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

P. Liskova, CJ. Evans, AE. Davidson, M. Zaliova, L. Dudakova, M. Trkova, V. Stranecky, N. Carnt, V. Plagnol, AL. Vincent, SJ. Tuft, AJ. Hardcastle,

. 2016 ; 24 (7) : 985-91. [pub] 20151028

Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc17031888
E-zdroje Online Plný text

NLK Free Medical Journals od 2009
PubMed Central od 2009 do Před 1 rokem
Europe PubMed Central od 2009 do Před 1 rokem
ProQuest Central od 2000-01-01 do 2017-12-31
Open Access Digital Library od 1998-01-01
Health & Medicine (ProQuest) od 2000-01-01 do 2017-12-31

Odkazy

PubMed 26508574
DOI 10.1038/ejhg.2015.232
Knihovny.cz E-zdroje

A substantial proportion of patients with posterior polymorphous corneal dystrophy (PPCD) lack a molecular diagnosis. We evaluated 14 unrelated probands who had a clinical diagnosis of PPCD who were previously determined to be negative for mutations in ZEB1 by direct sequencing. A combination of techniques was used including whole-exome sequencing (WES), single-nucleotide polymorphism (SNP) array copy number variation (CNV) analysis, quantitative real-time PCR, and long-range PCR. Segregation of potentially pathogenic changes with disease was confirmed, where possible, in family members. A putative run of homozygosity on chromosome 10 was identified by WES in a three-generation PPCD family, suggestive of a heterozygous deletion. SNP array genotyping followed by long-range PCR and direct sequencing to define the breakpoints confirmed the presence of a large deletion that encompassed multiple genes, including ZEB1. Identification of a heterozygous deletion spanning ZEB1 prompted us to further investigate potential CNVs at this locus in the remaining probands, leading to detection of two additional heterozygous ZEB1 gene deletions. This study demonstrates that ZEB1 mutations account for a larger proportion of PPCD than previously estimated, and supports the hypothesis that haploinsufficiency of ZEB1 is the underlying molecular mechanism of disease for PPCD3.

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