Human CHN1 mutations hyperactivate 2-chimaerin and cause Duane's retraction syndrome

Duane's retraction syndrome (DRS) is a complex congenital eye movement disorder caused by aberrant innervation of the extraocular muscles by axons of brainstem motor neurons. Studying families with a variant form of the disorder (DURS2-DRS), we have identified causative heterozygous missense mutations in CHN1, a gene on chromosome 2q31 that encodes a2-chimaerin, a Rac guanosine triphosphatase–activating protein (RacGAP) signaling protein previously implicated in the pathfinding of corticospinal axons in mice. We found that these are gain-of-function mutations that increase a2-chimaerin RacGAP activity in vitro. Several of the mutations appeared to enhance a2-chimaerin translocation to the cell membrane or enhance its ability to self-associate. Expression of mutant a2-chimaerin constructs in chick embryos resulted in failure of oculomotor axons to innervate their target extraocular muscles. We conclude that a2-chimaerin has a critical developmental function in ocular motor axon pathfinding.