Human CHN1 mutations hyperactivate alpha2-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 alpha2-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 alpha2-chimaerin RacGAP activity in vitro. Several of the mutations appeared to enhance alpha2-chimaerin translocation to the cell membrane or enhance its ability to self-associate. Expression of mutant alpha2-chimaerin constructs in chick embryos resulted in failure of oculomotor axons to innervate their target extraocular muscles. We conclude that alpha2-chimaerin has a critical developmental function in ocular motor axon pathfinding.
Miyake, N; Chilton, J; Psatha, M; Cheng, L; Andrews, C; Chan, W-M; Law, K; Crosier, M; Lindsay, S; Cheung, M; Allen, J; Gutowski, NJ; Ellard, S; Young, E; Iannaccone, A; Appukuttan, B; Stout, JT; Christiansen, S; Ciccarelli, ML; Baldi, A; Campioni, M; Zenteno, JC; Davenport, D; Mariani, LE; Sahin, M; Guthrie, S; Engle, EC
Volume / Issue
Start / End Page
Pubmed Central ID
Electronic International Standard Serial Number (EISSN)
Digital Object Identifier (DOI)