Mutational Spectrum of the ZEB1 Gene in Corneal Dystrophies Supports a Genotype-Phenotype Correlation

Judith Lechner, Durga P Dash, Dorota Muszynska, Mohsen Hosseini, Fani Segev, Sonia George, David G Frazer, Jonathan E Moore, Stephen B Kaye, Terri L Young, David A Simpson, Amanda J Churchill, Elise Heon, Colin E Willoughby

Research output: Contribution to journalArticle (Academic Journal)

35 Citations (Scopus)

Abstract

PURPOSE. MUTATIONS IN ZEB1 HAVE BEEN REPORTED IN POSTERIOR POLYMORPHOUS CORNEAL DYSTROPHY (PPCD3; MIM #609141) AND FUCHS ENDOTHELIAL CORNEAL DYSTROPHY (FECD6; MIM #613270). ALTHOUGH PPCD AND KERATOCONUS ARE CLINICALLY AND PATHOLOGICALLY DISTINCT, PPCD HAS BEEN ASSOCIATED WITH KERATOCONUS SUGGESTING A COMMON GENETIC BASIS. THE PURPOSE OF THIS STUDY WAS TO PERFORM MUTATIONAL SCREENING OF THE ZEB1 GENE IN PATIENTS AFFECTED WITH KERATOCONUS OR PPCD. METHODS. SANGER SEQUENCING OF ZEB1 WAS PERFORMED IN 70 UNRELATED PATIENTS WITH KERATOCONUS AND 18 UNRELATED PATIENTS WITH PPCD. RT-QPCR WAS PERFORMED ON RNA FROM CULTURED CORNEAL KERATOCYTES OBTAINED FROM A KERATOCONIC PATIENT HARBOURING A MISSENSE ZEB1 MUTATION (P.GLN640HIS) UNDERGOING CORNEAL TRANSPLANTATION. RESULTS. MUTATIONAL ANALYSIS OF ZEB1 IN PPCD IDENTIFIED A PREVIOUSLY REPORTED FRAMESHIFT MUTATION (C.1578_1579INSG) AND A NOVEL NONSENSE MUTATION (C.2249CA) IN EXON 7 OF ZEB1 CAUSING THE INSERTION OF A STOP CODON: p.Ser750X. In the keratoconus cohort a novel heterozygous pathogenic mutation in exon 7 (c.1920G>T; p.Gln640His) of ZEB1 was identified in a family affected with keratoconus and Fuchs endothelial corneal dystrophy. RT-qPCR performed on cultured corneal keratocytes harbouring the missense ZEB1 mutation (p.Gln640His) demonstrated that COL4A1 and COL4A2 were markedly down-regulated and COL4A3, COL4A4 and COL8A2 were moderately down-regulated. CONCLUSIONS. OUR DATA COMBINED WITH THE PREVIOUSLY REPORTED MUTATIONAL SPECTRUM OF ZEB1 SUPPORTS A GENOTYPE-PHENOTYPE CORRELATION: missense substitutions in the ZEB1 protein are associated with FECD6 and keratoconus whereas protein truncating ZEB1 mutations result in PPCD3. The dysregulation of α-type IV collagens represents a common link between ZEB1 mutation and the clinical phenotypes (PPCD3, FECD and keratoconus).
Original languageEnglish
JournalInvestigative Ophthalmology and Visual Science
DOIs
Publication statusPublished - 18 Apr 2013

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