Further genetic and clinical insights of posterior polymorphous corneal dystrophy 3

JAMA Ophthalmol. 2013 Oct;131(10):1296-303. doi: 10.1001/jamaophthalmol.2013.405.

Abstract

Importance: Posterior polymorphous corneal dystrophy (PPCD) is a very rare disorder characterized by primary changes of the posterior corneal layers. Sequence variants in 3 genes are associated with the development of PPCD, including ZEB1 that is responsible for PPCD3. Evidence suggests at least 1 more gene remains to be identified.

Objective: To determine the molecular genetic cause of PPCD3.

Design: We performed extensive ophthalmological examination, including rotating Scheimpflug imaging technology and specular microscopy, and direct sequencing of the ZEB1 coding region. Comprehensive review of published PPCD3-causing variants was undertaken.

Setting: Ophthalmology department of a university hospital.

Participants: Four Czech probands.

Main outcomes and measures: Results of ophthalmological examination and direct sequencing of the ZEB1 coding region.

Results: The following 2 novel frameshift mutations within ZEB1 were identified: c.2617dup in exon 8 in a 22-year-old woman, considered to be most likely de novo in origin, and c.698dup in exon 6 in a 20-year-old man. The first patient had mild changes consistent with PPCD and bilateral best-corrected visual acuity of 1.00. The corneal phenotype of the patient in the second case was more severe, with best-corrected visual acuity of 0.40 OD and 0.05 OS. Corneas of both probands were abnormally steep (keratometry readings, flat ≥ 47.4 diopters [D] and steep ≥ 49.2 D) with increased pachymetry values but no pattern indicative of keratoconus. Specular microscopy in both patients revealed reduced endothelial cell density (range, 1055/mm² to 1655/mm²). Both probands had a history of surgery for inguinal hernia; the male patient also reported hydrocele.

Conclusions and relevance: Nucleotide changes within the coding region of ZEB1 underlie the pathogenesis of PPCD in 4 of 23 Czech probands (17%). The cumulative de novo ZEB1 mutation rate is at least 14%. Possible involvement of ZEB1 sequence variants not readily identified by direct sequencing of coding regions needs to be further investigated. Our findings also have implications for patient counseling.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Count
  • Corneal Dystrophies, Hereditary / diagnosis
  • Corneal Dystrophies, Hereditary / genetics*
  • Corneal Endothelial Cell Loss / genetics*
  • Corneal Pachymetry
  • Corneal Topography
  • Endothelium, Corneal / pathology*
  • Exons / genetics
  • Female
  • Frameshift Mutation*
  • Homeodomain Proteins / genetics*
  • Humans
  • Intraocular Pressure
  • Male
  • Molecular Biology
  • Phenotype
  • Polymerase Chain Reaction
  • Transcription Factors / genetics*
  • Visual Acuity
  • Young Adult
  • Zinc Finger E-box-Binding Homeobox 1

Substances

  • Homeodomain Proteins
  • Transcription Factors
  • ZEB1 protein, human
  • Zinc Finger E-box-Binding Homeobox 1

Supplementary concepts

  • Corneal Dystrophy, Posterior Polymorphous, 3