Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State Transition and Causes Posterior Polymorphous Corneal Dystrophy 4

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11120%2F18%3A43916345" target="_blank" >RIV/00216208:11120/18:43916345 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11110/18:10375608 RIV/00064173:_____/18:N0000100 RIV/00064165:_____/18:10375608

Result on the web

<a href="https://doi.org/10.1016/j.ajhg.2018.02.002" target="_blank" >https://doi.org/10.1016/j.ajhg.2018.02.002</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ajhg.2018.02.002" target="_blank" >10.1016/j.ajhg.2018.02.002</a>

Result language

angličtina

Original language name

Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State Transition and Causes Posterior Polymorphous Corneal Dystrophy 4

Original language description

In a large family of Czech origin, we mapped a locus for an autosomal-dominant corneal endothelial dystrophy, posterior polymorphous corneal dystrophy 4 (PPCD4), to 8q22.3-q24.12. Whole-genome sequencing identified a unique variant (c.20+544G&gt;T) in this locus, within an intronic regulatory region of GRHL2. Targeted sequencing identified the same variant in three additional previously unsolved PPCD-affected families, including a de novo occurrence that suggests this is a recurrent mutation. Two further unique variants were identified in intron 1 of GRHL2 (c.20+257delT and c.20+133delA) in unrelated PPCD-affected families. GRHL2 is a transcription factor that suppresses epithelial-to-mesenchymal transition (EMT) and is a direct transcriptional repressor of ZEB1. ZEB1 mutations leading to haploinsufficiency cause PPCD3. We previously identified promoter mutations in OVOL2, a gene not normally expressed in the corneal endothelium, as the cause of PPCD1. OVOL2 drives mesenchymal-to-epithelial transition (MET) by directly inhibiting EMT-inducing transcription factors, such as ZEB1. Here, we demonstrate that the GRHL2 regulatory variants identified in PPCD4-affected individuals induce increased transcriptional activity in vitro. Furthermore, although GRHL2 is not expressed in corneal endothelial cells in control tissue, we detected GRHL2 in the corneal &quot;endothelium&quot; in PPCD4 tissue. These cells were also positive for epithelial markers E-Cadherin and Cytokeratin 7, indicating they have transitioned to an epithelial-like cell type. We suggest that mutations inducing MET within the corneal endothelium are a convergent pathogenic mechanism leading to dysfunction of the endothelial barrier and disease.

Czech name

—

Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30101 - Human genetics

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

V - Vyzkumna aktivita podporovana z jinych verejnych zdroju

Publication year

2018

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

The American Journal of Human Genetics

ISSN

0002-9297

e-ISSN

—

Volume of the periodical

102

Issue of the periodical within the volume

3

Country of publishing house

US - UNITED STATES

Number of pages

13

Pages from-to

447-459

UT code for WoS article

000426469600015

EID of the result in the Scopus database

2-s2.0-85042610720