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

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.

• 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)

Chemical References

• Chimerin 1

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