Mutations in PRDM5 in brittle cornea syndrome identify a pathway regulating extracellular matrix development and maintenance.

Extreme corneal fragility and thinning, which have a high risk of catastrophic spontaneous rupture, are the cardinal features of brittle
cornea syndrome (BCS), an autosomal-recessive generalized connective tissue disorder. Enucleation is frequently the only management
option for this condition, resulting in blindness and psychosocial distress. Even when the cornea remains grossly intact, visual function
could also be impaired by a high degree of myopia and keratoconus. Deafness is another common feature and results in combined
sensory deprivation. Using autozygosity mapping, we identified mutations in PRDM5 in families with BCS. We demonstrate that regulation
of expression of extracellular matrix components, particularly fibrillar collagens, by PRDM5 is a key molecular mechanism that
underlies corneal fragility in BCS and controls normal corneal development and maintenance. ZNF469, encoding a zinc finger protein of
hitherto undefined function, has been identified as a quantitative trait locus for central corneal thickness, and mutations in this gene
have been demonstrated in Tunisian Jewish and Palestinian kindreds with BCS.We show that ZNF469 and PRDM5, two genes that when
mutated cause BCS, participate in the same regulatory pathway.