Clinical and Laboratory Investigation of Humans With Informative Iron or Erythroid Phenotypes

Studies of iron and erythroid cells, have provided fundamental insights into structure function relationships of proteins, energy metabolism, and the molecular basis of many diseases. Based upon the importance of iron for hemoglobin production, the regulation of erythropoiesis and iron metabolism are closely linked, and iron deficiency anemia remains as one of the most common diseases worldwide. The discovery of sickle hemoglobin as having an abnormal electrophoretic mobility marked the beginning of the molecular medicine era. The advent of recombinant DNA technology and sequencing methodologies resulted in the characterization of erythroid cells well beyond that of protein based studies to include gene structure and expression. Globin gene research, in particular, has provided a wealth of information about the expression, regulation and insulation of mammalian genes. More recently, studies of iron absorption and trafficking provided new avenues of research aimed toward growth and energy homeostasis. Genome based approaches were also utilized for the discovery of direct relationships between erythroid cell biology and iron homeostasis. Hence, there is strong evidence that fundamental clinical advances in the field of iron and erythroid biology have been based upon the careful study of humans with informative phenotypes. Clinically based correlation of genotype and phenotype is a proven, systematic approach for understanding the molecular basis of disease.

With the completion of the sequencing of the human genome, a more complete, genetically based description of disease is now achievable. Efforts aimed toward haplotype mapping will further enhance genotype phenotype correlation directly from clinical samples. Considerable progress has already been made in this regard using normal human erythroid cells. In contrast to classic studies involving single genes or proteins, computational biology and high throughput technologies permit the analysis of complex erythroid phenotypes including those with related iron pathologies. This information will be invaluable for understanding those molecular mechanisms that are altered in disease states.

The immediate aim of this protocol is to perform phenotypic analyses in humans with informative iron or erythroid phenotypes. These studies are expected to result in detailed clinical phenotyping and the collection and banking of clinical specimens for further study. In addition, we predict an ongoing growth of new technologies that may eventually be used for molecular and genetic phenotyping of clinical samples (examples include oligonucleotide chips and high throughput mass spectroscopy). Based upon this prediction, we plan to use the samples collected here to assess possible clinical uses of those technologies as they become available. The eventual aim is the discovery of identifiers that may be predictive of disease pathogenesis, severity or clinical response to intervention.