Localization of a Gene for Duane Retraction Syndrome to Chromosome 2q31

Abstract

Duane retraction syndrome (DRS) is a congenital eye-movement disorder characterized by a failure of cranial nerve VI (the abducens nerve) to develop normally, resulting in restriction or absence of abduction, restricted adduction, and narrowing of the palpebral fissure and retraction of the globe on attempted adduction. DRS has a prevalence of approximately 0.1% in the general population and accounts for 5% of all strabismus cases. Undiagnosed DRS in children can lead to amblyopia, a permanent uncorrectable loss of vision. A large family with autosomal dominant DRS was examined and tested for genetic linkage. After exclusion of candidate regions previously associated with DRS, a genomewide search with highly polymorphic microsatellite markers was performed, and significant evidence for linkage was obtained at chromosome 2q31 (D2S2314 maximum LOD score 11.73 at maximum recombination fraction. 0). Haplotype analysis places the affected gene in a 17.8-cM region between the markers D2S2330 and D2S364. No recombinants were seen with markers between these two loci. The linked region contains the homeobox D gene cluster. Three of the genes within this cluster, known to participate in hindbrain development, were sequenced in affected and control individuals. Coding sequences for these genes were normal or had genetic alterations unlikely to be responsible for the DRS phenotype. Identifying the gene responsible for DRS may lead to an improved understanding of early cranial-nerve development.

Array-CGH fine mapping of minor and cryptic HR-CGH detected genomic imbalances in 80 out of 590 patients with abnormal development

“…This deletion on chromosome 2 is B5 Mb distal to the published locus for Duane retraction syndrome type 2 (DURS2), mapped by linkage analysis to 2q31. 29 Maybe the deletion is associated with an inversion disrupting the DURS2 gene. In case 4 with severe autism and self-destructive behaviour, a terminal deletion on 2q was found, a region previously found to be deleted in autistic patients.…”

HOXA1 mutations are not a common cause of Duane anomaly

“…A large dominant pedigree with isolated DA led to the identification of the DURS2 locus on chromosome 2 [Appukuttan et al, 1999;Evans et al, 2000], although the DURS2 gene has not yet been identified. Both DA and HGP can also occur in association with other congenital anomalies including skeletal defects, limb and digit dysplasia, scoliosis, and facial weakness Kirkham 1970;Pfaffenbach et al, 1972;Verzijl et al, 2003].…”

A family with Duane anomaly and distal limb abnormalities: A further family with the arthrogryposis‐ophthalmoplegia syndrome

“…Autopsy examination of two patients with Duane anomaly has shown hypoplasia of the VI nerve nucleus and absence of the VI nerve on the affected side, the ipsilateral lateral rectus being innervated by branches of the third nerve [Hotchkiss et al, 1980]. The prevalence is approximately 0.1% in the general population, and Duane anomaly accounts for 5% of all cases of strabismus [Appukuttan et al, 1999]. Up to 10% of cases are familial and follow an autosomal dominant pattern of inheritance.…”