2. Academic Validation
  3. Human CHN1 mutations hyperactivate alpha2-chimaerin and cause Duane's retraction syndrome

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

Affiliation

  • 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.

Figures