Alternative titles; symbols
HGNC Approved Gene Symbol: OVOL2
Cytogenetic location: 20p11.23 Genomic coordinates (GRCh38): 20:18,024,152-18,059,188 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20p11.23 | Corneal dystrophy, posterior polymorphous, 1 | 122000 | Autosomal dominant | 3 |
OVOL2 is a member of a large family of transcription factors named after its founding member, Drosophila ovo. The OVOL family shares a high degree of evolutionary conservation in a C2H2-type zinc finger domain (summary by Kumar et al., 2012).
By searching databases for sequences similar to mouse Ovol2, Li et al. (2002) identified 3 splice variants of human OVOL2. Two variants differ in their 3-prime UTRs and encode the same 274-amino acid protein, OVOL2A. OVOL2A has an N-terminal domain rich in charged residues and serines, 4 zinc finger domains, and a nuclear localization signal that partly overlaps the C-terminal end of the third zinc finger domain. The N-terminal domain has the characteristics of a transcription regulatory domain. The third variant encodes an N-terminally truncated protein, OVOL2B, that lacks the N-terminal domain of OVOL2A and has only 3 zinc finger domains. Northern blot analysis using a probe that detected all OVOL2 variants showed variable expression in 13 of 15 human tissues examined, with highest expression in skeletal muscle, heart, and thymus. A different pattern of Ovol2 expression was detected in mouse tissues, with high expression in testis, stomach, and intestine, and no expression in heart and skeletal muscle.
Unezaki et al. (2004) cloned 3 splice variants of mouse Ovol2, which they designated MovoA, MovoB, and MovoC, that differ in their 5-prime ends. The deduced proteins differ in their N termini but are identical in their C termini. Full-length MovoA has an N-terminal repressor domain, followed by a potential transactivation domain and a complete zinc finger domain. MovoB is N-terminally truncated compared with MovoA and has the zinc finger domain only, whereas MovoC begins with the putative transactivation domain and has the zinc finger domain. RT-PCR of mouse testis, ovary, and liver showed high expression of all 3 variants in testis, with MovoB as the major variant. Weaker Movo expression was detected in ovary, and little to no expression was detected in liver. In situ hybridization of mouse testis revealed that Movo mRNA was expressed in spermatocytes.
Kumar et al. (2012) reported that full-length mouse and human OVOL2 proteins contain 274 and 275 amino acids, respectively. The mouse and human proteins share highest identity in their C-terminal C2H2-type zinc finger domains.
Using RT-PCR in a variety of human corneal tissues and cultured cells, Davidson et al. (2016) detected OVOL2 expression in full-thickness corneal tissue but not in fetal or adult human endothelial cells. OVOL2 was also absent from cultured stromal fibroblasts. However, OVOL2 expression was detected in a human corneal epithelial culture derived from limbal epithelial stem cells and in a spontaneously immortalized human corneal epithelial cell line with progenitor-like characteristics.
Li et al. (2002) determined that the OVOL2 gene contains 6 exons, including 2 alternative first exons. Exons 2 and 4 contain translational start sites, and exon 6 is found only in a subset of OVOL2A transcripts.
Li et al. (2002) stated that the OVOL2 gene maps to chromosome 20p13-p11.2. They mapped the mouse Ovol2 gene to a region of chromosome 2G that shares homology of synteny with human chromosome 20p13-p11.2.
Hartz (2015) mapped the OVOL2 gene to chromosome 20p11.23 based on an alignment of the OVOL2 sequence (GenBank AL079276) with the genomic sequence (GRCh38).
Using random oligonucleotide selection, EMSA, and footprinting, Unezaki et al. (2004) found that mouse Movo bound to a G-rich sequence in the 5-prime flanking region of Movo itself and other testis-specific genes. MovoA tended to repress expression of a reporter gene with the Movo 5-prime G-rich motif, whereas MovoC activated it; MovoB had no effect. MovoA partially rescued oogenesis of a Drosophila ovo mutant.
Zhang et al. (2013) found that knockdown of Ovol2 via short hairpin RNA promoted neural conversion and inhibited expression of mesodermal and endodermal markers in mouse embryonic stem cells (ESCs). Knockdown of Ovol2 impaired the ability of Bmp4 (112262) to induce expression of mesodermal and endodermal markers in differentiating ESCs. In the presence of Bmp4, phosphorylated Smad1 (601595)/Smad5 (603110)/Smad8 (SMAD9; 603295) bound to a GC-rich enhancer in the upstream promoter of Ovol2. In contrast, overexpression of Ovol2a, the main Ovol2 isoform expressed in ESCs, inhibited neural conversion and promoted mesodermal differentiation of ESCs.
In 3 British kindreds and 16 Czech pedigrees segregating autosomal dominant posterior polymorphous corneal dystrophy (PPCD1; 122000), Davidson et al. (2016) identified heterozygous mutations in the promoter region of the OVOL2 gene (616441.0001-616441.0004) that segregated with disease in each family and were not found in controls. Interrogation of ChIP-seq data from ENCODE revealed that the OVOL2 promoter region has binding sites for multiple transcription factors, and RNA-seq data indicated that the majority of these transcription factors are expressed in human corneal endothelial cells. Functional analysis in transfected HEK293 cells demonstrated that each of the 4 mutants significantly increased promoter activity in vitro. In addition, Davidson et al. (2016) stated that OVOL2 is a known direct repressor of the PPCD3 (609141)-associated ZEB1 gene (189909), and suggested that dysregulation of the OVOL2-ZEB1 feedback loop was likely relevant to the pathogenetic mechanism in PPCD1.
In a large British kindred (BR1) with posterior polymorphous corneal dystrophy-1 (PPCD1; 122000), originally reported by Pearce et al. (1969), Davidson et al. (2016) identified a heterozygous 22-bp duplication (chr20.18,057,974_18,057,995dup, GRCh38) within the conserved promoter region of the OVOL2 gene that segregated fully with disease in the family and was not found in 209 ethnically matched British control samples. Functional analysis in transfected HEK293 cells demonstrated that the mutant significantly increased promoter activity in vitro compared to wildtype.
In 16 Czech pedigrees (C1-C14, C25, and C30) with posterior polymorphous corneal dystrophy-1 (PPCD1; 122000), including 2 families originally described by Gwilliam et al. (2005) and 12 families previously studied by Liskova et al. (2012), Davidson et al. (2016) identified heterozygosity for a c.-370T-C transition (c.-370T-C, NM_021220) within the conserved promoter region of the OVOL2 gene that segregated fully with disease in all 16 pedigrees and was not found in 216 ethnically matched control samples. Functional analysis in transfected HEK293 cells demonstrated that the mutant significantly increased promoter activity in vitro compared to wildtype.
In an affected mother and daughter from a 5-generation British family (BR3) with posterior polymorphous corneal dystrophy-1 (PPCD1; 122000), Davidson et al. (2016) identified heterozygosity for a c.-307T-C transition (c.-307T-C, NM_021220) within the highly conserved proximal promoter region of the OVOL2 gene. The mutation was not found in 209 ethnically matched control samples or in the 1000 Genomes Project or UCL WGS datasets. Both patients had mild vision loss with best-corrected visual acuity of 20/32, and neither had glaucoma or had undergone corneal grafting. Examination revealed bilateral opacities at the Descemet membrane and an irregular posterior corneal surface with peripheral adhesions between the iris and cornea; the mother also had a distorted iris in 1 eye. Functional analysis in transfected HEK293 cells demonstrated that the mutant significantly increased promoter activity in vitro compared to wildtype.
In the proband from a 4-generation British family (BR2) with posterior polymorphous corneal dystrophy-1 (PPCD1; 122000), Davidson et al. (2016) identified heterozygosity for a c.-274T-G transversion (c.-274T-G, NM_021220) within the highly conserved proximal promoter region of the OVOL2 gene. The mutation was not found in 209 ethnically matched control samples or in the 1000 Genomes Project or UCL WGS datasets. The patient reported poor vision due to corneal opacity since childhood, but her phenotype could not be reassessed due to multiple corneal graft and glaucoma drainage procedures on the right eye and enucleation of the left eye. Of 7 other affected family members, 6 were deceased and the remaining individual was unavailable for study. Functional analysis in transfected HEK293 cells demonstrated that the mutant significantly increased promoter activity in vitro compared to wildtype.
Davidson, A. E., Liskova, P., Evans, C. J., Dudakova, L., Noskova, L., Pontikos, N., Hartmannova, H., Hodanova, K., Stranecky, V., Kozmik, Z., Levis, H. J., Idigo, N., and 14 others. Autosomal-dominant corneal endothelial dystrophies CHED1 and PPCD1 are allelic disorders caused by non-coding mutations in the promoter of OVOL2. Am. J. Hum. Genet. 98: 75-89, 2016. [PubMed: 26749309] [Full Text: https://doi.org/10.1016/j.ajhg.2015.11.018]
Gwilliam, R., Liskova, P., Filipec, M., Kmoch, S., Jirsova, K., Huckle, E. J., Stables, C. L., Bhattacharya, S. S., Hardcastle, A. J., Deloukas, P., Ebenezer, N. D. Posterior polymorphous corneal dystrophy in Czech families maps to chromosome 20 and excludes the VSX1 gene. Invest. Ophthal. Vis. Sci. 46: 4480-4484, 2005. [PubMed: 16303937] [Full Text: https://doi.org/10.1167/iovs.05-0269]
Hartz, P. A. Personal Communication. Baltimore, Md. 6/26/2015.
Kumar, A., Bhandari, A., Sinha, R., Sardar, P., Sushma, M., Goyal, P., Goswami, C., Grapputo, A. Molecular phylogeny of OVOL genes illustrates a conserved C2H2 zinc finger domain coupled by hypervariable unstructured regions. PLoS One 7: e39399, 2012. [PubMed: 22737237] [Full Text: https://doi.org/10.1371/journal.pone.0039399]
Li, B., Dai, Q., Li, L., Nair, M., Mackay, D. R., Dai, X. Ovol2, a mammalian homolog of Drosophila ovo: gene structure, chromosomal mapping, and aberrant expression in blind-sterile mice. Genomics 80: 319-325, 2002. [PubMed: 12213202] [Full Text: https://doi.org/10.1006/geno.2002.6831]
Liskova, P., Gwilliam, R., Filipec, M., Jirsova, K., Merjava, S. R., Deloukas, P., Webb, T. R., Bhattacharya, S. S., Ebenezer, N. D., Morris, A. G., Hardcastle, A. J. High prevalence of posterior polymorphous corneal dystrophy in the Czech Republic: linkage disequilibrium mapping and dating an ancestral mutation. PLoS One 7: e45495, 2012. [PubMed: 23049806] [Full Text: https://doi.org/10.1371/journal.pone.0045495]
Pearce, W. G., Tripathi, R. C., Morgan, G. Congenital endothelial corneal dystrophy: clinical, pathological, and genetic study. Brit. J. Ophthal. 53: 577-591, 1969. [PubMed: 4900143] [Full Text: https://doi.org/10.1136/bjo.53.9.577]
Unezaki, S., Nishizawa, M., Okuda-Ashitaka, E., Masu, Y., Mukai, M., Kobayashi, S., Sawamoto, K., Okano, H., Ito, S. Characterization of the isoforms of MOVO zinc finger protein, a mouse homologue of Drosophila Ovo, as transcription factors. Gene 336: 47-58, 2004. [PubMed: 15225875] [Full Text: https://doi.org/10.1016/j.gene.2004.03.013]
Zhang, T., Zhu, Q., Xie, Z., Chen, Y., Qiao, Y., Li, L., Jing, N. The zinc finger transcription factor Ovol2 acts downstream of the bone morphogenetic protein pathway to regulate the cell fate decision between neuroectoderm and mesendoderm. J. Biol. Chem. 288: 6166-6177, 2013. [PubMed: 23319585] [Full Text: https://doi.org/10.1074/jbc.M112.418376]