal migration. Although DCX can function as a microtubule-associated protein (MAP), the potential relationship be-tween its MAP activity and neuronal migration is not understood. Here we show that the two clusters of pa-tient mutations precisely define an internal tandem re-peat. Each repeat alone binds tubulin, whereas neither repeat is sufficient for co-assembly with microtubules. The two tandem repeats are sufficient to mediate micro-tubule polymerization, and representative patient mis-sense mutations lead to impaired polymerization both in vitro and in vivo as well as impaired microtubule stabilization. Furthermore, each repeat is predicted to have the secondary structure of a b-grasp superfold mo