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.
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Authors | Noriko Miyake, 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 |
Journal | Science (New York, N.Y.)
(Science)
Vol. 321
Issue 5890
Pg. 839-43
(Aug 08 2008)
ISSN: 1095-9203 [Electronic] United States |
PMID | 18653847
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
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Topics |
- Abducens Nerve
(abnormalities)
- Amino Acid Sequence
- Animals
- Axons
(physiology)
- Cell Line
- Cell Membrane
(metabolism)
- Chick Embryo
- Chimerin 1
(chemistry, genetics, metabolism)
- Duane Retraction Syndrome
(genetics)
- Female
- Gene Expression Profiling
- Heterozygote
- Humans
- Male
- Molecular Sequence Data
- Mutation, Missense
- Oculomotor Muscles
(embryology, innervation, metabolism)
- Oculomotor Nerve
(abnormalities, embryology)
- Pedigree
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