title: Mutations in PRDM5 in brittle cornea syndrome identify a pathway regulating extracellular matrix development and maintenance.
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.
authors.affiliation: 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.
authors.forename: Emma M M
authors.initials: EMM
authors.lastname: Burkitt Wright
authors.affiliation: 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.
authors.forename: Helen L
authors.initials: HL
authors.lastname: Spencer
authors.affiliation: 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.
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Daly
authors.affiliation: 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.
authors.forename: Forbes D C
authors.initials: FDC
authors.lastname: Manson
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PL, UK.
authors.forename: Leo A H
authors.initials: LAH
authors.lastname: Zeef
authors.affiliation: 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.
authors.forename: Jill
authors.initials: J
authors.lastname: Urquhart
authors.affiliation: Division of Biology and Genetics, Department of Biomedical Sciences and Biotechnology, Medical Faculty, University of Brescia, 25123 Brescia, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Zoppi
authors.affiliation: 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.
authors.forename: Richard
authors.initials: R
authors.lastname: Bonshek
authors.affiliation: National Specialist Ophthalmic Pathology Laboratory, Manchester Royal Infirmary, Central Manchester Foundation Trust, Manchester M13 9WL, UK.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Tosounidis
authors.affiliation: Department of Ophthalmology, Royal Blackburn Hospital, Blackburn BB2 3HH, UK.
authors.forename: Meyyammai
authors.initials: M
authors.lastname: Mohan
authors.affiliation: Department of Paediatric Audiology, Moss Side Health Centre, Monton Street, Manchester M14 4GP, UK.
authors.forename: Colm
authors.initials: C
authors.lastname: Madden
authors.affiliation: Department of Audiology, St Peter's Centre, Church Street, Burnley BB11 2DL, UK.
authors.forename: Annabel
authors.initials: A
authors.lastname: Dodds
authors.affiliation: 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.
authors.forename: Kate E
authors.initials: KE
authors.lastname: Chandler
authors.affiliation: 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.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Banka
authors.affiliation: Manchester Royal Eye Hospital, Central Manchester Foundation Trust, Manchester M13 9WL, UK.
authors.forename: Leon
authors.initials: L
authors.lastname: Au
authors.affiliation: 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.
authors.forename: Jill
authors.initials: J
authors.lastname: Clayton-Smith
authors.affiliation: 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.
authors.forename: Naz
authors.initials: N
authors.lastname: Khan
authors.affiliation: 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.
authors.forename: Leslie G
authors.initials: LG
authors.lastname: Biesecker
authors.affiliation: Department of Clinical Genetics, Children's Hospital at Westmead, Westmead Sydney, NSW 2145, Australia.
authors.forename: Meredith
authors.initials: M
authors.lastname: Wilson
authors.affiliation: Division of Metabolism, Connective Tissue Unit, University Children's Hospital and Children's Research Center, 8032 Zurich, Switzerland.
authors.forename: Marianne
authors.initials: M
authors.lastname: Rohrbach
authors.affiliation: Division of Biology and Genetics, Department of Biomedical Sciences and Biotechnology, Medical Faculty, University of Brescia, 25123 Brescia, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Colombi
authors.affiliation: Division of Metabolism, Connective Tissue Unit, University Children's Hospital and Children's Research Center, 8032 Zurich, Switzerland.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Giunta
authors.affiliation: 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: graeme.black@manchester.ac.uk.
authors.forename: Graeme C M
authors.initials: GCM
authors.lastname: Black
mesh_terms: D002648:Child; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D004535:Ehlers-Danlos Syndrome / Q000235:genetics / Q000473:pathology; D005109:Extracellular Matrix / Q000235:genetics* / Q000502:physiology; D005124:Eye Abnormalities; D005260:Female; D006801:Humans; D007593:Joint Instability / Q000151:congenital; D008297:Male; D009154:Mutation; D010375:Pedigree; D012868:Skin Abnormalities; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C487762:PRDM5 protein, human; D014157:Transcription Factors; C530065:ZNF469 protein, human