ARIX gene polymorphisms in patients with congenital superior oblique muscle palsy

Abstract

Abstract: : Purpose: ARIX gene mutations have been found in patients with congenital fibrosis of extraocular muscles (CFEOM) type 2. In patients with CFEOM, oculomotor and trochlear nuclei and their corresponding nerves are not formed. We hypothesize that congenital superior oblique muscle palsy be a clinically milder variant of CFEOM. The purpose of this study is to identify ARIX gene polymorphisms in patients with congenital superior oblique muscle palsy and to find the relation between ARIX gene and congenital superior oblique muscle palsy. Methods: The three exons of the ARIX gene were sequenced by genomic DNA amplification with polymerase chain reaction (PCR) and direct sequencing in 25 patients with congenital superior oblique muscle palsy and in 54 normal individuals. PCR products cloned into plasmids were also sequenced. A family with father and a daughter, each having congenital superior oblique muscle palsy, was also involved in this study. Results: Six patients with congenital superior oblique muscle palsy carried heterozygous nucleotide changes in the ARIX gene. One patient with the absence of the superior oblique muscle had T7C in the 5’–UTR of the exon 1 and C–44A in the promoter region, both of which were located on the same strand. Another unrelated patient with congenital superior oblique muscle palsy had C76G in the 5’–UTR of the exon 1 and C–9A in the promoter region on the same strand. A heterozygous change, G153A in the 5’–UTR of the exon 1, was found in common in two affected members of a family with congenital superior oblique muscle palsy. The remaining 2 patients with the palsy had G153A in the 5’–UTR of the exon 1. This G153A in the 5’–UTR of the exon 1 was also present in 4 unrelated normal individuals. No other heterozygous nucleotide changes were found in normal individuals. Conclusions: The nucleotide change (G153A) in the 5’–UTR of the exon 1 cosegregated with congenital superior oblique muscle palsy in one family. Other four nucleotide changes in the exon 1 or the promoter region were found only in patients with congenital superior oblique muscle palsy. These nucleotide polymorphisms may be one of risk factors for the development of congenital superior oblique muscle palsy.

Keywords: gene screening • strabismus: etiology • extraocular muscles: structure