Localization of a gene for Duane retraction syndrome to chromosome 2q31

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