PAthology
germline mutations of DCX in X-linked lissencephaly (X-linked subcortical laminar heterotopia) (XLIS/SCLH) (MIM.300067)
DCX mutations cause X-linked subcortical-band heterotopia (or double cortex) in females, owing to defective migration of some neurons, and lissencephaly in male.
Pathogenesis
Studies on DCX, further highlight the role of the centrosome in neuronal migration and support the notion that nucleokinesis is dependent on this organelle.
In migrating cells, microtubules that emanate from the centrosome form a cage-like microtubule network that surrounds the nucleus and possibly holds it in the correct position during cell movement.
DCX binds and stabilizes microtubules and interacts with LIS1, indicating that DCX and LIS1 might function together with dynein to link the centrosome and nucleus during neuronal migration.
Furthermore, the LIS1-NDEL1-dynein complex is required for the maintenance of the microtubule cage, as RNAi targeting of any of these genes leads to a disruption of this structure and the concomitant separation between the nucleus and the centrosome.
The centrosome is tethered to the leading edge and the nucleus through the microtubule network; LIS1, positioned at the centrosome, together with DCX, which is located in the nuclear microtubule ’cage’, might link the nucleus to the microtubule network and allow dynein to move the nucleus towards the centrosome.
References
Badano JL, Teslovich TM, Katsanis N. The centrosome in human genetic disease. Nat Rev Genet. 2005 Mar;6(3):194-205. PMID: 15738963