Further Genetic and Clinical Insights of Posterior Polymorphous Corneal Dystrophy 3

Abstract

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 Ն 47.4 diopters [D] and steep Ն 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/mm 2 to 1655/mm 2). 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.

Heterozygous deletions at the ZEB1 locus verify haploinsufficiency as the mechanism of disease for posterior polymorphous corneal dystrophy type 3

“…20,24 PPCD often presents in small nuclear families or as an isolated case such that linkage to a specific genomic region is not conclusive, or is confounded by incomplete penetrance in some cases, so a substantial proportion of patients currently lack a molecular diagnosis. [9][10][11][12][14][15][16][17] In this study we demonstrate that, in some of these cases, PPCD can be attributed to heterozygous deletions at the ZEB1 locus, providing insights into the molecular diagnosis of previously unexplained PPCD cases and verifying haploinsufficiency as the mechanism of disease for PPCD3.…”

“…[9][10][11][12][13][14][15][16][17] There are regional variations in the contribution of these PPCD subtypes, and the proportion attributed to ZEB1 mutations (PPCD3) has been reported to be 9% in New Zealand, 20% in the Czech Republic, 30% in the United Kingdom and Canada, and 34% in the United States. [9][10][11][12][13][14][15][16][17] In contrast to other PPCD subtypes, PPCD3 is often associated with corneal steepening. 16,18 Systemic features such as inguinal hernias have also been described.…”

“…[9][10][11][12][13][14][15][16][17] In contrast to other PPCD subtypes, PPCD3 is often associated with corneal steepening. 16,18 Systemic features such as inguinal hernias have also been described. 9,10,16 There is a substantial variability in disease onset and presentation even among affected members of the same family.…”

“…16,18 Systemic features such as inguinal hernias have also been described. 9,10,16 There is a substantial variability in disease onset and presentation even among affected members of the same family. 19 PPCD3 can arise as a result of de novo mutations, and some individuals with a pathogenic mutation in ZEB1 do not exhibit clinical signs of the disease indicating either incomplete, or age-related, penetrance.…”

“…19 PPCD3 can arise as a result of de novo mutations, and some individuals with a pathogenic mutation in ZEB1 do not exhibit clinical signs of the disease indicating either incomplete, or age-related, penetrance. 9,14,16,19 ZEB1 encodes a zinc finger transcription factor (zinc finger E-box binding homeobox 1) that has a role in many cellular processes, including epithelial-mesenchymal transition (EMT) that involves the transformation of adhesive, non-mobile, epithelial cells into cells with a mesenchymal phenotype that have the ability to migrate. 20,21 ZEB1 induces EMT by suppressing the expression of epithelial-specific factors such as E-cadherin.…”