title: 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.affiliation: Department of Medicine (Genetics), Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.forename: John
authors.initials: J
authors.lastname: Chilton
authors.forename: Maria
authors.initials: M
authors.lastname: Psatha
authors.forename: Long
authors.initials: L
authors.lastname: Cheng
authors.forename: Caroline
authors.initials: C
authors.lastname: Andrews
authors.forename: Wai-Man
authors.initials: WM
authors.lastname: Chan
authors.forename: Krystal
authors.initials: K
authors.lastname: Law
authors.forename: Moira
authors.initials: M
authors.lastname: Crosier
authors.forename: Susan
authors.initials: S
authors.lastname: Lindsay
authors.forename: Michelle
authors.initials: M
authors.lastname: Cheung
authors.forename: James
authors.initials: J
authors.lastname: Allen
authors.forename: Nick J
authors.initials: NJ
authors.lastname: Gutowski
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Young
authors.forename: Alessandro
authors.initials: A
authors.lastname: Iannaccone
authors.forename: Binoy
authors.initials: B
authors.lastname: Appukuttan
authors.forename: J Timothy
authors.initials: JT
authors.lastname: Stout
authors.forename: Stephen
authors.initials: S
authors.lastname: Christiansen
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Ciccarelli
authors.forename: Alfonso
authors.initials: A
authors.lastname: Baldi
authors.forename: Mara
authors.initials: M
authors.lastname: Campioni
authors.forename: Juan C
authors.initials: JC
authors.lastname: Zenteno
authors.forename: Dominic
authors.initials: D
authors.lastname: Davenport
authors.forename: Laura E
authors.initials: LE
authors.lastname: Mariani
authors.forename: Mustafa
authors.initials: M
authors.lastname: Sahin
authors.forename: Sarah
authors.initials: S
authors.lastname: Guthrie
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Engle
mesh_terms: D000010:Abducens Nerve / Q000002:abnormalities; D000595:Amino Acid Sequence; D000818:Animals; D001369:Axons / Q000502:physiology; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002642:Chick Embryo; D020848:Chimerin 1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D004370:Duane Retraction Syndrome / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D006579:Heterozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009801:Oculomotor Muscles / Q000196:embryology / Q000294:innervation / Q000378:metabolism; D009802:Oculomotor Nerve / Q000002:abnormalities / Q000196:embryology; D010375:Pedigree
chemical_list: D020848:Chimerin 1