Human CHN1 mutations hyperactivate alpha2-chimaerin and cause Duane's retraction syndrome.
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.
Miyake
Noriko
N
Department of Medicine (Genetics), Children's Hospital Boston, Boston, MA 02115, USA.
Chilton
John
J
Psatha
Maria
M
Cheng
Long
L
Andrews
Caroline
C
Chan
Wai-Man
WM
Law
Krystal
K
Crosier
Moira
M
Lindsay
Susan
S
Cheung
Michelle
M
Allen
James
J
Gutowski
Nick J
NJ
Ellard
Sian
S
Young
Elizabeth
E
Iannaccone
Alessandro
A
Appukuttan
Binoy
B
Stout
J Timothy
JT
Christiansen
Stephen
S
Ciccarelli
Maria Laura
ML
Baldi
Alfonso
A
Campioni
Mara
M
Zenteno
Juan C
JC
Davenport
Dominic
D
Mariani
Laura E
LE
Sahin
Mustafa
M
Guthrie
Sarah
S
Engle
Elizabeth C
EC
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
D020848:Chimerin 1