Ovol2 promoter mutations in mice and human illuminate species-specific phenotypic divergence
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064165%3A_____%2F24%3A10480189" target="_blank" >RIV/00064165:_____/24:10480189 - isvavai.cz</a>
Alternative codes found
RIV/00216208:11110/24:10480189
Result on the web
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=0IAeiMU58H" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=0IAeiMU58H</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1093/hmg/ddad195" target="_blank" >10.1093/hmg/ddad195</a>
Alternative languages
Result language
angličtina
Original language name
Ovol2 promoter mutations in mice and human illuminate species-specific phenotypic divergence
Original language description
Pathogenic variants in the highly conserved OVOL2 promoter region cause posterior polymorphous corneal dystrophy (PPCD) 1 by inducing an ectopic expression of the endothelial OVOL2 mRNA. Here we produced an allelic series of Ovol2 promoter mutations in the mouse model including the heterozygous c.-307T>C variant (RefSeq NM_021220.4) causing PPCD1 in humans. Despite the high evolutionary conservation of the Ovol2 promoter, only some alterations of its sequence had phenotypic consequences in mice. Four independent sequence variants in the distal part of the Ovol2 promoter had no significant effect on endothelial Ovol2 mRNA level or caused any ocular phenotype. In contrast, the mutation c.-307T>C resulted in increased Ovol2 expression in the corneal endothelium. However, only a small fraction of adult mice c.-307T>C heterozygotes developed ocular phenotypes such as irido-corneal adhesions, and corneal opacity. Interestingly, phenotypic penetrance was increased at embryonic stages. Notably, c.-307T>C mutation is located next to the Ovol1/Ovol2 transcription factor binding site. Mice carrying an allele with a deletion encompassing the Ovol2 binding site c.-307_-320del showed significant Ovol2 gene upregulation in the cornea endothelium and exhibited phenotypes similar to the c.-307T>C mutation. In conclusion, although the mutations c.-307T>C and -307_-320del lead to a comparably strong increase in endothelial Ovol2 expression as seen in PPCD1 patients, endothelial dystrophy was not observed in the mouse model, implicating species-specific differences in endothelial cell biology. Nonetheless, the emergence of dominant ocular phenotypes associated with Ovol2 promoter variants in mice implies a potential role of this gene in eye development and disease.
Czech name
—
Czech description
—
Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
—
OECD FORD branch
30101 - Human genetics
Result continuities
Project
<a href="/en/project/ED1.1.00%2F02.0109" target="_blank" >ED1.1.00/02.0109: Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University</a><br>
Continuities
V - Vyzkumna aktivita podporovana z jinych verejnych zdroju
Others
Publication year
2024
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Human Molecular Genetics
ISSN
0964-6906
e-ISSN
1460-2083
Volume of the periodical
33
Issue of the periodical within the volume
6
Country of publishing house
GB - UNITED KINGDOM
Number of pages
10
Pages from-to
491-500
UT code for WoS article
001187532600001
EID of the result in the Scopus database
2-s2.0-85186697986