RESUMO
Rare diseases are powerful windows into biological processes and can serve as models for the development of therapeutic strategies. The progress made on the premature aging disorder Progeria is a shining example of the impact that studies of rare diseases can have.
Assuntos
Progéria/tratamento farmacológico , Progéria/fisiopatologia , Pesquisa Translacional Biomédica , Envelhecimento/genética , Envelhecimento/patologia , Criança , Farnesiltranstransferase/antagonistas & inibidores , Humanos , Lamina Tipo A , Proteínas Nucleares/metabolismo , Progéria/genética , Progéria/patologia , Precursores de Proteínas/metabolismoRESUMO
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease with widespread phenotypic features resembling premature aging. HGPS was recently shown to be caused by dominant mutations in the LMNA gene, resulting in the in-frame deletion of 50 amino acids near the carboxyl terminus of the encoded lamin A protein. Children with this disease typically succumb to myocardial infarction or stroke caused by severe atherosclerosis at an average age of 13 years. To elucidate further the molecular pathogenesis of this disease, we compared the gene expression patterns of three HGPS fibroblast cell strains heterozygous for the LMNA mutation with three normal, age-matched cell strains. We defined a set of 361 genes (1.1% of the approximately 33,000 genes analysed) that showed at least a 2-fold, statistically significant change. The most prominent categories encode transcription factors and extracellular matrix proteins, many of which are known to function in the tissues severely affected in HGPS. The most affected gene, MEOX2/GAX, is a homeobox transcription factor implicated as a negative regulator of mesodermal tissue proliferation. Thus, at the gene expression level, HGPS shows the hallmarks of a developmental disorder affecting mesodermal and mesenchymal cell lineages. The identification of a large number of genes implicated in atherosclerosis is especially valuable, because it provides clues to pathological processes that can now be investigated in HGPS patients or animal models.
Assuntos
Arteriosclerose/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/genética , Mesoderma/metabolismo , Progéria/genética , Adolescente , Arteriosclerose/complicações , Linhagem Celular , Criança , Regulação para Baixo/genética , Matriz Extracelular/genética , Feminino , Fibroblastos/metabolismo , Predisposição Genética para Doença/genética , Heterozigoto , Proteínas de Homeodomínio/genética , Humanos , Lamina Tipo A/genética , Masculino , Mutação , Progéria/complicações , Progéria/patologia , RNA/genética , RNA/isolamento & purificação , RNA/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/genética , Regulação para Cima/genéticaAssuntos
Progéria/genética , Envelhecimento/fisiologia , Animais , Criança , Ensaios Clínicos como Assunto , Congressos como Assunto , Dano ao DNA/fisiologia , Humanos , Lamina Tipo A/genética , Laminina/fisiologia , Progéria/tratamento farmacológico , Progéria/fisiopatologia , Projetos de Pesquisa , Células-Tronco/fisiologiaRESUMO
Hutchinson-Gilford progeria syndrome (HGPS) is a rare, progressive segmental premature aging disease that includes scleroderma-like skin, progressive joint contracture, and atherosclerosis. Affected individuals die prematurely of heart attacks or strokes. Extracellular matrix dysregulation is implicated as a factor in disease progression. We analyzed messenger RNA and protein levels for matrix metalloproteinases (MMPs)-2,-3, and -9 in HGPS primary human dermal fibroblasts using real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and gelatin zymography. MMP-3 messenger RNA and protein levels decreased significantly with increasing donor age in HGPS fibroblasts but not in controls. MMP-2 messenger RNA also showed a donor age-dependent decrease in HGPS fibroblasts, but levels of secreted protein were unchanged. MMP-9 was similar in HGPS and control cultures. The decreased MMP-3 may represent a shift in the inherent extracellular matrix-degrading proteolytic balance in favor of matrix deposition in HGPS. This metalloproteinase has the potential to serve as a biomarker of therapeutic efficacy when assessing treatments for HGPS.