PubMed · 5258334
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Chan Ying Fatt. 1969. Cebocephaly--a case report.. https://pubmed.ncbi.nlm.nih.gov/5258334/
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DNA methylation is necessary for normal embryogenesis in animals. Here we show that loss of the maintenance methyltransferase, xDnmt1p, triggers an apoptotic response during Xenopus development, which accounts for the loss of specific cell populations in hypomethylated embryos. Hypomethylation-induced apoptosis is accompanied by a stabilization in xp53 protein levels after the mid-blastula transition. Ectopic expression of HPV-E6, which promotes xp53 degradation, prevents cell death, implying that the apoptotic signal is mediated by xp53. In addition, inhibition of caspase activation by overexpression of Bcl-2 results in the development of cellular masses that resemble embryonic blastomas. Embryonic tissue explant experiments suggest that hypomethylation alters the developmental potential of early embryo cells and that apoptosis is triggered by differentiation. Our results imply that loss of DNA methylation in differentiated somatic cells provides a signal via p53 that activates cell death pathways.
Mutations in the PITX2 bicoid-like homeobox gene cause Rieger syndrome. Rieger syndrome is an autosomal-dominant human disorder characterized by glaucoma as well as dental hypoplasia, mild craniofacial dysmorphism, and umbilical stump abnormalities. PITX2 has also been implicated in the development of multiple organs and left-right asymmetry in the body plan. The PITX2 homeodomain has a lysine at position 50, which has been shown to impart the bicoid-type (TAATCC) DNA binding specificity to other homeodomain proteins. A mutation (K88E), found in a Rieger syndrome patient, changes this lysine to glutamic acid. We were intrigued by the relatively pronounced phenotypic consequences of this K88E mutation. In the initial analyses, the mutant protein appeared to simply be inactive, with essentially no DNA binding and transactivation activities and, unlike the wild type protein, with an inability to synergize with another transcription factor, Pit-1. However, when the K88E DNA was cotransfected with wild type PITX2, analogous to the patient genotype, the K88E mutant suppressed the synergism of wild type PITX2 with Pit-1. In contrast, a different PITX2 homeodomain mutant, T68P, which is also defective in DNA binding, transactivation, and Pit-1 synergism activities, did not suppress the wild type synergism with Pit-1. These results describe the first dominant negative missense mutation in a homeodomain and support a model that may partially explain the phenotypic variation within Rieger syndrome.
The relationship of choanal atresia to various systemic malformations is well acknowledged by the CHARGE acronym: colobomas, heart defects, atresia choanae, retarded growth and development, genito-urinary defects, and ear defects. In the past, we have reported the finding of an isolated skull base malformation associated with choanal atresia. We report here a unique case of choanal atresia associated with a patent foramen cecum and intracranial extension of a dermoid sinus. The embryogenesis of this condition is accounted for by the mesodermal flow theory of choanal atresia formation, and implies a need for thorough imaging of the anterior skull base in cases of bilateral atresia.