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1.
J Invest Dermatol ; 133(1): 68-77, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22931925

RESUMO

IFN regulatory factor 6 (IRF6) is a transcription factor that, in mammals, is required for the differentiation of skin, breast epithelium, and oral epithelium. However, the transcriptional targets that mediate these effects are currently unknown. In zebrafish and frog embryos, Irf6 is necessary for differentiation of the embryonic superficial epithelium, or periderm. Here we use microarrays to identify genes that are expressed in the zebrafish periderm and whose expression is inhibited by a dominant-negative variant of Irf6 (dnIrf6). These methods identify Grainyhead-like 3 (Grhl3), an ancient regulator of the epidermal permeability barrier, as acting downstream of Irf6. In human keratinocytes, IRF6 binds conserved elements near the GRHL3 [corrected] promoter. We show that one of these elements has enhancer activity in human keratinocytes and zebrafish periderm, suggesting that Irf6 directly stimulates Grhl3 expression in these tissues. Simultaneous inhibition of grhl1 and grhl3 disrupts periderm differentiation in zebrafish, and, intriguingly, forced grhl3 expression restores periderm markers in both zebrafish injected with dnIrf6 and frog embryos depleted of Irf6. Finally, in Irf6-deficient mouse embryos, Grhl3 expression in the periderm and oral epithelium is virtually absent. These results indicate that Grhl3 is a key effector of Irf6 in periderm differentiation.


Assuntos
Proteínas de Ligação a DNA/biossíntese , Camadas Germinativas/crescimento & desenvolvimento , Camadas Germinativas/metabolismo , Fatores Reguladores de Interferon/metabolismo , Fatores de Transcrição/biossíntese , Proteínas de Peixe-Zebra/biossíntese , Proteínas de Peixe-Zebra/metabolismo , Animais , Proteínas de Ligação a DNA/genética , Elementos Facilitadores Genéticos , Regulação da Expressão Gênica no Desenvolvimento/genética , Inativação Gênica , Camadas Germinativas/embriologia , Humanos , Queratinócitos/metabolismo , Camundongos , Regiões Promotoras Genéticas , Fatores de Transcrição/genética , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
2.
Blood ; 107(8): 3084-90, 2006 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-16397136

RESUMO

Monozygotic twin sisters, with nonhematologic symptoms of Fanconi anemia (FA), were discovered to be somatic mosaics for mutations in the FANCA gene. Skin fibroblasts, but not lymphocytes or committed hematopoietic progenitors, were sensitive to DNA cross-linking agents. Molecular analysis revealed, in skin cells of both twins, a frameshift causing deletion in exon 27 (2555deltaT) and an exon 28 missense mutation (2670G>A/R880Q). The latter resulted in primarily cytoplasmic expression and reduced function of the mutant FANCA (R880Q) protein. Surprisingly, the same acquired exon 30 missense change (2927G>A/E966K) was detected in the hematopoietic cells of both sisters, but not in their fibroblasts, nor in either parent. This compensatory mutation existed in cis with the maternal exon 28 mutation, and it restored function and nuclear localization of the resulting protein. Both sisters have been free of hematologic symptoms for more than 2 decades, suggesting that this de novo mutation occurred prenatally in a single hematopoietic stem cell (HSC) in one twin and that descendants of this functionally corrected HSC, via intra-uterine circulation, repopulated the blood lineages of both sisters. This finding suggests that treating FA patients with gene therapy might require transduction of only a few hematopoietic stem cells.


Assuntos
Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Anemia de Fanconi/genética , Mutação da Fase de Leitura , Regulação da Expressão Gênica/genética , Células-Tronco Hematopoéticas/metabolismo , Mutação de Sentido Incorreto , Transporte Ativo do Núcleo Celular/genética , Núcleo Celular/genética , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Reagentes de Ligações Cruzadas/farmacologia , Éxons/genética , Anemia de Fanconi/metabolismo , Anemia de Fanconi/patologia , Proteína do Grupo de Complementação A da Anemia de Fanconi/metabolismo , Feminino , Células-Tronco Hematopoéticas/patologia , Humanos , Troca Materno-Fetal , Mosaicismo , Gravidez , Pele/metabolismo , Pele/patologia
3.
Hum Mutat ; 23(6): 576-81, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15146462

RESUMO

Multiple sulfatase deficiency (MSD) is a rare disorder characterized by impaired activity of all known sulfatases. The gene mutated in this disease is SUMF1, which encodes a protein involved in a post-translational modification at the catalytic site of all sulfatases that is necessary for their function. SUMF1 strongly enhances the activity of sulfatases when coexpressed with sulfatase in Cos-7 cells. We performed a mutational analysis of SUMF1 in 20 MSD patients of different ethnic origin. The clinical presentation of these patients was variable, ranging from severe neonatal forms to mild phenotypes showing mild neurological involvement. A total of 22 SUMF1 mutations were identified, including missense, nonsense, microdeletion, and splicing mutations. We expressed all missense mutations in culture to study their ability to enhance the activity of sulfatases. Of the predicted amino acid changes, 11 (p.R349W, p.R224W, p.L20F, p.A348P, p.S155P, p.C218Y, p.N259I, p.A279V, p.R349Q, p.C336R, p.A177P) resulted in severely impaired sulfatase-enhancing activity. Two (p.R345C and p.P266L) showed a high residual activity on some, but not all, of the nine sulfatases tested, suggesting that some SUMF1 mutations may have variable effects on the activity of each sulfatase. This study compares, for the first time, clinical, biochemical, and molecular data in MSD patients. Our results show lack of a direct correlation between the type of molecular defect and the severity of phenotype.


Assuntos
Mutação , Esfingolipidoses/genética , Sulfatases/genética , Animais , Células COS , Humanos , Oxirredutases atuantes sobre Doadores de Grupo Enxofre , Esfingolipidoses/enzimologia , Sulfatases/deficiência
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