Human CHN1 mutations hyperactivate alpha2-chimaerin and cause Duane's retraction syndrome by Miyake Noriko, Chilton John, Psatha Maria, Cheng Long, Andrews Caroline, Chan Wai-Man, Law Krystal, Crosier Moira, Lindsay Susan, Cheung Michelle, Allen James, Gutowski Nick J, Ellard Sian, Young Elizabeth, Iannaccone Alessandro, Appukuttan Binoy, Stout J Timothy, Christiansen Stephen, Ciccarelli Maria Laura, Baldi Alfonso, Campioni Mara, Zenteno Juan C, Davenport Dominic, Mariani Laura E, Sahin Mustafa, Guthrie Sarah, Engle Elizabeth C in Science (New York, N.Y.) (2008).

[PMID: 18653847] PubMed


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.

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