Alternative titles; symbols
ORPHA: 98974; DO: 11555;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 10p11.22 | Corneal dystrophy, Fuchs endothelial, 6 | 613270 | Autosomal dominant | 3 | ZEB1 | 189909 |
A number sign (#) is used with this entry because of evidence that Fuchs endothelial corneal dystrophy-6 (FECD6) is caused by heterozygous mutation in the ZEB1 gene (189909) on chromosome 10p11.
Another form of corneal dystrophy, posterior polymorphous corneal dystrophy-3 (PPCD3; 609141), is also caused by heterozygous mutation in the ZEB1 gene.
Fuchs endothelial corneal dystrophy (FECD) is the most common genetic disorder of the corneal endothelium. Late-onset FECD is marked by thickening of Descemets membrane and excrescences, called guttae, that typically appear in the fourth or fifth decade. Disease progression results in decreased visual acuity as a result of increasing corneal edema, and end-stage disease is marked by painful epithelial bullae (summary by Riazuddin et al., 2013). Patients with keratoconus have been observed (Lechner et al., 2013).
For a discussion of genetic heterogeneity of Fuchs endothelial corneal dystrophy, see FECD1 (136800).
Lechner et al. (2013) reported a mother with FECD and her son and daughter with keratoconus, who all had mutation in the ZEB1 gene. The mother was diagnosed with FECD at age 56, based on the presence of more than 5 mm confluent central corneal endothelial guttae in each eye. At age 65, she exhibited bilateral mild corneal epithelial and stromal edema associated with increased corneal thickness. She did not show evidence of keratoconus. Her 39-year-old son was diagnosed with keratoconus at age 25; there were no other anterior segment abnormalities and endothelium was normal. Corneal topography confirmed keratoconus. Her 37-year-old daughter was diagnosed with keratoconus at age 19 and had undergone bilateral corneal transplantation.
Gupta et al. (2015) reported 7 unrelated patients with FECD and mutation in the ZEB1 gene. The patients were part of a cohort of individuals diagnosed clinically with FECD based on the presence of central guttae changes, frequent morning blurring of vision, progressive disease, increased central corneal thickness, and reduced endothelial cell count on specular microscopy.
The transmission pattern of FECD6 in the pedigree (family TH) reported by Riazuddin et al. (2010) was consistent with autosomal dominant inheritance.
Riazuddin et al. (2010) analyzed the ZEB1 gene in 192 unrelated patients with adult-onset FECD and identified 4 different heterozygous missense mutations in 4 patients, respectively, that were not found in 560 unrelated, ethnically matched controls. Sequencing the ZEB1 gene in an independent cohort of 192 FECD probands, Riazuddin et al. (2010) identified 3 missense mutations in 3 patients, respectively, 2 of which had been identified in the earlier cohort, N78T (189909.0003) and Q840P (189909.0004). One of the probands with the Q840P mutation came from a large pedigree (family TH) in which none of 7 unaffected members carried 840P, but the mutation was present in only 7 of 12 affected individuals. A genomewide scan in the pedigree identified an additional locus for late-onset FECD on chromosome 9p24.1-p22.1 (see FECD7, 613271) in 10 of the 12 affected individuals. The 3 oldest of 5 individuals carrying both the Q840P mutation and the disease-transmitting haplotype on 9p had a severe FECD phenotype and all 3 had undergone corneal transplantation; Riazuddin et al. (2010) suggested that mutations in either ZEB1 or at the 9p locus are sufficient for disease, and that genetic interaction between the 2 loci can lead to a more severe form of the disease.
In a cohort of 70 unrelated patients with keratoconus, Lechner et al. (2013) performed Sanger sequencing of the ZEB1 gene and identified 1 proband who was heterozygous for a pathogenic missense substitution (Q640H; 189909.0005). His mother, who had FECD, and his sister, who had keratoconus, were both heterozygous for the mutation, which was not found in public variant databases.
By direct sequencing of the ZEB1 gene in 82 patients from northern India with late-onset FECD, Gupta et al. (2015) identified a novel splice site mutation (IVS2+276C-T) in 11 patients (14%) as well as 2 novel missense mutations and 1 novel nonsense mutation in 1 patient each. One patient was found to have a previously identified missense mutation (Q840P; 189909.0004).
Lechner et al. (2013) tabulated published reports of ZEB1-associated corneal dystrophy, demonstrating that missense substitutions were associated with cases of FECD6, whereas protein-truncating mutations were associated with posterior polymorphous corneal dystrophy-3 (PPCD3; 609141).
Gupta, R., Kumawat, B. L., Paliwal, P., Tandon, R., Sharma, N., Sen, S., Kashyap, S., Nag, T. C., Vajpayee, R. B., Sharma, A. Association of ZEB1 and TCF4 rs613872 changes with late onset Fuchs endothelial corneal dystrophy in patients from northern India. Molec. Vision 21: 1252-1260, 2015. [PubMed: 26622166]
Lechner, J., Dash, D. P., Muszynska, D., Hosseini, M., Segev, F., George, S., Frazer, D. G., Moore, J. E., Kaye, S. B., Young, T., Simpson, D. A., Churchill, A. J., Heon, E., Willoughby, C. E. Mutational spectrum of the ZEB1 gene in corneal dystrophies supports a genotype-phenotype correlation. Invest. Ophthal. Vis. Sci. 54: 3215-3223, 2013. [PubMed: 23599324] [Full Text: https://doi.org/10.1167/iovs.13-11781]
Riazuddin, S. A., Vasanth, S., Katsanis, N., Gottsch, J. D. Mutations in AGBL1 cause dominant late-onset Fuchs corneal dystrophy and alter protein-protein interaction with TCF4. Am. J. Hum. Genet. 93: 758-764, 2013. [PubMed: 24094747] [Full Text: https://doi.org/10.1016/j.ajhg.2013.08.010]
Riazuddin, S. A., Zaghloul, N. A., Al-Saif, A., Davey, L., Diplas, B. H., Meadows, D. N., Eghrari, A. O., Minear, M. A., Li, Y.-J., Klintworth, G. K., Afshari, N., Gregory, S. G., Gottsch, J. D., Katsanis, N. Missense mutations in TCF8 cause late-onset Fuchs corneal dystrophy and interact with FCD4 on chromosome 9p. Am. J. Hum. Genet. 86: 45-53, 2010. [PubMed: 20036349] [Full Text: https://doi.org/10.1016/j.ajhg.2009.12.001]