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

Am J Hum Genet. 2011 Jun 10;88(6):767-777. doi: 10.1016/j.ajhg.2011.05.007.

Emma M M Burkitt Wright ¹, Helen L Spencer ¹, Sarah B Daly ¹, Forbes D C Manson ¹, Leo A H Zeef ², Jill Urquhart ¹, Nicoletta Zoppi ³, Richard Bonshek ⁴, Ioannis Tosounidis ⁵, Meyyammai Mohan ⁶, Colm Madden ⁷, Annabel Dodds ⁸, Kate E Chandler ¹, Siddharth Banka ¹, Leon Au ⁹, Jill Clayton-Smith ¹, Naz Khan ¹, Leslie G Biesecker ¹⁰, Meredith Wilson ¹¹, Marianne Rohrbach ¹², Marina Colombi ³, Cecilia Giunta ¹², Graeme C M Black ¹³

Affiliations

1 Genetic Medicine Research Group, Manchester Biomedical Research Centre, Manchester Academic Health Sciences Centre, University of Manchester and Central Manchester Foundation Trust, St Mary's Hospital, Manchester M13 9WL, UK.
2 Faculty of Life Sciences, University of Manchester, Manchester M13 9PL, UK.
3 Division of Biology and Genetics, Department of Biomedical Sciences and Biotechnology, Medical Faculty, University of Brescia, 25123 Brescia, Italy.
4 Manchester Royal Eye Hospital, Central Manchester Foundation Trust, Manchester M13 9WL, UK; National Specialist Ophthalmic Pathology Laboratory, Manchester Royal Infirmary, Central Manchester Foundation Trust, Manchester M13 9WL, UK.
5 National Specialist Ophthalmic Pathology Laboratory, Manchester Royal Infirmary, Central Manchester Foundation Trust, Manchester M13 9WL, UK.
6 Department of Ophthalmology, Royal Blackburn Hospital, Blackburn BB2 3HH, UK.
7 Department of Paediatric Audiology, Moss Side Health Centre, Monton Street, Manchester M14 4GP, UK.
8 Department of Audiology, St Peter's Centre, Church Street, Burnley BB11 2DL, UK.
9 Manchester Royal Eye Hospital, Central Manchester Foundation Trust, Manchester M13 9WL, UK.
10 National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20814, USA; National Institutes of Health Intramural Sequencing Center (NISC), National Institutes of Health, Rockville, MD 20892, USA.
11 Department of Clinical Genetics, Children's Hospital at Westmead, Westmead Sydney, NSW 2145, Australia.
12 Division of Metabolism, Connective Tissue Unit, University Children's Hospital and Children's Research Center, 8032 Zurich, Switzerland.
13 Genetic Medicine Research Group, Manchester Biomedical Research Centre, Manchester Academic Health Sciences Centre, University of Manchester and Central Manchester Foundation Trust, St Mary's Hospital, Manchester M13 9WL, UK. Electronic address: [email protected].

PMID: 21664999 DOI: 10.1016/j.ajhg.2011.05.007

Abstract

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.

Name
Email *

	Sorry, but the email address you supplied was invalid.