Identification of a novel mutation in the cornea specific keratin 12 gene causing Meesmann's corneal dystrophy in a German family.

PURPOSE: To report a novel missense mutation of the cornea specific keratin 12 (KRT12) gene in two generations of a German family diagnosed with Meesmann;s corneal dystrophy. METHODS: Ophthalmologic examination of the proband and sequencing of keratin 3 (KRT3) and KRT12 of the proband and three other family members were performed. Restriction enzyme analysis was used to confirm the detected mutation in affected individuals of the family. RESULTS: Slit-lamp biomicroscopy of the proband revealed multiple intraepithelial microcysts comparable to a Meesmann dystrophy phenotype. A novel heterozygous A-->G transversion at the first nucleotide position of codon 129 (ATG>GTG, M129V) in exon 1 of KRT12 was detected in the proband, her two affected sons but not in her unaffected husband or 50 control individuals. CONCLUSIONS: We have identified a novel missense mutation within the highly conserved helix-initiation motif of KRT12 causing Meesmann;s corneal dystrophy in a German family.

A corneal dystrophy associated with transforming growth factor beta-induced Gly623Asp mutation an amyloidogenic phenotype.

PURPOSE: To present the light and electron microscopic findings of a unique corneal dystrophy never before described in a German family carrying the Gly623Asp Mutation of the TGFBI gene with late clinical onset. DESIGN: Experimental study. PARTICIPANTS: Four affected and 6 nonaffected family members. METHODS: Slit-lamp examination, photographic documentation, and isolation of genomic DNA from peripheral blood leucocytes obtained from each family member examined. Exons 3, 4, 5, and 11 to 14 of the TGFBI gene were amplified and sequenced in these family members. Five corneal buttons of 3 affected siblings were excised at the time of penetrating keratoplasty. Light and electron microscopic examination were performed including immunohistochemistry with antibodies against keratoepithelin (KE) 2 and 15. MAIN OUTCOME MEASURES: Clinical and histologic characteristics of corneal opacification in affected patients and presence of coding region changes in the TGFBI gene. RESULTS: The specimens showed destructive changes in Bowman's layer and the adjacent stroma. Patchy Congo red-positive amyloid deposits were found within the epithelium in 1 cornea, in Bowman's layer and in the anterior stroma of all specimens also showing KE2, but not KE15, immunostaining. Electron microscopy revealed deposits mainly located in the anterior stroma and Bowman's layer and in small amounts in the basal area of some epithelial cells. The destroyed areas were strongly Alcian blue-positive, the Masson Trichrome stain proved mainly negative for the deposits. All affected but none of the unaffected family members had a heterozygous missense mutation in exon 14 of the TGFBI gene (G-->A transition at nucleotide 1915) replacing glycin by aspartic acid amino acid (Gly623Asp) at position 623 of the KE protein. CONCLUSIONS: In contrast with the patient carrying the Gly623Asp mutation of the TGFBI gene described by Afshari et al, our cases presented with Salzmann's nodular degeneration-like clinical features and their specimens contained KE2-positive amyloid. The reason for this now "meeting the expectation histologic phenotype" is unclear. The histologic findings emphasize that this is a unique corneal dystrophy, which shares no clinical characteristics with Reis-Bücklers' dystrophy and should be treated as a distinct entity. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

Lineage-specific effects of polychlorinated biphenyls (PCB) on gene expression in the rabbit blastocyst.

The ubiquitous toxic environmental contaminants polychlorinated biphenyls (PCBs) change gene expression in preimplantation embryos. Cell lineage-specific effects of PCB are not known. Rabbit day 6 blastocysts were exposed in vitro to low (0.1 ng/congener/mL medium) and high (1 microg) PCB levels of coplanar (PCB 77, 126, and 169) or non-coplanar PCBs (PCB 28, 52, 101, 118, 138, 153, and 180). Embryoblast (ICM) and trophoblast cells (TE) were separated and analyzed for transcriptional changes of PCB-and implantation-associated genes by semiquantitative RT-PCR. PCBs increased CYP 1A1 mRNA only in the ICM. CYP 1B1, VEGFR2, and COX-2 transcript numbers were elevated in both ICM and TE. Transcripts for HIF-1alpha were decreased in the ICM. No obvious differences in gene expression following exposure to coplanar and non-coplanar PCBs were detected. Our results show that transcriptional responses to PCBs differ between the cell lineages of the rabbit blastocyst, indicating that PCBs can influence the highly sensitive process of early mammalian development.