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Science. 2008 Aug 8;321(5890):839-43. doi: 10.1126/science.1156121. Epub 2008 Jul 24.

Human CHN1 mutations hyperactivate alpha2-chimaerin and cause Duane's retraction syndrome.

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  • 1Department of Medicine (Genetics), Children's Hospital Boston, Boston, MA 02115, USA.

Abstract

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.

PMID:
18653847
[PubMed - indexed for MEDLINE]
PMCID:
PMC2593867
Free PMC Article
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