Mutation Screening of 6 Positional Candidate Genes for the Autosomal Dominant High–Grade Myopia 5 Locus (MYP5)

Abstract

Abstract: : Purpose: Myopia is a common complex eye disorder, with implications for blindness due to increased risk of retinal detachment, chorioretinal degeneration, premature cataracts, and glaucoma. A genomic interval of 7.71 centiMorgans (cM) was defined on chromosome 17q21–23 in a multigenerational English/Canadian family with autosomal dominant high myopia and was designated the high–grade myopia 5 (MYP5) locus. We screened for sequence variants by using direct sequencing in 6 positional candidate genes: Collagen 1A1 (COL1A1), Integrin alpha 3 (ITGA3), Chondroadherin (CHAD), Carbonic anhydrase 4 (CA4), T–box gene 2 (TBX2), and T–box gene 4 (TBX4). Methods: Gene selection was based on expression data garnered from public databases. Coding regions, intron–exon boundaries and untranslated exons of all known genes were sequenced using genomic DNA samples from 4 affected and 3 unaffected MYP5 pedigree members, and from 1 external control. Nucleotide base–pair sequence changes were compared to known variants derived from public single nucleotide polymorphism (SNP) databases. Results: In total, 62 polymorphisms were found using direct sequencing– 17 were missense/silent, 7 were not translated, 24 were intronic, 8 were insertions, and 6 were homozygous deletions. Novel SNPs and known SNP observed frequencies were submitted to the public database. No sequence alterations segregated with the disease phenotype. Conclusions: Mutation analysis of 6 positional candidate genes within the MYP5 locus yielded no sequence alterations that are associated with high myopia. Further studies of MYP5 candidate genes are underway. We continue with efforts to reduce the 7.71 cM critical region through recruitment and analysis of new families.

Keywords: myopia • gene screening • candidate gene analysis