Mutations in PRDM5 and ZNF469 cause brittle cornea syndrome by influencing extracellular matrix development and maintenance

Extreme corneal fragility and thinning, with a high risk of catastrophic spontaneous rupture, is the most devastating feature of brittle cornea syndrome (BCS), an autosomal recessive generalised connective tissue disorder. Enucleation frequently becomes necessary, with resultant blindness and psychosocial distress. Even when the cornea remains grossly intact, sensory function may be severely impaired by high myopia, keratoconus and concurrent deafness. The ZNF469 locus, encoding a zinc finger protein of undefined function, has been recurrently identified as a quantitative trait locus for central corneal thickness, and mutations in ZNF469 are known to cause BCS. We found such mutations in 15 affected families. Autozygosity mapping identified mutations in PRDM5, encoding a transcription factor, in 7 of 8 additional families with BCS without ZNF469 mutations. Expression microarray, quantitative PCR, and immunofluorescence of dermal fibroblasts from patients with mutation in either PRDM5 or ZNF469, compared to controls, demonstrated highly similar results for all patient-derived cell lines, with altered expression of many extracellular matrix components, particularly fibrillar collagens. This work demonstrates that PRDM5 and ZNF469 participate in the same regulatory pathway, provides initial evidence of a key molecular mechanism influencing both normal corneal structure and function and the ocular fragility of BCS, and allows for effective molecular diagnosis of this condition.