RESUMO
The nineties witnessed the discovery of the copper ATPases, enzymes which transport copper across the cytoplasmic membranes of bacteria and eukaryotes. In the same decade, several other key components of copper homeostasis have also been discovered, like copper chaperones and plasma membrane copper transporters. This has finally led to a molecular understanding of two inherited human diseases related to copper: Menkes disease, manifested by systemic copper deficiency, and Wilson disease, caused by defective secretion of excess copper. A historic perspective and untold stories of the events leading up to these discoveries are presented here.
Assuntos
Cobre/uso terapêutico , Degeneração Hepatolenticular/história , Síndrome dos Cabelos Torcidos/história , Proteínas de Transporte de Cátions/genética , Cobre/deficiência , Degeneração Hepatolenticular/diagnóstico , Degeneração Hepatolenticular/tratamento farmacológico , Degeneração Hepatolenticular/genética , História do Século XX , Homeostase , Humanos , Síndrome dos Cabelos Torcidos/diagnóstico , Síndrome dos Cabelos Torcidos/tratamento farmacológico , Síndrome dos Cabelos Torcidos/genética , Mutação/genéticaRESUMO
Menkes disease and occipital horn syndrome (OHS) are related disorders of copper transport that involve abnormal neurodevelopment, connective tissue problems, and often premature death. Location of the gene responsible for these conditions on the X chromosome was indicated by pedigree analysis from the time of these syndromes' earliest descriptions. Characterization of an affected female with an X-autosomal translocation was used to identify the Menkes/OHS gene, which encodes a highly evolutionarily conserved, copper-transporting P-type ATPase. The gene normally is expressed in nearly all human tissues, and it localizes to the trans-Golgi network of cells. However, in over 70% of Menkes and OHS patients studied, expression of this gene has been demonstrated to be abnormal. Major gene deletions detectable by Southern blotting account for 15-20% of patients, and an interesting spectrum of other mutations is evident among 58 families whose precise molecular defects have been reported as of this writing. The center region of the gene seems particularly prone to mutation, and those that influence mRNA processing and splicing appear to be relatively common. Further advances in understanding the molecular and cell biological mechanisms involved in normal copper transport may ultimately yield new and better approaches to the management of these disorders.