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.

- INCLUSION CRITERIA:

A clinically definable iron or erythroid cell phenotype as defined by:

Group 1: Patients with known iron or erythroid diseases (examples: iron deficient anemia or
ineffective erythropoiesis).

OR

Group 2: Patients with diseases of unknown etiology (example: unexplained iron overload or
anemia).

OR

Group 3: Patients with an informative phenotype in the absence of overt clinical disease
(example: hereditary persistence of fetal hemoglobin).

OR

Group 4: Healthy volunteers whose blood or bone marrow samples will be utilized to
understand normal iron and erythroid biology and for comparison with the other groups
described above.

AGE AND GENDER CONSIDERATIONS:

- Age range: Infancy to unlimited

- Adults: Adults who fall into Groups 1-4 are eligible to enroll in this protocol. They
must possess the ability to comprehend the investigational nature of the study and
provide informed consent.

- Minors: Minors who fall into groups 1-4 are eligible to enroll in the study for
collection of research blood. Within Group 4 (healthy volunteers, minors), the
research will not involve greater than minimal risk.

GENERAL EXCLUSION CRITERIA:

Healthy volunteers and Subjects with iron or erythroid diseases who are unable to
comprehend the investigational nature of the laboratory research are ineligible to enroll
in this protocol.

INCLUSION AND EXCLUSION CRITERIA FOR BONE MARROW SAMPLING:

With the exception of minors, pregnant females, and breast-feeding mothers, volunteers who
meet the General Inclusion Criteria for blood collection may be offered the option of bone
marrow sampling as part of this protocol. Minors, pregnant females, and breastfeeding
mothers will be excluded from bone marrow sampling specifically performed for this
protocol. However, they will be asked to consent for collection of up to an additional
sample of bone marrow if 1) they are undergoing a bone marrow sampling procedure for
clinical purposes, and 2) collection of the additional bone marrow undergoing a clinical
procedure if the research sample collection doesn t alter the clinical procedure.

Other bone marrow sampling exclusion criteria include: 1) allergy to xylocaine (lidocaine)
or the skin cleansing medication chlorhexidine/Hibiclens. 2) clotting disorders, low
platelets (<50,000k) or are taking medications that interfere with blood clotting, such as
aspirin, non-steroidal anti-inflammatory agents (such as Motrin or Advil) or blood thinning
agents (such as coumadin/warfarin).