Duane's retraction syndrome (DRS) is a complex congenital eye movement disorder that can be associated with absence of the abducens cranial nerve and motor neurons. By studying families with a variant form of this disorder (DURS2-DRS), we identified causative heterozygous missense mutations in CHN1, a gene on chromosome 2q31 that encodes alpha2-chimaerin. Alpha2-chimaerin is a Rac guanosine triphosphatase-activating protein (RacGAP) known to be highly expressed in developing neurons. We demonstrated that DURS2-DRS results from gain-of-function mutations that increase alpha2-chimaerin RacGAP activity in vitro. Several mutations enhance alpha2-chimaerin’s translocation to the cell membrane or enhance its ability to self-associate. Expression of mutant alpha2-chimaerin constructs in chick embryos resulted in the failure of oculomotor axons to innervate their target extraocular muscles. It thus appears that alpha2-chimaerin has a critical developmental function in ocular motor axon guidance.
We are using genetic engineering to further study the role of wildtype and mutant alpha2-chimaerin in axon guidance and pathfinding.