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

Miyake, Noriko, Chilton, John, Psatha, Maria, Cheng, Long, Andrews, Caroline, Chan, Wai-Man, Law, Krystal, Crosier, Moira, Lindsay, Susan, Cheung, Michelle, Guthrie, Sarah and et al, (2008) Human CHN1 mutations hyperactivate 2-chimaerin and cause Duane's retraction syndrome. Science, 321 (5890). pp. 839-843. ISSN 0036-8075

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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 α2-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 α2-chimaerin RacGAP activity in vitro. Several of the mutations appeared to enhance α2-chimaerin translocation to the cell membrane or enhance its ability to self-associate. Expression of mutant α2-chimaerin constructs in chick embryos resulted in failure of oculomotor axons to innervate their target extraocular muscles. We conclude that α2-chimaerin has a critical developmental function in ocular motor axon pathfinding.

Item Type: Article
Schools and Departments: School of Life Sciences > Neuroscience
Depositing User: Catrina Hey
Date Deposited: 28 Jun 2017 11:40
Last Modified: 28 Jun 2017 11:40
URI: http://sro.sussex.ac.uk/id/eprint/68845
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