Phenotypic characterisation and ZEB1 mutational analysis in posterior polymorphous corneal dystrophy in a New Zealand population

[摘要] Purpose: Posterior PolymorphousDystrophy (PPCD) is a genetically heterogeneous corneal dystrophy, withlinkage to three different chromosomal loci, with several genes inthese loci being implicated. The role of both VSX1 and COL8A2in PPCD remains controversial but recent work suggests that mutationsin the transcription factor gene ZEB1/TCF8 account for diseasein up to 30% of subjects, with a significant association withconnective tissue abnormalities. This study aimed to determine thephenotype and contribution of ZEB1 mutations in a New ZealandPPCD population Methods: Following informed consent, 11probands with PPCD underwent extensive clinical characterization;including a questionnaire to determine birth history, general health,and the incidence of connective tissue abnormalities, slit lampexamination, photography and in vivo confocal microscopy. Familymembers were recruited where available. Biological specimens underwentmutational analysis of all nine coding exons of ZEB1. Results: ZEB1 mutational analysisidentified one mutation in the 11 probands (9.1%), a novel mutation inthe initiating methionine of exon 1, c.1A→G that results in the proteinchange p.Met1Val, with resultant aberrant initiation of translation.This mutation segregated with disease in the family, and was notpresent in 100 control chromosomes. No other ZEB1 mutationswere observed in this cohort. Conclusion: Recent studies suggest that ZEB1mutations may account for PPCD in 18 to 30% of cases, with the majorityof the mutations in exons 5 and 7. Clinical and molecular analyses inthis New Zealand cohort show a much lower incidence of ZEB1sequence change, confirming the genetic heterogeneity of PPCD. We alsoreport identification of a novel mutation in the initiating methioninethat removes the Kozak sequence, thereby altering the site ofinitiation translation.

[学科分类] 生物化学/生物物理