Human CHN1 Mutations Hyperactivate α2-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 α2-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 α2-chimaerin RacGAP activity in vitro. Several of the mutations appeared to enhance α2-chimaerin translocation to the cell membrane or enhance its ability to self-associate. Expression of mutant α2-chimaerin constructs in chick embryos resulted in failure of oculomotor axons to innervate their target extraocular muscles. We conclude that α2-chimaerin has a critical developmental function in ocular motor axon pathfinding.

Axon guidance in the developing ocular motor system and Duane retraction syndrome depends on Semaphorin signaling via alpha2-chimaerin

“…Mutations characterized in DURS2 patients such as the G228S mutation confer gain of function on α2-chn, leading to a hyperactivation of downstream signaling pathways (3). OMN neurons transfected with the G228S-α2-chn isoform manifested a higher percentage of collapsed growth cones, per se, than GFP-transfected control neurons (Fig.…”

“…Neuroimaging studies suggest that DURS2 may involve absence of the abducens concomitant with aberrant innervation of the LR muscle by the OMN, and/or hypoplasia of both the abducens and oculomotor nerves (4,5). We have previously shown that expression of α2-chn forms harboring identified human mutations, in the oculomotor nerves of chicken embryos, leads to characteristic axon guidance defects, suggesting a role for α2-chn in axon pathfinding (3). Such a function for α2-chn is supported by its role in corticospinal tract formation, where it is thought to transduce ephrin-B-EphA4 axon guidance signals (6).…”

“…Mutations in the α2-chn protein isoform encoded by the chimaerin-1 (CHN1) gene have recently been shown to be responsible for the DURS2 variant of a congenital form of strabismus, Duane retraction syndrome (DRS) (3). In DRS, defects in horizontal eye movements result from incoordination of the medial and lateral recti muscles, which are innervated by the oculomotor and the abducens nerves, respectively (2).…”

Congenital innervation dysgenesis syndrome (CID)/congenital cranial dysinnervation disorders (CCDDs)

“…59,60 It is suggested that human CHN1 mutations alter the development of abducens and, to a lesser extent, oculomotor axons. 60 …”

Duane Retraction Syndrome: Clinical Features at the Time of Initial Examination and Our Approach

“…4,5,8,9 DRS, klasik olarak etkilenen gözdeki bakış kısıtlılığının yönüne ve abdüksiyon-addüksiyon-daki kısıtlılığın asimetri miktarına göre sınıflan-dırılmaktadır. 1,10 Temel olarak 3 tipi mevcuttur.…”