Exclusion of known corneal dystrophy genes in an autosomal dominant pedigree of a unique anterior membrane corneal dystrophy

[摘要] Purpose: With advances in phenotypingtools and availability of molecular characterization, an increasingnumber of phenotypically and genotypically diverse inherited cornealdystrophies are described. We aimed to determine the underlyingcausative genetic mechanism in a three-generation pedigree affectedwith a unique anterior membrane corneal dystrophy characterized byearly onset recurrent corneal erosions, small discrete focal opacitiesat the level of Bowman layer and anterior stroma, anterior stromalflecks, and prominent corneal nerves. Methods: Twenty affected and unaffectedmembers of a three-generation family were examined and extensivelyclinically characterized including corneal topography and in vivoconfocal microscopy, and biological specimens were collected for DNAextraction. Mutational analysis of two corneal genes (TGFBI[Transforming Growth factor-beta induced] and ZEB1 [zinc fingerE box-binding homeobox 1]) was undertaken, in addition to testing withthe Asper Corneal Dystrophy gene chip (Asper Ophthalmics, Tartu,Estonia). Subsequent Genotyping To 11 Known Corneal Gene Loci (COL8A2[Collagen, Type VIII, Alpha-2], TACSTD2 [Tumor-AssociatedCalcium Signal Transducer 2], PIP5K3[Phosphatidylinositol-3-Phosphate 5-Kinase, Type III], GSN[Gelsolin], KERA [Keratocan], VSX1 [Visual SystemHomeobox Gene 1], COL6A1 [Collagen, Type VI, Alpha-1], MMP9[Matrix Metalloproteinase 9], KRT3 [Keratin 3]), and twoputative loci, 3p14-q13 and 15q22.33–24) was undertaken usingpolymorphic markers, and haplotypes constructed. Multipoint linkageanalysis was performed to generate LOD scores and produce LOD plotsacross the candidate intervals. Results: No pathogenic sequencevariations were detected in TGFBI or ZEB1 of theprobandnoron the Asper Corneal Dystrophy gene chip (302 mutations in 12 genes).Multipoint linkage analysis of 11 known corneal genes and locigenerated negative LOD plots and was able to exclude all genes testedincluding PIP5K3.Conclusions: Exclusion of linkage tocandidate corneal loci combined with an absence of pathogenic mutationsin known corneal genes in this pedigree suggest a different geneticcausative mechanism in this dystrophy than the previously documentedcorneal genes. This unique phenotype of an anterior membrane dystrophymay therefore provide an opportunity to identify a new gene responsiblefor corneal disease.

[学科分类] 生物化学/生物物理