title: Bruch's membrane abnormalities in PRDM5-related brittle cornea syndrome.
abstract: BACKGROUND
  Brittle cornea syndrome (BCS) is a rare, generalized connective tissue disorder associated with extreme corneal thinning and a high risk of corneal rupture. Recessive mutations in transcription factors ZNF469 and PRDM5 cause BCS. Both transcription factors are suggested to act on a common pathway regulating extracellular matrix genes, particularly fibrillar collagens. We identified bilateral myopic choroidal neovascularization as the presenting feature of BCS in a 26-year-old-woman carrying a novel PRDM5 mutation (p.Glu134*). We performed immunohistochemistry of anterior and posterior segment ocular tissues, as expression of PRDM5 in the eye has not been described, or the effects of PRDM5-associated disease on the retina, particularly the extracellular matrix composition of Bruch's membrane.
  
  
  METHODS
  Immunohistochemistry using antibodies against PRDM5, collagens type I, III, and IV was performed on the eyes of two unaffected controls and two patients (both with Δ9-14 PRDM5). Expression of collagens, integrins, tenascin and fibronectin in skin fibroblasts of a BCS patient with a novel p.Glu134* PRDM5 mutation was assessed using immunofluorescence.
  
  
  RESULTS
  PRDM5 is expressed in the corneal epithelium and retina. We observe reduced expression of major components of Bruch's membrane in the eyes of two BCS patients with a PRDM5 Δ9-14 mutation. Immunofluorescence performed on skin fibroblasts from a patient with p.Glu134* confirms the generalized nature of extracellular matrix abnormalities in BCS.
  
  
  CONCLUSIONS
  PDRM5-related disease is known to affect the cornea, skin and joints. Here we demonstrate, to the best of our knowledge for the first time, that PRDM5 localizes not only in the human cornea, but is also widely expressed in the retina. Our findings suggest that ECM abnormalities in PRDM5-associated disease are more widespread than previously reported.
authors.affiliation: Institute of Human Development, Centre for Genomic Medicine, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Saint Mary's Hospital, Oxford Road, Manchester, M13 9WL, UK. louise.porter@liverpool.ac.uk.|Manchester Royal Eye Hospital, Central Manchester University Hospitals NHS Foundation Trust, Oxford Road, Manchester, M13 9WL, UK. louise.porter@liverpool.ac.uk.|Department of Eye and Vision Science, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK. louise.porter@liverpool.ac.uk.
authors.forename: Louise F
authors.initials: LF
authors.lastname: Porter
authors.affiliation: Department of Ophthalmology, Unit of Macula, University and Polytechnic Hospital La Fe, Valencia, Spain. Robertogallegopinazo@gmail.com.
authors.forename: Roberto
authors.initials: R
authors.lastname: Gallego-Pinazo
authors.affiliation: Histopathology, Central Manchester University Hospitals, NHS Foundation Trust, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL, UK. Catherine.Keeling@cmft.nhs.uk.
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Keeling
authors.affiliation: Histopathology, Central Manchester University Hospitals, NHS Foundation Trust, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL, UK. Martyna.kamieniorz@cmft.nhs.uk.
authors.forename: Martyna
authors.initials: M
authors.lastname: Kamieniorz
authors.affiliation: Division of Biology and Genetics, Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Brescia, Italy. Nicoletta.zoppi@unibs.it.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Zoppi
authors.affiliation: Division of Biology and Genetics, Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Brescia, Italy. Marina.colombi@unibs.it.
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 Centre, (CRC) Zurich, Switzerland. Cecilia.Giunta@kispi.uzh.ch.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Giunta
authors.affiliation: Manchester Royal Eye Hospital, Central Manchester University Hospitals NHS Foundation Trust, Oxford Road, Manchester, M13 9WL, UK. Richard.Bonshek@cmft.nhs.uk.|Department of Histopathology, National Ophthalmic Pathology Service (NSOPS) Laboratory, Central Manchester University Hospitals, NHS Foundation Trust, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL, UK. Richard.Bonshek@cmft.nhs.uk.
authors.forename: Richard
authors.initials: R
authors.lastname: Bonshek
authors.affiliation: Institute of Human Development, Centre for Genomic Medicine, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Saint Mary's Hospital, Oxford Road, Manchester, M13 9WL, UK. Forbes.Manson@manchester.ac.uk.
authors.forename: Forbes D
authors.initials: FD
authors.lastname: Manson
authors.affiliation: Institute of Human Development, Centre for Genomic Medicine, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Saint Mary's Hospital, Oxford Road, Manchester, M13 9WL, UK. Graeme.Black@manchester.ac.uk.|Centre for Genomic Medicine, Central Manchester University Hospitals, NHS Foundation Trust, MAHSC, Saint Mary's Hospital, Oxford Road, Manchester, M13 9WL, UK. Graeme.Black@manchester.ac.uk.
authors.forename: Graeme C
authors.initials: GC
authors.lastname: Black
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D016570:Bruch Membrane / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D002648:Child; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D005124:Eye Abnormalities / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007593:Joint Instability / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D012868:Skin Abnormalities / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; C487762:PRDM5 protein, human; D014157:Transcription Factors