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CORNEAL DYSTROPHY, POSTERIOR POLYMORPHOUS, 3; PPCD3

CORNEAL DYSTROPHY, POSTERIOR POLYMORPHOUS, 3; PPCD3

Moroi et al. (2003) reported a woman with PPCD who had a prominent retrocorneal membrane. The authors stated that this feature had not previously been reported w...

Moroi et al. (2003) reported a woman with PPCD who had a prominent retrocorneal membrane. The authors stated that this feature had not previously been reported with PPCD. Many of the woman's relatives were affected by PPCD with 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.

▼ 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 (203780), 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.

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.

Tags: 10p11.22