Mutation Screen in the COCH Gene in 190 Patients with Glaucoma

Abstract

Purpose: : Cochlin (COCH), a protein mutated in patients with the autosomal dominant nonsyndromic auditory and vestibular disorder DFNA9, was recently found to be present in trabecular meshwork (TM) samples obtained from primary open angle glaucoma donors in association with mucopolysaccharide deposits, but absent in normal human TM. Cochlin deposits were also observed in the TM of 8–month–old glaucomatous DBA/2J mice, coincident with the reported onset of increased intraocular pressure (IOP) and optic nerve damage, but found to be absent in the TM of three other mouse lines that do not develop elevated IOP. For these reasons, we investigated COCH as a candidate gene in patients with glaucoma.

Methods: : All eleven coding exons of COCH have been screened for mutations in 190 unrelated patients with glaucoma using exon–by–exon SSCP. Variant bands were detected in exons 5, 7, 9, and 10 and were further analyzed by direct genomic sequencing.

Results: : Four sequence changes (IVS4–8A→G, Thr352Ser, Phe389Phe, Asp423Asp) were identified in COCH. The Thr352Ser missense change had a minor allele frequency of 34.4% in patients and was determined to be a non–pathogenic polymorphism. IVS4–8A→G was identified heterozygously in one patient with glaucoma yielding a minor allele frequency of 0.28%. The Phe389Phe missense change had a minor allele frequency of 0.56% in patients while the Asp423Asp missense change had a minor allele frequency of 1.1% in patients. Additional SSCP variant bands were identified in exons 7, 9, and 10 and are currently being sequenced.

Conclusions: : We report four sequence changes in COCH in patients with glaucoma; however to date, we are unable to associate these changes with disease. We are proceeding with an evaluation of the remaining variant bands identified in these patients and an evaluation of all exons in additional patients.

Keywords: gene screening • outflow: trabecular meshwork • genetics