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Ovol2 promoter mutations in mice and human illuminate species-specific phenotypic divergence
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SYSNO ASEP 0584843 Document Type J - Journal Article R&D Document Type The record was not marked in the RIV Subsidiary J Článek ve WOS Title Ovol2 promoter mutations in mice and human illuminate species-specific phenotypic divergence Author(s) Sunny, Sweetu Susan (UMG-J) ORCID
Láchová, Jitka (UMG-J)
Kašpárek, P. (US)
Pálková, Marcela (UMG-J)
Špoutil, František (UMG-J)
Procházka, Jan (UMG-J) ORCID
Sedláček, Radislav (UMG-J) RID
Lišková, P. (CZ)
Kozmik, Zbyněk (UMG-J) RIDNumber of authors 9 Source Title Human Molecular Genetics. - : Oxford University Press - ISSN 0964-6906
Roč. 33, č. 6 (2024), s. 491-500Number of pages 10 s. Language eng - English Country US - United States Keywords polymorphous corneal-dystrophy ; epithelial-mesenchymal transition ; noncoding mutations ; drosophila-ovo ; expression ; zeb1 ; gene ; classification ; identification ; suppression ; cornea ; ppcd1 ; Ovol2 ; pathogenic variant ; corneal endothelium OECD category Biochemistry and molecular biology R&D Projects GA21-27364S GA ČR - Czech Science Foundation (CSF) LM2018126 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LM2023036 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) EF18_046/0015861 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) ED2.1.00/19.0395 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) ED1.1.00/02.0109 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Limited access Institutional support UMG-J - RVO:68378050 UT WOS 001187532600001 EID SCOPUS 85186697986 DOI 10.1093/hmg/ddad195 Annotation 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 and307_-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. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2025 Electronic address https://academic.oup.com/hmg/article-abstract/33/6/491/7424510?redirectedFrom=fulltext&login=false
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