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.
Original language | English |
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Pages (from-to) | 839-843 |
Number of pages | 5 |
Journal | Science |
Volume | 321 |
Issue number | 5890 |
Early online date | 24 Jul 2008 |
DOIs | |
Publication status | Published - 8 Aug 2008 |
Keywords
- 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