Several different genes have been linked to PPCD, leading to subclassification of the disease based on gene mutation. PPCD1 has been reported to occur with mutations of the visual systems homeobox 1 gene (
VSX1); however, more recent studies appear to exclude the
VSX1 locus.
7 8 9 PPCD2 appears to occur from a mutation of the
COL8A2 gene, which encodes the α2 chain of type VIII collagen, a major component of Descemet membrane. Thus far, only a single mutation has been identified in two related patients.
10 Gene mutations in the zinc finger homeodomain transcription factor
ZEB1 (also known as
TCF8) are linked to PPCD3.
6 11 Indeed, in these studies it was estimated that
ZEB1 mutations may be responsible for half of all PPCD cases.
6 Accordingly, a recent study of 10 unrelated Czech and British families found that four of the families carried
ZEB1 mutations.
11 No linkage to either
COL8A2 or
VSX1 was found, suggesting that an unknown mutation is responsible for PPCD in the other six families. Mutations in type IV collagen genes, such as
COL4A3,
COL4A4, and
COL4A5, lead to basement membrane defects and cause the fibrotic hereditary renal disease known as Alport syndrome, which can also be associated with PPCD.
12 COL4A3 expression was found to be deregulated in the cornea in PPCD, and
COL4A3 contains consensus binding sites for ZEB1 in its promoter, leading to a potential scenario in which the mutation of
ZEB1 causes the derepression of
COL4A3 and, in turn, an altered Descemet membrane (which is normally composed primarily of type VIII collagen).
6