ORPHA: 233; DO: 0061028;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q31.1 | Duane retraction syndrome 2 | 604356 | Autosomal dominant | 3 | CHN1 | 118423 |
A number sign (#) is used with this entry because of evidence that Duane retraction syndrome-2 (DURS2) is caused by heterozygous mutation in the CHN1 gene (118423) on chromosome 2q31.
Duane retraction syndrome (DURS) is a congenital disorder characterized by restricted horizontal eye movement with globe retraction and palpebral fissure narrowing on attempted adduction. DURS is observed in approximately 0.1% of the general population, accounts for 1 to 5% of all strabismus, and if untreated in childhood can result in loss of binocular vision and amblyopia. Postmortem examinations of individuals with sporadic DURS have shown absence of the abducens motor neurons and abducens cranial nerve on the affected side(s), and aberrant innervation of the lateral rectus by axons of the oculomotor nerve that normally innervate the medial rectus muscle. Most patients are affected unilaterally and have no family history of the disorder (summary by Miyake et al., 2010).
For a discussion of genetic heterogeneity of Duane retraction syndrome, see DURS1 (126800).
Appukuttan et al. (1999) reported a large 4-generation Mexican family in which 25 living members were affected with Duane anomaly transmitted in an autosomal dominant pattern. Chung et al. (2000) studied 110 of the family members and examined the 25 patients in detail. None of the unaffected family members had evidence of neurologic abnormalities. All but 1 of the 25 patients had bilateral Duane anomaly of type 1 or type 3, and there was a high prevalence of manifest strabismus (76%) and amblyopia (48%). In 1 family subgroup, 3 patients had a unilateral fourth cranial nerve palsy. Other ophthalmic and neurologic abnormalities included unilateral congenital ptosis, upper eyelid retraction with downgaze, unilateral congenital deafness, nystagmus, and seizures, each observed in 1 patient. None of the patients had visible external ear or facial anomalies.
Evans et al. (2000) described a 4-generation family in the United Kingdom with autosomal dominant transmission of isolated bilateral Duane syndrome. Of 9 affected family members, 5 cases were type 1 bilaterally, 2 cases were type 3 bilaterally, and 2 cases were type 1 in the right eye and type 3 in the left eye. Eight cases had a primary position esotropia, and there was a vertical eye movement abnormality in 8 cases, 5 with a 'V' configuration and 3 with an 'A' configuration.
Demer et al. (2007) used high-resolution, multipositional MRI in a study of 5 male and 3 female affected members of 2 families with autosomal dominant Duane retraction syndrome mapping to chromosome 2. All patients had unilateral or bilateral limitation of abduction, or of both abduction and adduction, with palpebral fissure narrowing and globe retraction in adduction. Orbital motor nerves were typically small, with the abducens nerve (cranial nerve 6; CN6) often nondetectable. Lateral rectus muscles were structurally abnormal in 7 patients, with structural and motility evidence of oculomotor nerve (CN3) innervation from vertical rectus extraocular muscles (EOM) leading to A or V patterns of strabismus in 3 cases. Four cases had superior oblique, 2 cases superior rectus, and 2 cases levator EOM hypoplasia. Only the medial and inferior rectus and inferior oblique EOMs were spared. Two cases had small CN3s. Demer et al. (2007) concluded that DURS2 is a diffuse congenital cranial dysinnervation disorder involving but not limited to CN6.
Miyake et al. (2011) reported 5 family members with distinctive ocular dysmotility patterns that cosegregated with a novel hyperactivating CHN1 mutation. All 5 clinically affected family members exhibited monocular or binocular supraduction deficits, 3 in the absence of DURS2. MRI in 4 affected individuals demonstrated small or absent abducens nerves in all 4, small oculomotor nerve in 1, and small optic nerves in 3. Superior oblique muscle volume was also decreased in 3 of the individuals, supporting trochlear nerve hypoplasia. Miyake et al. (2011) concluded that their analysis of this pedigree expanded the phenotypic spectrum of hyperactivating CHN1 mutations to include vertical strabismus and supraduction deficits in the absence of Duane retraction syndrome.
The transmission pattern of DURS2 in the family reported by Appukuttan et al. (1999) was consistent with autosomal dominant inheritance.
In a large 4-generation Mexican family with autosomal dominant Duane retraction syndrome, Appukuttan et al. (1999) demonstrated linkage to 2q31 (maximum lod score = 11.73 at theta = 0.0 for D2S2314). Haplotype analysis placed the affected gene in a 17.8-cM region. No recombinants were seen with markers between these 2 loci. The linked region contains the homeobox D gene cluster (see HOXD1; 142987).
In a 4-generation family with Duane syndrome in the U.K., Evans et al. (2000) demonstrated linkage to an interval of 8.8-cM on 2q31.
In 2 additional families with Duane retraction syndrome, one Hispanic and the other Caucasian, Engle et al. (2007) demonstrated linkage of the disorder within the same 8.8-cM interval, with maximum lod scores of 2.1 and 2.3 at D2S2314, respectively.
Miyake et al. (2008) further analyzed the recombination events that defined the DURS2 critical region (Appukuttan et al., 1999; Evans et al., 2000), reducing it from 9.9 to 4.6 Mb.
In 4 large families with Duane retraction syndrome mapping to chromosome 2q, previously reported by Appukuttan et al. (1999), Evans et al. (2000), and Engle et al. (2007), Miyake et al. (2008) screened 22 candidate genes and identified heterozygous missense changes in the CHN1 gene (118423.0001-118423.0004), which encodes 2 Rac-specific guanosine triphosphatase (GTPase)-activating alpha-chimerin isoforms. Analysis of CHN1 in 16 smaller DURS pedigrees revealed heterozygous mutations in 3 additional families (118423.0004-118423.0007). All 7 nucleotide substitutions cosegregated with the affected haplotypes. None were present in online SNP databases or on 788 control chromosomes. Five of the 7 resulted in nonconservative amino acid substitutions. All were predicted to alter amino acids that are conserved in 8 different species.
Miyake et al. (2010) screened the CHN1 gene in 140 sporadic patients with Duane retraction syndrome but did not detect any mutations, in contrast to the 35% detection rate of CHN1 mutation in familial DURS (7 of 20 pedigrees) found by Miyake et al. (2008). Miyake et al. (2010) concluded that CHN1 mutations are not a major cause of DURS among patients with sporadic disease.
In 2 families segregating Duane retraction syndrome, Chan et al. (2011) identified heterozygous gain-of-function mutations in the CHN1 gene (118423.0008-118423.0009).
To test the hypothesis that overexpression of alpha-2-chimerin may result in aberrant axon development in vivo, Miyake et al. (2008) used the chick in ovo system to overexpress alpha-2-chimerin in the embryonic oculomotor nucleus. In the majority (71-87%) of embryos overexpressing wildtype or mutant constructs, the oculomotor nerve stalled and its axons terminated prematurely adjacent to the dorsal rectus muscle.
Appukuttan, B., Gillanders, E., Juo, S.-H., Freas-Lutz, D., Ott, S., Sood, R., Van Auken, A., Bailey-Wilson, J., Wang, X., Patel, R. J., Robbins, C. M., Chung, M., Annett, G., Weinberg, K., Borchert, M. S., Trent, J. M., Brownstein, M. J., Stout, J. T. Localization of a gene for Duane retraction syndrome to chromosome 2q31. Am. J. Hum. Genet. 65: 1639-1646, 1999. [PubMed: 10577917] [Full Text: https://doi.org/10.1086/302656]
Chan, W.-M., Miyake, N., Zhu-Tam, L., Andrews, C., Engle, E. C. Two novel CHN1 mutations in 2 families with Duane retraction syndrome. Arch. Ophthal. 129: 649-652, 2011. [PubMed: 21555619] [Full Text: https://doi.org/10.1001/archophthalmol.2011.84]
Chung, M., Stout, J. T., Borchert, M. S. Clinical diversity of hereditary Duane's retraction syndrome. Ophthalmology 107: 500-503, 2000. [PubMed: 10711888] [Full Text: https://doi.org/10.1016/s0161-6420(99)00090-1]
Demer, J. L., Clark, R. A., Lim, K.-H., Engle, E. C. Magnetic resonance imaging evidence for widespread orbital dysinnervation in dominant Duane's retraction syndrome linked to the DURS2 locus. Invest. Ophthal. Vis. Sci. 48: 194-202, 2007. [PubMed: 17197533] [Full Text: https://doi.org/10.1167/iovs.06-0632]
Engle, E. C., Andrews, C., Law, K., Demer, J. L. Two pedigrees segregating Duane's retraction syndrome as a dominant trait map to the DURS2 genetic locus. Invest. Ophthal. Vis. Sci. 48: 189-193, 2007. [PubMed: 17197532] [Full Text: https://doi.org/10.1167/iovs.06-0631]
Evans, J. C., Frayling, T. M., Ellard, S., Gutowski, N. J. Confirmation of linkage of Duane's syndrome and refinement of the disease locus to an 8.8-cM interval on chromosome 2q31. Hum. Genet. 106: 636-638, 2000. [PubMed: 10942112] [Full Text: https://doi.org/10.1007/s004390000311]
Miyake, N., Andrews, C., Fan, W., He, W., Chan, W.-M., Engle, E. C. CHN1 mutations are not a common cause of sporadic Duane's retraction syndrome. (Letter) Am. J. Med. Genet. 152A: 215-217, 2010. [PubMed: 20034095] [Full Text: https://doi.org/10.1002/ajmg.a.33168]
Miyake, N., Chilton, J., Psatha, M., Cheng, L., Andrews, C., Chan, W.-M., Law, K., Crosier, M., Lindsay, S., Cheung, M., Allen, J., Gutowski, N. J., and 15 others. Human CHN1 mutations hyperactivate alpha-2-chimaerin and cause Duane's retraction syndrome. Science 321: 839-843, 2008. [PubMed: 18653847] [Full Text: https://doi.org/10.1126/science.1156121]
Miyake, N., Demer, J. L., Shaaban, S., Andrews, C., Chan, W.-M., Christiansen, S. P., Hunter, D. G., Engle, E. C. Expansion of the CHN1 strabismus phenotype. Invest. Ophthal. Vis. Sci. 52: 6321-8328, 2011. [PubMed: 21715346] [Full Text: https://doi.org/10.1167/iovs.11-7950]