Mutation Screen in the ETX1 Gene in Patients With Glaucoma

Abstract

Purpose:: ETX1 (exon trapped X chromosome clone 1) was first identified as a candidate gene for X-linked retinitis pigmentosa (XLRP). The function of the protein remains unknown; however, it is predicted to contain one hyaline repeat and three complement control or sushi repeat domains. ETX1 was recently found to be present in trabecular meshwork (TM) samples obtained from primary open angle glaucoma (POAG) donors but absent in normal human TM. We investigated ETX1 as a candidate gene in patients with glaucoma.

Methods:: All ten coding exons of ETX1 have been screened for mutations in 285 unrelated patients with glaucoma using exon-by-exon SSCP. Variant bands were detected in exons 1, 2, 3, 7, 9 and 10 and were further analyzed by direct genomic sequencing.

Results:: We found six sequence changes in ETX1. These comprised three missense changes (Lys116Arg, Met395Leu, Ser413Phe), two isocoding changes (Asp36, Ser277), and one deletion (c.68_70delTGC). The sequence changes c.68_70delTGC and Ser413Phe were both previously identified in patients with XLRP and controls and are not considered pathogenic. The Met395Leu variant was observed homozygously in two patients with POAG and was not found in 363 controls, yielding a minor allele frequency of 0.7%. Lys116Arg was identified in 14 patients yielding a minor allele frequency of 4.4%. Both isocoding changes were identified homozygously in one patient. Cosegregation analysis is pending to determine whether the observed sequence anomalies are pathogenic.

Conclusions:: We report six sequence changes in ETX1 in patients with glaucoma. The possible pathogenic role of the reported missense changes is under further investigation. We are proceeding with an evaluation of all exons in additional patients.

Keywords: genetics • candidate gene analysis • mutations