Genomewide linkage analysis of affected pedigrees has demonstrated evidence of linkage to several different chromosomal loci, including 5q14.3-q21.1,
9 16q22.3-q23.1 (designated keratoconus 2),
7 3p14-q13 (keratoconus 3),
10 and 2p24 (keratoconus 4).
11 However, the genetic locus designated keratoconus 1 on chromosome 20p11.2 was not identified by linkage analysis. Instead, the visual system homeobox 1 gene (
VSX1), located within the chromosome 20p11-q11 candidate gene region for posterior polymorphous corneal dystrophy (PPCD; MIM, 122000), was initially selected for screening in patients with PPCD.
12 The
VSX1 gene belongs to a family of homeodomain transcription factors that are thought to control cell differentiation in craniofacial and ocular development, making it a good functional candidate gene for PPCD.
13 14 Although neither Fuchs endothelial corneal dystrophy (FECD) nor keratoconus has been linked to this region, screening of the
VSX1 gene was performed in patients with FECD because PPCD and FECD are corneal endothelial dystrophies and may share common clinical features.
12 Previous reports linking PPCD and keratoconus
15 16 17 18 19 led the authors to speculate regarding a common genetic etiology for the two disorders; thus, they also performed mutation screening of the
VSX1 gene in patients with keratoconus (these patients did not have PPCD). The authors did acknowledge, however, that the two disorders demonstrate distinct clinical features and that the major pathologic defects in keratoconus lie in the anterior cornea, whereas PPCD is limited to the posterior cornea.
12