Allelic homogeneity due to a founder mutation in Japanese patients with lattice corneal dystrophy type IIIA

Lattice corneal dystrophies (LCDs) are caused by mutations of the transforming growth factor beta-induced gene (TGFBI, formerly betaig-h3). LCD type IIIA (LCDIIIA) has been reported mostly from Japan. In this study, we demonstrate allelic homogeneity for Japanese patients with LCDIIIA, using intragenic polymorphic markers. When exon 11 of TGFBI was analyzed, all 18 patients examined were found to be heterozygous for both a P501T mutation and an IVS10-3C --> T variation. On the other hand, none of 54 normal Japanese control subjects had the P501T, and 5 of the controls were heterozygous for IVS10-3C --> T. Haplotype analysis of the patients revealed that both P501T and IVS10-3C --> T were located on the same chromosome, and a significant linkage disequilibrium (P < 0.001, Fisher's exact probability test) was observed between LCDIIIA (P501T) and IVS10-3C --> T. When exon 8 of the gene was analyzed, all these patients possessed the "G allele" of a 1028G/A polymorphism. A significant linkage disequilibrium (P < 0.003; chi-square test) was also observed between P501T and the G allele in the patients. These results suggest that allelic homogeneity seen in Japanese patients with LCDIIIA may result from a single founder mutation.