# 609141

CORNEAL DYSTROPHY, POSTERIOR POLYMORPHOUS, 3; PPCD3


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
10p11.22 Corneal dystrophy, posterior polymorphous, 3 609141 AD 3 ZEB1 189909
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal dominant
HEAD & NECK
Eyes
- Reduced vision
- Corectopia
- Focal corneal endothelial opacifications
- Corneal endothelial vesicles
- Corneal steepening
- Keratoconus (in some patients)
- Iridocorneal adhesions
- Peripheral anterior synechiae
- Ectropion uveae
- Increased intraocular pressure
- Retrocorneal membrane
- 'Rail tracks' appearance of corneal endothelium
- Stratified endothelium of the cornea
- Decreased endothelial cell count
- Polymegathism of endothelial cells
- Polymorphism of endothelial cells
- Corneal microvilli, tonofilaments, and desmosomes seen on electron microscopy (epithelial-like endothelial transformation)
MISCELLANEOUS
- Inter- and intrafamilial variability in severity
MOLECULAR BASIS
- Caused by mutation in the zinc finger E box-binding homeobox-1 gene (ZEB1, 189909.0001)

TEXT

A number sign (#) is used with this entry because of evidence that posterior polymorphous corneal dystrophy-3 (PPCD3) is caused by heterozygous mutation in the ZEB1 gene (189909) on chromosome 10p11.

Another form of corneal dystrophy, Fuchs endothelial corneal dystrophy-6 (FECD6; 613270), is also caused by heterozygous mutation in the ZEB1 gene.


Description

Posterior polymorphous corneal dystrophy-3 (PPCD3) is a rare disorder involving metaplasia and overgrowth of corneal endothelial cells (Krafchak et al., 2005). In patients with PPCD, these cells manifest in an epithelial morphology and gene expression pattern, produce an aberrant basement membrane, and sometimes spread over the iris and nearby structures in a way that increases the risk for glaucoma. Symptoms range from very aggressive to asymptomatic and nonprogressive, even within the same family. The age of diagnosis is most often in the second or third decade of life.

PPCD3 is often associated with corneal steepening, and some patients may be diagnosed with keratoconus before PPCD (Fernandez-Gutierrez et al., 2023). Retrocorneal membranes have been reported, sometimes extending onto the lens (Moroi et al., 2003).

For a discussion of genetic heterogeneity of posterior polymorphous corneal dystrophy, see PPCD1 (122000).


Clinical Features

Moroi et al. (2003) reported a woman with PPCD who had a prominent retrocorneal membrane that extended onto the crystalline lens and later onto the anterior surface of an intraocular lens implant. The authors stated that this feature had not previously been reported with PPCD. The proband had 12 affected relatives over 3 generations (family UM:139), showing apparent autosomal dominant inheritance.

In the family reported by Moroi et al. (2003), Shimizu et al. (2004) noted that guttae, a common corneal finding sometimes observed along with PPCD, were found among both affected and unaffected members of the proband's sibship, but were absent in the younger generations of the family. Because the expressivity of the PPCD phenotype varied widely in this family, Shimizu et al. (2004) suggested that differences in disease severity could be due to genetic background or other factors independent of the PPCD3 locus.

Krafchak et al. (2005) noted that patients with PPCD3 have been reported with inguinal hernia, hydrocele, and possible bone anomalies. They suggested that these patients should be examined for nonocular anomalies.

Lechner et al. (2013) reported a family from the United Kingdom in which 6 patients over 3 generations had PPCD and mutation in the ZEB1 gene. Affected individuals had bilateral corneal vesicles, dot-like opacities, and endothelial corneal changes with reduced endothelial cell count. Topography performed in 1 patient showed corneal steepening but no signs of keratoconus.

Fernandez-Gutierrez et al. (2023) studied a 64-year-old woman with PPCD and mutation in the ZEB1 gene. She had been diagnosed previously with keratoconus, and intrastromal rings had been implanted in the left eye. Biomicroscopy showed focal opacification of the corneal endothelium in the right eye, as well as anterior iridoendothelial synechiae and superonasal corectopia. In the left eye, there was an intrastromal segment observed, as well as 'rail tracks' in the paracentral corneal endothelium, associated with patchy endothelial opacification. Specular microscopy showed a decreased endothelial cell count, polymegathism, polymorphism of endothelial cells, and a number of vesicles. Confocal microscopy revealed posterior stromal keratocytes with spindle nuclei and polymorphism, polymegathism, and giant endothelial cells, with a number of nucleated cells bilaterally. The left eye also showed a hyporeflective crater-shaped lesion and curvilinear hyperreflective band lesion.


Inheritance

The transmission pattern of PPCD3 in the family reported by Moroi et al. (2003) was consistent with autosomal dominant inheritance.


Mapping

In a family segregating PPCD, Moroi et al. (2003) excluded the candidate genes VSX1 (605020) and COL8A2 (120252) by linkage and haplotype analysis. They also excluded linkage to the PPCD1 (122000) and CHED (217700) loci.

Shimizu et al. (2004) performed a genome scan in 26 members of the family reported by Moroi et al. (2003) and found significant linkage of PPCD to markers on chromosome 10, with a maximum multipoint lod score of 4.35 at marker D10S1780. Affected family members shared a haplotype in an 8.55-cM critical interval that was bounded by markers D10S213 and D10S578.


Pathogenesis

Krafchak et al. (2005) detected transcripts of all 3 identified PPCD-associated genes in the cornea: VSX1, COL8A2, and TCF8. They demonstrated a complex (core plus secondary) binding site for TCF8 in the promoter of the COL4A3 gene (120070), which is mutant in Alport syndrome (see 104200), and presented immunohistochemical evidence of ectopic expression of COL4A3 in corneal endothelium of the proband of the original PPCD3 family. Identification of TCF8 as the PPCD3 gene provided a valuable tool for the study of critical gene regulation events in PPCD pathology and suggested a possible role for TCF8 mutations in altered structure and function of cells lining body cavities other than the anterior chamber of the eye. This study identified TCF8 as the gene responsible for approximately half of the cases of PPCD, implicated TCF8 mutations in developmental abnormalities outside the eye, and revealed COL4A3, the TCF8 regulatory target, as a key, shared molecular component of 2 different diseases, PPCD and Alport syndrome.


Molecular Genetics

Krafchak et al. (2005) identified a heterozygous frameshift mutation in the TCF8 (ZEB1) gene (189909.0001) in affected members of the family with PPCD reported by Moroi et al. (2003) and 4 different heterozygous nonsense and frameshift mutations in TCF8 in 4 other PPCD probands (see, e.g., 189909.0002).

Liskova et al. (2007) analyzed the ZEB1 gene in 6 Czech and 4 British families with PPCD, and identified 4 pathogenic mutations in 4 of the families. The authors noted that although a systematic clinical examination was not performed, their findings did not support an association between ZEB1 changes and self-reported nonocular anomalies.

In a cohort of 18 unrelated patients with PPCD, Lechner et al. (2013) performed Sanger sequencing of the ZEB1 gene and identified a previously reported frameshift mutation in an affected mother and son, as well as a nonsense mutation (S750X; 189909.0006) in a family from the United Kingdom with 6 affected individuals over 3 generations. Neither mutation was found in 96 controls or in public variant databases.

In a 64-year-old woman with keratoconus and PPCD, Fernandez-Gutierrez et al. (2023) analyzed 6 PPCD-associated genes and identified heterozygosity for a missense mutation in the ZEB1 gene (M1L; 189909.0007) that was confirmed by Sanger sequencing. Her unaffected 36-year-old son, who had normal biomicroscopy and specular microscopy findings, did not carry the mutation.


Genotype/Phenotype Correlations

Lechner et al. (2013) tabulated published reports of ZEB1-associated corneal dystrophy, demonstrating that missense substitutions were associated with cases of Fuchs endothelial corneal dystrophy-6 (FECD6; 613270), whereas protein-truncating mutations were associated with PPCD3.


REFERENCES

  1. Fernandez-Gutierrez, E., Fernandez-Perez, P., Boto-De-Los-Bueis, A., Garcia-Fernandez, L., Rodriguez-Solana, P., Solis, M., Vallespin, E. Posterior polymorphous corneal dystrophy in a patient with a novel ZEB1 gene mutation. Int. J. Molec. Sci. 24: 209, 2023. [PubMed: 36613650, images, related citations] [Full Text]

  2. Krafchak, C. M., Pawar, H., Moroi, S. E., Sugar, A., Lichter, P. R., Mackey, D. A., Mian, S., Nairus, T., Elner, V., Schteingart, M. T., Downs, C. A., Kijek, T. G., and 9 others. Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells. Am. J. Hum. Genet. 77: 694-708, 2005. [PubMed: 16252232, images, related citations] [Full Text]

  3. 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, related citations] [Full Text]

  4. Liskova, P., Tuft, S. J., Gwilliam, R., Ebenezer, N. D., Jirsova, K., Prescott, Q., Martincova, R., Pretorius, M., Sinclair, N., Boase, D. L., Jeffrey, M. J., Deloukas, P., Hardcastle, A. J., Filipec, M., Bhattacharya, S. S. Novel mutations in the ZEB1 gene identified in Czech and British patients with posterior polymorphous corneal dystrophy. (Abstract) Hum. Mutat. 28: 638 only, 2007. Note: Full article online.

  5. Moroi, S. E., Gokhale, P. A., Schteingart, M. T., Sugar, A., Downs, C. A., Shimizu, S., Krafchak, C., Fuse, N., Elner, S. G., Elner, V. M., Flint, A., Epstein, M. P., Boehnke, M., Richards, J. E. Clinicopathologic correlation and genetic analysis in a case of posterior polymorphous corneal dystrophy. Am. J. Ophthal. 135: 461-470, 2003. [PubMed: 12654361, related citations] [Full Text]

  6. Shimizu, S., Krafchak, C., Fuse, N., Epstein, M. P., Schteingart, M. T., Sugar, A., Eibschitz-Tsimhoni, M., Downs, C. A., Rozsa, F., Trager, E. H., Reed, D. M., Boehnke, M., Moroi, S. E., Richards, J. E. A locus for posterior polymorphous corneal dystrophy (PPCD3) maps to chromosome 10. Am. J. Med. Genet. 130A: 372-377, 2004. [PubMed: 15384081, images, related citations] [Full Text]


Marla J. F. O'Neill - updated : 01/23/2023
Marla J. F. O'Neill - updated : 3/30/2016
Victor A. McKusick - updated : 10/12/2005
Creation Date:
Marla J. F. O'Neill : 1/5/2005
alopez : 10/06/2023
carol : 01/24/2023
alopez : 01/23/2023
alopez : 01/23/2023
alopez : 01/23/2023
carol : 03/31/2016
carol : 3/30/2016
terry : 8/6/2010
carol : 2/24/2010
alopez : 10/13/2005
alopez : 10/13/2005
terry : 10/12/2005
carol : 1/5/2005

# 609141

CORNEAL DYSTROPHY, POSTERIOR POLYMORPHOUS, 3; PPCD3


ORPHA: 98973;   DO: 0110857;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
10p11.22 Corneal dystrophy, posterior polymorphous, 3 609141 Autosomal dominant 3 ZEB1 189909

TEXT

A number sign (#) is used with this entry because of evidence that posterior polymorphous corneal dystrophy-3 (PPCD3) is caused by heterozygous mutation in the ZEB1 gene (189909) on chromosome 10p11.

Another form of corneal dystrophy, Fuchs endothelial corneal dystrophy-6 (FECD6; 613270), is also caused by heterozygous mutation in the ZEB1 gene.


Description

Posterior polymorphous corneal dystrophy-3 (PPCD3) is a rare disorder involving metaplasia and overgrowth of corneal endothelial cells (Krafchak et al., 2005). In patients with PPCD, these cells manifest in an epithelial morphology and gene expression pattern, produce an aberrant basement membrane, and sometimes spread over the iris and nearby structures in a way that increases the risk for glaucoma. Symptoms range from very aggressive to asymptomatic and nonprogressive, even within the same family. The age of diagnosis is most often in the second or third decade of life.

PPCD3 is often associated with corneal steepening, and some patients may be diagnosed with keratoconus before PPCD (Fernandez-Gutierrez et al., 2023). Retrocorneal membranes have been reported, sometimes extending onto the lens (Moroi et al., 2003).

For a discussion of genetic heterogeneity of posterior polymorphous corneal dystrophy, see PPCD1 (122000).


Clinical Features

Moroi et al. (2003) reported a woman with PPCD who had a prominent retrocorneal membrane that extended onto the crystalline lens and later onto the anterior surface of an intraocular lens implant. The authors stated that this feature had not previously been reported with PPCD. The proband had 12 affected relatives over 3 generations (family UM:139), showing apparent autosomal dominant inheritance.

In the family reported by Moroi et al. (2003), Shimizu et al. (2004) noted that guttae, a common corneal finding sometimes observed along with PPCD, were found among both affected and unaffected members of the proband's sibship, but were absent in the younger generations of the family. Because the expressivity of the PPCD phenotype varied widely in this family, Shimizu et al. (2004) suggested that differences in disease severity could be due to genetic background or other factors independent of the PPCD3 locus.

Krafchak et al. (2005) noted that patients with PPCD3 have been reported with inguinal hernia, hydrocele, and possible bone anomalies. They suggested that these patients should be examined for nonocular anomalies.

Lechner et al. (2013) reported a family from the United Kingdom in which 6 patients over 3 generations had PPCD and mutation in the ZEB1 gene. Affected individuals had bilateral corneal vesicles, dot-like opacities, and endothelial corneal changes with reduced endothelial cell count. Topography performed in 1 patient showed corneal steepening but no signs of keratoconus.

Fernandez-Gutierrez et al. (2023) studied a 64-year-old woman with PPCD and mutation in the ZEB1 gene. She had been diagnosed previously with keratoconus, and intrastromal rings had been implanted in the left eye. Biomicroscopy showed focal opacification of the corneal endothelium in the right eye, as well as anterior iridoendothelial synechiae and superonasal corectopia. In the left eye, there was an intrastromal segment observed, as well as 'rail tracks' in the paracentral corneal endothelium, associated with patchy endothelial opacification. Specular microscopy showed a decreased endothelial cell count, polymegathism, polymorphism of endothelial cells, and a number of vesicles. Confocal microscopy revealed posterior stromal keratocytes with spindle nuclei and polymorphism, polymegathism, and giant endothelial cells, with a number of nucleated cells bilaterally. The left eye also showed a hyporeflective crater-shaped lesion and curvilinear hyperreflective band lesion.


Inheritance

The transmission pattern of PPCD3 in the family reported by Moroi et al. (2003) was consistent with autosomal dominant inheritance.


Mapping

In a family segregating PPCD, Moroi et al. (2003) excluded the candidate genes VSX1 (605020) and COL8A2 (120252) by linkage and haplotype analysis. They also excluded linkage to the PPCD1 (122000) and CHED (217700) loci.

Shimizu et al. (2004) performed a genome scan in 26 members of the family reported by Moroi et al. (2003) and found significant linkage of PPCD to markers on chromosome 10, with a maximum multipoint lod score of 4.35 at marker D10S1780. Affected family members shared a haplotype in an 8.55-cM critical interval that was bounded by markers D10S213 and D10S578.


Pathogenesis

Krafchak et al. (2005) detected transcripts of all 3 identified PPCD-associated genes in the cornea: VSX1, COL8A2, and TCF8. They demonstrated a complex (core plus secondary) binding site for TCF8 in the promoter of the COL4A3 gene (120070), which is mutant in Alport syndrome (see 104200), and presented immunohistochemical evidence of ectopic expression of COL4A3 in corneal endothelium of the proband of the original PPCD3 family. Identification of TCF8 as the PPCD3 gene provided a valuable tool for the study of critical gene regulation events in PPCD pathology and suggested a possible role for TCF8 mutations in altered structure and function of cells lining body cavities other than the anterior chamber of the eye. This study identified TCF8 as the gene responsible for approximately half of the cases of PPCD, implicated TCF8 mutations in developmental abnormalities outside the eye, and revealed COL4A3, the TCF8 regulatory target, as a key, shared molecular component of 2 different diseases, PPCD and Alport syndrome.


Molecular Genetics

Krafchak et al. (2005) identified a heterozygous frameshift mutation in the TCF8 (ZEB1) gene (189909.0001) in affected members of the family with PPCD reported by Moroi et al. (2003) and 4 different heterozygous nonsense and frameshift mutations in TCF8 in 4 other PPCD probands (see, e.g., 189909.0002).

Liskova et al. (2007) analyzed the ZEB1 gene in 6 Czech and 4 British families with PPCD, and identified 4 pathogenic mutations in 4 of the families. The authors noted that although a systematic clinical examination was not performed, their findings did not support an association between ZEB1 changes and self-reported nonocular anomalies.

In a cohort of 18 unrelated patients with PPCD, Lechner et al. (2013) performed Sanger sequencing of the ZEB1 gene and identified a previously reported frameshift mutation in an affected mother and son, as well as a nonsense mutation (S750X; 189909.0006) in a family from the United Kingdom with 6 affected individuals over 3 generations. Neither mutation was found in 96 controls or in public variant databases.

In a 64-year-old woman with keratoconus and PPCD, Fernandez-Gutierrez et al. (2023) analyzed 6 PPCD-associated genes and identified heterozygosity for a missense mutation in the ZEB1 gene (M1L; 189909.0007) that was confirmed by Sanger sequencing. Her unaffected 36-year-old son, who had normal biomicroscopy and specular microscopy findings, did not carry the mutation.


Genotype/Phenotype Correlations

Lechner et al. (2013) tabulated published reports of ZEB1-associated corneal dystrophy, demonstrating that missense substitutions were associated with cases of Fuchs endothelial corneal dystrophy-6 (FECD6; 613270), whereas protein-truncating mutations were associated with PPCD3.


REFERENCES

  1. Fernandez-Gutierrez, E., Fernandez-Perez, P., Boto-De-Los-Bueis, A., Garcia-Fernandez, L., Rodriguez-Solana, P., Solis, M., Vallespin, E. Posterior polymorphous corneal dystrophy in a patient with a novel ZEB1 gene mutation. Int. J. Molec. Sci. 24: 209, 2023. [PubMed: 36613650] [Full Text: https://doi.org/10.3390/ijms24010209]

  2. Krafchak, C. M., Pawar, H., Moroi, S. E., Sugar, A., Lichter, P. R., Mackey, D. A., Mian, S., Nairus, T., Elner, V., Schteingart, M. T., Downs, C. A., Kijek, T. G., and 9 others. Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells. Am. J. Hum. Genet. 77: 694-708, 2005. [PubMed: 16252232] [Full Text: https://doi.org/10.1086/497348]

  3. 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]

  4. Liskova, P., Tuft, S. J., Gwilliam, R., Ebenezer, N. D., Jirsova, K., Prescott, Q., Martincova, R., Pretorius, M., Sinclair, N., Boase, D. L., Jeffrey, M. J., Deloukas, P., Hardcastle, A. J., Filipec, M., Bhattacharya, S. S. Novel mutations in the ZEB1 gene identified in Czech and British patients with posterior polymorphous corneal dystrophy. (Abstract) Hum. Mutat. 28: 638 only, 2007. Note: Full article online.

  5. Moroi, S. E., Gokhale, P. A., Schteingart, M. T., Sugar, A., Downs, C. A., Shimizu, S., Krafchak, C., Fuse, N., Elner, S. G., Elner, V. M., Flint, A., Epstein, M. P., Boehnke, M., Richards, J. E. Clinicopathologic correlation and genetic analysis in a case of posterior polymorphous corneal dystrophy. Am. J. Ophthal. 135: 461-470, 2003. [PubMed: 12654361] [Full Text: https://doi.org/10.1016/s0002-9394(02)02032-9]

  6. Shimizu, S., Krafchak, C., Fuse, N., Epstein, M. P., Schteingart, M. T., Sugar, A., Eibschitz-Tsimhoni, M., Downs, C. A., Rozsa, F., Trager, E. H., Reed, D. M., Boehnke, M., Moroi, S. E., Richards, J. E. A locus for posterior polymorphous corneal dystrophy (PPCD3) maps to chromosome 10. Am. J. Med. Genet. 130A: 372-377, 2004. [PubMed: 15384081] [Full Text: https://doi.org/10.1002/ajmg.a.30267]


Contributors:
Marla J. F. O'Neill - updated : 01/23/2023
Marla J. F. O'Neill - updated : 3/30/2016
Victor A. McKusick - updated : 10/12/2005

Creation Date:
Marla J. F. O'Neill : 1/5/2005

Edit History:
alopez : 10/06/2023
carol : 01/24/2023
alopez : 01/23/2023
alopez : 01/23/2023
alopez : 01/23/2023
carol : 03/31/2016
carol : 3/30/2016
terry : 8/6/2010
carol : 2/24/2010
alopez : 10/13/2005
alopez : 10/13/2005
terry : 10/12/2005
carol : 1/5/2005