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

Emma M M Burkitt Wright, Helen L Spencer, Sarah B Daly, Forbes D C Manson, Leo A H Zeef, Jill Urquhart, Nicoletta Zoppi, Richard Bonshek, Ioannis Tosounidis, Meyyammai Mohan, Colm Madden, Annabel Dodds, Kate E Chandler, Siddharth Banka, Leon Au, Jill Clayton-Smith, Naz Khan, Leslie G Biesecker, Meredith Wilson, Marianne RohrbachMarina Colombi, Cecilia Giunta, Graeme C M Black

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)767-77
Number of pages11
JournalAmerican Journal of Human Genetics
Issue number6
Publication statusPublished - 10 Jun 2011


  • Child
  • DNA Mutational Analysis
  • DNA-Binding Proteins
  • Ehlers-Danlos Syndrome
  • Extracellular Matrix
  • Eye Abnormalities
  • Female
  • Humans
  • Joint Instability
  • Male
  • Mutation
  • Pedigree
  • Skin Abnormalities
  • Transcription Factors


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