Ovol2 promoter mutations in mice and human illuminate species-specific phenotypic divergence

0584843 - ÚMG 2025 US eng J - Článek v odborném periodiku
Sunny, Sweetu Susan - Láchová, Jitka - Kašpárek, P. - Pálková, Marcela - Špoutil, František - Procházka, Jan - Sedláček, Radislav - Lišková, P. - Kozmik, Zbyněk
Ovol2 promoter mutations in mice and human illuminate species-specific phenotypic divergence.
Human Molecular Genetics. Roč. 33, č. 6 (2024), s. 491-500. ISSN 0964-6906. E-ISSN 1460-2083
Grant CEP: GA ČR GA21-27364S; GA MŠMT(CZ) LM2018126; GA MŠMT LM2023036; GA MŠMT EF18_046/0015861; GA MŠMT ED2.1.00/19.0395; GA MŠMT(CZ) ED1.1.00/02.0109
Institucionální podpora: RVO:68378050
Klíčová slova: polymorphous corneal-dystrophy * epithelial-mesenchymal transition * noncoding mutations * drosophila-ovo * expression * zeb1 * gene * classification * identification * suppression * cornea * ppcd1 * Ovol2 * pathogenic variant * corneal endothelium
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 3.5, rok: 2022
Způsob publikování: Omezený přístup
https://academic.oup.com/hmg/article-abstract/33/6/491/7424510?redirectedFrom=fulltext&login=false

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.
Trvalý link: https://hdl.handle.net/11104/0352866