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

  • Science. 2008 Aug 8;321(5890):839-43. doi: 10.1126/science.1156121.
Noriko Miyake  1 ,  John Chilton ,  Maria Psatha ,  Long Cheng ,  Caroline Andrews ,  Wai-Man Chan ,  Krystal Law ,  Moira Crosier ,  Susan Lindsay ,  Michelle Cheung ,  James Allen ,  Nick J Gutowski ,  Sian Ellard ,  Elizabeth Young ,  Alessandro Iannaccone ,  Binoy Appukuttan ,  J Timothy Stout ,  Stephen Christiansen ,  Maria Laura Ciccarelli ,  Alfonso Baldi ,  Mara Campioni ,  Juan C Zenteno ,  Dominic Davenport ,  Laura E Mariani ,  Mustafa Sahin ,  Sarah Guthrie ,  Elizabeth C Engle
Affiliations
  • 1. Department of Medicine (Genetics), Children's Hospital Boston, Boston, MA 02115, USA.
PMID: 18653847 DOI: 10.1126/science.1156121
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.