We identified mutations in the VSX1 homeobox gene for two distinct inherited corneal
dystrophies; posterior polymorphous dystrophy (PPD) and keratoconus. One of the mutation
(R166W) responsible for keratoconus altered the homeodomain and impaired DNA binding.
Two other sequence changes (L159M and G160D) were associated with keratoconus and
PPD, respectively, and involved a region adjacent to the homeodomain. The G160D substitution,
and a fourth defect affecting the highly conserved CVC domain (P247R), occurred in
a child with very severe PPD who required a corneal transplant at 3 months of age.
In this family, relatives with the G160D change alone had mild to moderate PPD, while
P247R alone caused no corneal abnormalities. However, with either the G160D or P247R
mutation, electroretinography detected abnormal function of the inner retina, where
VSX1 is expressed. These data define the molecular basis of two important corneal
dystrophies and reveal the importance of the CVC domain in the human retina.