Editors' ChoiceMEDICINE

Axonal Pathfinding in Sight

Science Signaling  12 Aug 2008:
Vol. 1, Issue 32, pp. ec291
DOI: 10.1126/scisignal.132ec291

About 1 in 1000 people are afflicted with Duane’s retraction syndrome (DRS), a complex congenital eye disorder characterized by a restricted ability to move the eye(s) outward or inward. The condition is thought to arise from faulty innervation of extraocular muscles by cranial motor neurons, which probably occurs early in embryogenesis. Miyake et al. now provide genetic evidence that strongly supports this hypothesis. Studying families with a variant form of DRS, the authors discovered that the mutations responsible for the disorder fall within a gene on chromosome 2 encoding α2-chimaerin, a RacGAP signaling protein previously implicated in axonal pathfinding of corticospinal nerves in mice. The human mutations cause α2-chimaerin to become overactive, and expression of the mutant protein in a chick embryo model did indeed disrupt oculomotor axon development.

N. Miyake, J. Chilton, M. Psatha, L. Cheng, C. Andrews, W.-M. Chan, K. Law, M. Crosier, S. Lindsay, M. Cheung, J. Allen, N. J. Gutowski, S. Ellard, E. Young, A. Iannaccone, B. Appukuttan, J. T. Stout, S. Christiansen, M. L. Ciccarelli, A. Baldi, M. Campioni, J. C. Zenteno, D. Davenport, L. E. Mariani, M. Sahin, S. Guthrie, E. C. Engle, Human CHN1 mutations hyperactivate α2-chimaerin and cause Duane's retraction syndrome. Science 321, 839-843 (2008). [Abstract] [Full Text]