title: Phenotypic characterisation and ZEB1 mutational analysis in posterior polymorphous corneal dystrophy in a New Zealand population.
abstract: OBJECTIVE
  Posterior Polymorphous Dystrophy (PPCD) is a genetically heterogeneous corneal dystrophy, with linkage to three different chromosomal loci, with several genes in these loci being implicated. The role of both VSX1 and COL8A2 in PPCD remains controversial but recent work suggests that mutations in the transcription factor gene ZEB1/TCF8 account for disease in up to 30% of subjects, with a significant association with connective tissue abnormalities. This study aimed to determine the phenotype and contribution of ZEB1 mutations in a New Zealand PPCD population
  
  
  METHODS
  Following informed consent, 11 probands with PPCD underwent extensive clinical characterization; including a questionnaire to determine birth history, general health, and the incidence of connective tissue abnormalities, slit lamp examination, photography and in vivo confocal microscopy. Family members were recruited where available. Biological specimens underwent mutational analysis of all nine coding exons of ZEB1.
  
  
  RESULTS
  ZEB1 mutational analysis identified one mutation in the 11 probands (9.1%), a novel mutation in the initiating methionine of exon 1, c.1A-->G that results in the protein change p.Met1Val, with resultant aberrant initiation of translation. This mutation segregated with disease in the family, and was not present in 100 control chromosomes. No other ZEB1 mutations were observed in this cohort.
  
  
  CONCLUSIONS
  Recent studies suggest that ZEB1 mutations may account for PPCD in 18 to 30% of cases, with the majority of the mutations in exons 5 and 7. Clinical and molecular analyses in this New Zealand cohort show a much lower incidence of ZEB1 sequence change, confirming the genetic heterogeneity of PPCD. We also report identification of a novel mutation in the initiating methionine that removes the Kozak sequence, thereby altering the site of initiation translation.
authors.affiliation: Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Science, University of Auckland, Auckland, New Zealand. a.vincent@auckland.ac.nz
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Vincent
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Niederer
authors.forename: Amanda
authors.initials: A
authors.lastname: Richards
authors.forename: Betina
authors.initials: B
authors.lastname: Karolyi
authors.forename: Dipika V
authors.initials: DV
authors.lastname: Patel
authors.forename: Charles N J
authors.initials: CN
authors.lastname: McGhee
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D017124:Conserved Sequence; D003315:Cornea / Q000473:pathology; D003317:Corneal Dystrophies, Hereditary / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D003710:Demography; D005260:Female; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009520:New Zealand; D010641:Phenotype; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D018398:Homeodomain Proteins; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1