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Human CHN1 Mutations Hyperactivate 2-Chimaerin and Cause Duane's Retraction Syndrome
Noriko Miyake,1,2John Chilton,3*Maria Psatha,4*Long Cheng,1,2Caroline Andrews,1,2,5Wai-Man Chan,1Krystal Law,1Moira Crosier,6Susan Lindsay,6Michelle Cheung,4James Allen,3Nick J. Gutowski,7,8Sian Ellard,8,9Elizabeth Young,8Alessandro Iannaccone,10Binoy Appukuttan,11J. Timothy Stout,11Stephen Christiansen,12Maria Laura Ciccarelli,13Alfonso Baldi,14Mara Campioni,14Juan C. Zenteno,15Dominic Davenport,4Laura E. Mariani,5Mustafa Sahin,2,5Sarah Guthrie,4Elizabeth C. Engle1,2,5,16,17
Duane's retraction syndrome (DRS) is a complex congenital eyemovement disorder caused by aberrant innervation of the extraocularmuscles by axons of brainstem motor neurons. Studying familieswith a variant form of the disorder (DURS2-DRS), we have identifiedcausative heterozygous missense mutations in CHN1, a gene onchromosome 2q31 that encodes 2-chimaerin, a Rac guanosine triphosphatase–activatingprotein (RacGAP) signaling protein previously implicated inthe pathfinding of corticospinal axons in mice. We found thatthese are gain-of-function mutations that increase 2-chimaerinRacGAP activity in vitro. Several of the mutations appearedto enhance 2-chimaerin translocation to the cell membrane orenhance its ability to self-associate. Expression of mutant2-chimaerin constructs in chick embryos resulted in failureof oculomotor axons to innervate their target extraocular muscles.We conclude that 2-chimaerin has a critical developmental functionin ocular motor axon pathfinding.
1 Department of Medicine (Genetics), Children's Hospital Boston, Boston, MA 02115, USA. 2 Harvard Medical School, Boston, MA02115, USA. 3 Institute of Biomedical and Clinical Science, Peninsula Medical School, Research Way, Plymouth PL6 8BU, UK. 4 MRC Centre for Developmental Neurobiology, King's College, Guy's Campus, London SE1 1UL, UK. 5 Department of Neurology, Children's Hospital Boston, Boston, MA 02115, USA. 6 MRC-Wellcome Trust Human Developmental Biology Resource (Newcastle), Institute of Human Genetics, Newcastle University, International Centre for Life, Newcastle upon Tyne NE1 3BZ, UK. 7 Department of Neurology, Royal Devon and Exeter Hospital, Barrack Road, Exeter, Devon EX2 5DW, UK. 8 Peninsula Medical School, Barrack Road, Exeter EX2 5DW, UK. 9 Department of Molecular Genetics, Royal Devon and Exeter Hospital, Barrack Road, Exeter, Devon EX2 5DW, UK. 10 University of Tennessee Health Science Center, Hamilton Eye Institute, 930 Madison Avenue, Suite 731, Memphis, TN 38163, USA. 11 Casey Eye Institute, Oregon Health and Science University, 3375 SW Terwilliger Boulevard, Portland, OR 97239, USA. 12 Department of Ophthalmology, University of Minnesota, MMC 493, 420 Delaware Street SE, Minneapolis, MN 55455, USA. 13 Fatebenefratelli Hospital, Division of Ophthalmology, Isola Tiberina, Rome 00100, Italy. 14 Department of Biochemistry "F. Cedrangolo," Section of Pathologic Anatomy, Second University of Naples, Naples 80138, Italy. 15 Department of Genetics and Research Unit, Institute of Ophthalmology "Conde de Valenciana," Mexico City 06700, Mexico. 16 Department of Ophthalmology, Children's Hospital Boston, Boston, MA 02115, USA. 17 Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
* These authors contributed equally to this work.
Deceased.
To whom correspondence should be addressed. E-mail: elizabeth.engle{at}childrens.harvard.edu
2-Chimaerin and Cause Duane's Retraction Syndrome
2-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 
Deceased. 
To whom correspondence should be addressed. E-mail: 
