Article

Posterior polymorphous corneal dystrophy is associated with TCF8 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: 2.05). 12/2007; 143A(21):2549-56. DOI: 10.1002/ajmg.a.31978
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
142 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Inguinal hernia is a common surgical disease, majority of which are indirect inguinal hernia (IIH). A positive family history has indicated that genetic factors play important roles in the IIH development. To date, genetic causes and underlying mechanisms for inguinal hernia remain largely unknown. During the embryonic development, GATA transcription factor 6 (GATA 6) plays an essential role. Mutations in GATA6 gene and changed GATA6 levels have been associated with human diseases. As GATA6 acts in a dosage-dependent manner, we speculated that changed GATA6 levels, resulting from DNA sequence variants (DSVs) within the gene regulatory regions, may mediate the IIH development. In this study, the GATA6 gene promoter was genetically and functionally analyzed in IIH patients and ethnic-matched controls. Eleven DNA sequence variants (DSVs), including four SNPs and seven new variants, within the GATA6 gene promoter were identified. Two heterozygous DSVs, g.22168361C>A and g.22169106C>T, were identified in two IIH patients, but in none of controls. In cultured human fibroblast, these DSVs significantly reduced the GATA6 gene promoter activities. In addition, three heterozygous DSVs were only found in three controls. Five DSVs, including four SNPs and one new variant, were found in both IIH patients and controls with similar frequencies. Therefore, the DSVs within the GATA6 gene promoter may contribute to the IIH development as a risk factor by changing the GATA6 levels.
    Gene 06/2014; DOI:10.1016/j.gene.2014.06.030 · 2.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose:To assess the impact of zinc finger E-box binding homeobox 1(ZEB1) gene mutations associated with posterior polymorphous corneal dystrophy 3 (PPCD3) and Fuchs endothelial corneal dystrophy (FECD). Methods:Thirteen of the 27 previously reported ZEB1 truncating mutations associated with PPCD3 and the 6 previously reported ZEB1 missense mutations associated with FECD were generated and transiently transfected into a corneal endothelial cell line. Protein abundance was determined by immunoblotting, while intracellular localization was determined by fluorescence confocal microscopy. Results:Three of the 13 ZEB1 truncated mutants, and none of the missense mutants, showed significant decrease in mutant ZEB1 protein levels. Predominant nuclear localization was observed for truncated ZEB1 mutant proteins with a predicted molecular weight of less than 92 kilodaltons. The two largest mutant proteins that lacked a putative nuclear localization signal (NLS), p.(Ser638Cysfs*5) and p.(Gln884Argfs*37), primarily localized to the cytoplasm, while the NLS-containing mutant proteins, p.(Glu997Alafs*7) and p.(Glu1039Glyfs*6), primarily localized to the nucleus. All the missense ZEB1 mutant proteins were exclusively present in the nucleus. Conclusions:ZEB1 truncating mutations result in a significant decrease and/or impaired nuclear localization of the encoded protein, indicating that ZEB1 haploinsufficiency in PPCD3 may result from decreased protein production and/or impaired cellular localization. Conversely, as the reported ZEB1 missense mutations do not significantly impact protein abundance or nuclear localization, the effect of these mutations on ZEB1 function and their relationship to FECD, if any, remain to be elucidated.
    Investigative Ophthalmology &amp Visual Science 09/2014; 55(10). DOI:10.1167/iovs.14-15247 · 3.66 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Posterior polymorphous corneal dystrophy 3 (PPCD3) is a rare autosomal dominant disorder caused by mutations in ZEB1. To date all identified disease-causing variants were unique to the studied families, except for c.1576dup. We have detected six novel ZEB1 mutations; c.1749_1750del; p.(Pro584*) and c.1717_1718del; p.(Val573Phefs*12) in two Czech families, c.1176dup; p.(Ala393Serfs*19), c.1100C>A; p.(Ser367*), c.627del; p.(Phe209Leufs*11) in three British families and a splice site mutation, c.685–2A>G, in a patient of Sri Lankan origin. An additional British proband had the c.1576dup; p.(Val526Glyfs*3) mutation previously reported in other populations. Clinical findings were variable and included bilateral congenital corneal opacity in one proband, development of opacity before the age of 2 years in another individual and bilateral iris flocculi in yet another subject. The majority of eyes examined by corneal topography (10 out of 16) had an abnormally steep cornea (flat keratometry 46.5–52.7 diopters, steep keratometry 48.1–54.0 diopters). One proband underwent surgery for cryptorchidism. Our study further demonstrates that PPCD3 can present as corneal edema in early childhood, and that an abnormally steep keratometry is a common feature of this condition. As cryptorchidism has been previously observed in two other PPCD3 cases, its association with the disease warrants further investigation.
    Annals of Human Genetics 11/2014; 79(1). DOI:10.1111/ahg.12090 · 1.93 Impact Factor

Full-text (2 Sources)

Download
142 Downloads
Available from
Jun 3, 2014