Human CHN1 Mutations Hyperactivate α2-Chimaerin and Cause Duane's Retraction Syndrome

• Published in: Science (American Association for the Advancement of Science) 2008-08, Vol.321 (5890), p.839-843
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Axons; Embryos; Genetic mutation; Messenger RNA; Midbrain; Motor neurons; Nerves; Neurons; Oculomotor nerve; Visual fixation
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1156121

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.