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

Noriko Miyake, John Chilton, Maria Psatha, Long Cheng, Stuart Christopher Andrews, Wai-Man Chan, Krystal Law, Moira Crosier, Sandra Lindsay, Michelle Cheung, James Allen, Nick J Gutowski, Sian Ellard, Elizabeth Iona Margaret Young, Alessandro Iannaccone, Binoy Appukuttan, J Timothy Stout, Stephen Christiansen, Maria Laura Ciccarelli, Alfonso BaldiMara Campioni, Juan C Zenteno, Dominic Davenport, Laura E Mariani, Mustafa Sahin, Sarah Guthrie, Elizabeth C Engle

Research output: Contribution to journalArticlepeer-review

130 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)839-843
Number of pages5
Issue number5890
Early online date24 Jul 2008
Publication statusPublished - 8 Aug 2008


  • Abducens Nerve
  • Amino Acid Sequence
  • Animals
  • Axons
  • Cell Line
  • Cell Membrane
  • Chick Embryo
  • Chimerin 1
  • Duane Retraction Syndrome
  • Female
  • Gene Expression Profiling
  • Heterozygote
  • Humans
  • Male
  • Molecular Sequence Data
  • Mutation, Missense
  • Oculomotor Muscles
  • Oculomotor Nerve
  • Pedigree


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