RESUMO
Revertant mosaicism, or "natural gene therapy", is the phenomenon in which germline mutations are corrected by somatic events. In recent years, revertant mosaicism has been identified in all major types of epidermolysis bullosa, the group of heritable blistering disorders caused by mutations in the genes encoding epidermal adhesion proteins. Moreover, revertant mosaicism appears to be present in all patients with a specific subtype of recessive epidermolysis bullosa. We therefore hypothesized that revertant mosaicism should be expected at least in all patients with recessive forms of epidermolysis bullosa. Naturally corrected, patient-own cells are of extreme interest for their promising therapeutic potential, and their presence in all patients would open exciting, new treatment perspectives to those patients. To test our hypothesis, we determined the probability that single nucleotide reversions occur in patients' skin using a mathematical developmental model. According to our model, reverse mutations are expected to occur frequently (estimated 216x) in each patient's skin. Reverse mutations should, however, occur early in embryogenesis to be able to drive the emergence of recognizable revertant patches, which is expected to occur in only one per ~10,000 patients. This underestimate, compared to our clinical observations, can be explained by the "late-but-fitter revertant cell" hypothesis: reverse mutations arise at later stages of development, but provide revertant cells with a selective growth advantage in vivo that drives the development of recognizable healthy skin patches. Our results can be extrapolated to any other organ with stem cell division numbers comparable to skin, which may offer novel future therapeutic options for other genetic conditions if these revertant cells can be identified and isolated.
Assuntos
Epidermólise Bolhosa/genética , Epidermólise Bolhosa/fisiopatologia , Queratinócitos/citologia , Modelos Biológicos , Mosaicismo , Mutação , Polimorfismo de Nucleotídeo Único , Idoso , Autoantígenos/genética , Proliferação de Células/genética , Criança , Epidermólise Bolhosa/embriologia , Epidermólise Bolhosa/patologia , Mutação em Linhagem Germinativa , Humanos , Queratinócitos/patologia , Queratinócitos/fisiologia , Masculino , Pessoa de Meia-Idade , Colágenos não Fibrilares/genética , Pele/crescimento & desenvolvimento , Pele/patologia , Pele/fisiopatologia , Células-Tronco , Colágeno Tipo XVIIRESUMO
Mutations of integrin-interacting protein Kindlin-1 cause Kindler syndrome and deregulation of Kindlin-1 is implicated in human cancers. The Kindlin-1-related diseases are confined in limited tissue types. However, Kindlin-1 tissue distribution and the dogma that governs Kindlin-1 expression in normal human body are elusive. This study examined Kindlin-1 expression in normal human adult organs, human and mouse embryonic organs by immunohistochemical analyses. We identified a general principle that the level of Kindlin-1 expression in tissues is tightly correlated with the corresponding germ layers from which these tissues originate. We compared the expression of Kindlin-1 with Kindlin-2 and found that Kindlin-1 is highly expressed in epithelial tissues derived from ectoderm and endoderm, whereas Kindlin-2 is mainly expressed in mesoderm-derived tissues. Likewise, Kindlin-1 was also found highly expressed in endoderm/ectoderm-derived tissues in human and mouse embryos. Our findings indicate that Kindlin-1 may play an importance role in the development of endoderm/ectoderm related tissues.
Assuntos
Vesícula/embriologia , Vesícula/metabolismo , Proteínas de Transporte/metabolismo , Epidermólise Bolhosa/embriologia , Epidermólise Bolhosa/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Doenças Periodontais/embriologia , Doenças Periodontais/metabolismo , Transtornos de Fotossensibilidade/embriologia , Transtornos de Fotossensibilidade/metabolismo , Adulto , Animais , Vesícula/genética , Proteínas de Transporte/genética , Ectoderma/embriologia , Ectoderma/metabolismo , Endoderma/embriologia , Endoderma/metabolismo , Epidermólise Bolhosa/genética , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Proteínas de Membrana/genética , Mesoderma/embriologia , Mesoderma/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Proteínas de Neoplasias/genética , Neoplasias/metabolismo , Doenças Periodontais/genética , Transtornos de Fotossensibilidade/genética , Gravidez , Distribuição TecidualRESUMO
We report on the prenatal diagnosis of epidermolysis bullosa letalis with pyloric atresia in a pregnancy not known to be at risk for this condition. Elevated maternal serum alpha-fetoprotein levels led to ultrasonography which demonstrated gastric dilatation, consistent with pyloric atresia, and echogenic particles in the amniotic fluid, the "snowflake sign," previously described in two pregnancies of fetuses with disorders of skin sloughing. Amniotic fluid alpha-fetoprotein was markedly elevated and the acetylcholinesterase was positive. The diagnosis of epidermolysis bullosa letalis with pyloric atresia was confirmed after delivery by electron microscopy of fetal skin which showed typical changes of hypoplastic absent hemidesmosomes and separation along the dermal-epidermal junction. None of these abnormal prenatal findings are consistently present in pregnancies with epidermolysis bullosa with pyloric atresia. Thus, although useful when abnormal, when the test results are normal, the need for confirmatory fetoscopy and fetal skin biopsy remains.
