Posterior polymorphous corneal dystrophy is associated withTCF8 gene mutations and abdominal hernia

The Jules Stein Eye Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 11/2007; 143A(21):2549-56. DOI: 10.1002/ajmg.a.31978
Source: PubMed


Mutations in the two-handed zinc-finger homeodomain transcription factor gene (TCF8) have been associated with posterior polymorphous corneal dystrophy (PPCD) and extraocular developmental abnormalities. We performed screening of TCF8 in 32 affected, unrelated probands, affected and unaffected family members of probands identified with a TCF8 mutation, and in 100 control individuals. Eight different pathogenic mutations were identified in eight probands: four frameshift (c.953_954insA, c.1506dupA, c.1592delA, and c.3012_3013delAG); three nonsense (Gln12X, Gln214X, Arg325X); and one missense (Met1Arg). Screening of TCF8 in affected and unaffected family members in six families demonstrated that each identified mutation segregated with the disease phenotype in each family; two probands did not have additional family members available for analysis. None of the eight TCF8 mutations was identified in 200 control chromosomes. The prevalence of hernias of the abdominal region in affected individuals with PPCD associated with TCF8 mutations was significantly higher than the prevalence in both individuals with PPCD not associated with a TCF8 mutation and in unaffected individuals. Therefore, PPCD is associated with TCF8 mutations in one quarter of affected families in this study, or about one third of all PPCD families that have been screened thus far. In these families, the presence of apparently causative TCF8 mutations is associated with abdominal and inguinal hernias.

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    • "Krafchak and colleagues reported frameshift mutations in the zinc finger E-box binding homeodomain 1 gene (ZEB1 gene; OMIM 189909) in the PPCD3 locus in five of 11 probands and demonstrated altered endothelial expression of the collagen IV, alpha 3 (COL4A3; OMIM 120070) gene in the corneal endothelium of an affected individual, leading to their proposed theory of pathogenesis of PPCD3 [8]. We confirmed the role of ZEB1 in PPCD3 by reporting eight additional frameshift mutations in 32 probands who were screened, and provided additional evidence to support the role of ZEB1 in negative regulation of COL4A3 transcription [7]. "
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    ABSTRACT: To report the identification of five novel nonsense mutations in the zinc finger E-box binding homeobox 1 (ZEB1) gene and exclusion of promoter region mutations in individuals without ZEB1 coding region mutations in posterior polymorphous corneal dystrophy (PPCD). Slit-lamp examination and DNA collection were performed for individuals diagnosed with PPCD and, when available, affected and unaffected family members. Genomic DNA prepared from peripheral blood leukocytes and buccal epithelial cells underwent PCR amplification and automated sequencing of the ZEB1 gene and 1 kb 5' of ZEB1, presumably containing the ZEB1 promoter region. Thirteen unrelated individuals with PPCD were identified, and genomic DNA was collected from each individual. ZEB1 mutations were identified in six of the 13 probands, five of which were novel: p.(Gly150Alafs*36; spontaneous), p.(His230Argfs*7), p.(Ser638Cysfs*5), p.(Glu1039Glyfs*6), and p.(Gln884Argfs*37). Screening of the ZEB1 promoter region in 31 probands with PPCD without a ZEB1 coding region mutation identified only two known single nucleotide polymorphisms (SNPs) whose frequency in the affected probands did not differ significantly from that in the general population. We report five novel frame-shift mutations, one confirmed as spontaneous, in the ZEB1 gene associated with PPCD, bringing the total number of reported pathogenic mutations to 24, and the percentage of PPCD associated with ZEB1 mutations to 32%. The absence of ZEB1 promoter region mutations in probands without a ZEB1 coding region mutation indicates that other genetic loci, such as the PPCD1 locus, are involved in the pathogenesis of PPCD.
    Molecular vision 03/2013; 19:575-80. · 1.99 Impact Factor
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    • "Moreover, the causal involvement of SLC4A11 also reinforces and extends the notion that the corneal endothelial dystrophies represent a phenotypic continuum with significant genetic overlap, despite their discrete clinical manifestation. We have shown recently that adult-onset FCD and juvenile-onset PPCD are allelic, by virtue of the presence of heterozygous TCF8 missense mutations in FCD patients (Riazuddin et al., 2010); haploinsufficiency at that locus causes PPCD, since all known PPCD mutations lead to null alleles (Krafchak et al., 2005; Aldave et al., 2007), whereas residual protein activity gives rise to a later-onset disorder, FCD. A similar model can be proposed for the observed CHED-FCD relationship, where biallelic SLC4A11 mutations give rise to the congenital disorder, whereas partial loss of function (haploinsufficiency) causes the same molecular problems but is of late onset. "
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    ABSTRACT: Homozygous mutations in the Borate Cotransporter SLC4A11 cause two early-onset corneal dystrophies: congenital hereditary endothelial dystrophy (CHED) and Harboyan syndrome. More recently, four sporadic patients with late-onset Fuchs corneal dystrophy (FCD), a common age-related disorder, were also reported to harbor heterozygous mutations at this locus. We therefore tested the hypothesis that SLC4A11 contributes to FCD and asked whether mutations in SLC4A11 are responsible for familial cases of late-onset FCD. We sequenced SLC4A11 in 192 sporadic and small nuclear late-onset FCD families and found seven heterozygous missense novel variations that were absent from ethnically matched controls. Familial data available for one of these mutations showed segregation under a dominant model in a three-generational family. In silico analyses suggested that most of these substitutions are intolerant, whereas biochemical studies of the mutant protein indicated that these alleles impact the localization and/or posttranslational modification of the protein. These results suggest that heterozygous mutations in SLC4A11 are modest contributors to the pathogenesis of adult FCD, suggesting a causality continuum between FCD and CHED. Taken together with a recent model between FCD and yet another early onset corneal dystrophy, PPCD, our data suggest a shared pathomechanism and genetic overlap across several corneal dystrophies.
    Human Mutation 11/2010; 31(11):1261-8. DOI:10.1002/humu.21356 · 5.14 Impact Factor
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    • "Human PPCD, like many eye disorders, exhibits genetic heterogeneity and has been linked to three chromosomal loci, 10p11, 20p11.2, and 1p34.3-p32. The transcription factor ZEB1 gene, at 10p11, is the best characterized PPCD gene (PPCD3, MIM #609141) [13], [14], [15], [16]. Recently, missense mutations in ZEB1 in association with a locus on chromosome 9 have also been linked to FECD [17]. "
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    ABSTRACT: The PPCD1 mouse, a spontaneous mutant that arose in our mouse colony, is characterized by an enlarged anterior chamber resulting from metaplasia of the corneal endothelium and blockage of the iridocorneal angle by epithelialized corneal endothelial cells. The presence of stratified multilayered corneal endothelial cells with abnormal patterns of cytokeratin expression are remarkably similar to those observed in human posterior polymorphous corneal dystrophy (PPCD) and the sporadic condition, iridocorneal endothelial syndrome. Affected eyes exhibit epithelialized corneal endothelial cells, with inappropriate cytokeratin expression and proliferation over the iridocorneal angle and posterior cornea. We have termed this the "mouse PPCD1" phenotype and mapped the mouse locus for this phenotype, designated "Ppcd1", to a 6.1 Mbp interval on Chromosome 2, which is syntenic to the human Chromosome 20 PPCD1 interval. Inheritance of the mouse PPCD1 phenotype is autosomal dominant, with complete penetrance on the sensitive DBA/2J background and decreased penetrance on the C57BL/6J background. Comparative genome hybridization has identified a hemizygous 78 Kbp duplication in the mapped interval. The endpoints of the duplication are located in positions that disrupt the genes Csrp2bp and 6330439K17Rik and lead to duplication of the pseudogene LOC100043552. Quantitative reverse transcriptase-PCR indicates that expression levels of Csrp2bp and 6330439K17Rik are decreased in eyes of PPCD1 mice. Based on the observations of decreased gene expression levels, association with ZEB1-related pathways, and the report of corneal opacities in Csrp2bp(tm1a(KOMP)Wtsi) heterozygotes and embryonic lethality in nulls, we postulate that duplication of the 78 Kbp segment leading to haploinsufficiency of Csrp2bp is responsible for the mouse PPCD1 phenotype. Similarly, CSRP2BP haploinsufficiency may lead to human PPCD.
    PLoS ONE 08/2010; 5(8):e12213. DOI:10.1371/journal.pone.0012213 · 3.23 Impact Factor
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