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Next Article 
Blood, Vol. 92 No. 6 (September 15), 1998:
pp. 1845-1851
REVIEW ARTICLE
Iron Is Hot: An Update on the Pathophysiology of Hemochromatosis
By
Nancy C. Andrews and
Joanne E. Levy
From the Howard Hughes Medical Institute and the Division of
Hematology/Oncology, Children's Hospital, the Department of
Pediatrics, Harvard Medical School, the Division of
Hematology/Oncology, Brigham and Women's Hospital, Boston, MA.
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INTRODUCTION |
GENETIC IRON OVERLOAD disorders are
prevalent yet poorly understood. Over the past 3 years, the discoveries
of the hereditary hemochromatosis gene and an intestinal iron
transporter have significantly advanced our understanding of iron
metabolism. Furthermore, they have suggested novel links between
molecules involved in immune defense and iron homeostasis. These
findings lay the foundation for developing novel strategies for
understanding, diagnosing, and treating patients afflicted with iron
overload disorders.
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NORMAL IRON METABOLISM |
All mammalian cells have an absolute requirement for iron, most likely
because iron is abundant, comprising 5% of the earth's crust, and
versatile, existing in two interconvertible redox states. Our
Paleolithic ancestors enjoyed a rich meat diet, high in readily absorbable heme iron. Iron deficiency would have been a rare disorder for early humans.1 However, dietary iron deficiency likely became prevalent with the development of agriculture and the consequent decrease in intake of animal products over the past 10,000 years. Hereditary hemochromatosis (HHC), a disorder characterized by inappropriately high intestinal iron absorption, may have conferred a
selective advantage in an era when dietary iron was relatively scarce.2 Twentieth century industrialization has been
accompanied by a return to increased meat consumption1 and
an increase in life expectancy. Under these circumstances, iron loading
is no longer an advantage, and HHC has become a prominent disease.
Most iron in mammals exists either as heme, present in heme proteins,
or as ferritin, a mobilizable storage form. Only a small fraction
enters and leaves the body on a daily basis. Most iron is recycled from
the breakdown of effete red blood cells by macrophages of the
reticuloendothelial system (RES). At any given time, approximately 0.1% (3 mg) of total body iron circulates in an exchangeable plasma pool. In normal individuals, essentially all circulating plasma iron is
bound to transferrin (Tf). The mechanism(s) by which Tf acquires iron
from intestinal absorptive cells and RES cells is unknown. Tf is a
powerful chelator, binding iron with a dissociation constant of
1022 mol/L 1.3 This chelation
serves three purposes: it renders iron soluble under physiologic
conditions, it prevents iron-mediated free radical toxicity, and it
facilitates transport into cells. Radioactive tracer studies indicate
that at least 80% of the iron bound to circulating Tf is delivered to
the bone marrow.4 However, when the iron binding capacity
of plasma Tf is saturated, as in patients with HHC, the excess non-Tf
bound iron is rapidly taken up by hepatocytes and other cells.
Iron is taken into erythroid cells by receptor-mediated endocytosis of
Tf (reviewed in Harford et al5). Specific receptors (TfRs)
on the outer face of the plasma membrane bind diferric-Tf with high
affinity. Once internalized, endosomes are acidified to pH 5.5 to 6.0 through the action of an ATP-dependent proton pump.6-9
Endosomal acidification weakens binding of iron to Tf and produces
conformational changes in both Tf and TfR, strengthening their
association.10,11 Iron release may also be facilitated by a
plasma membrane oxidoreductase.12,13 The apo-Tf-TfR complex is recycled back to the plasma membrane, where apo-Tf is discharged, thereby completing an elegant and efficient cycle. Previously, it was
not clear how iron exited from the transferrin cycle endosome. However,
recent results have given new insights into this process and
demonstrated a surprising link between the Tf cycle and intestinal iron
absorption (see below).
Iron homeostasis is regulated strictly at the level of intestinal
absorption. In normal individuals, intestinal iron absorption is
influenced by body iron stores, hypoxia, and erythropoietic activity.
The signals regulating absorption remain obscure. Oxidation state,
intraluminal pH, and ancillary nutrients such as ascorbic acid can
affect the efficiency of uptake. Ferrous iron is most efficiently
absorbed. A ferric reductase present on duodenal microvillus membranes
may promote absorption by converting dietary ferric iron to the ferrous
form.14,15 The intestinal iron transport system also
transports cobalt and manganese, the transition metals that flank iron
in the periodic table.16,17
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HHC |
Since the late 1800s, the clinical triad of skin hyperpigmentation,
hepatic cirrhosis, and adult onset diabetes has been recognized as
evidence of iron overload. It is now clear that HHC is the most
prevalent genetic disease in individuals of northern European descent.
Patients with this disorder chronically absorb a small excess of iron,
and middle-aged homozygotes frequently have 10 times normal body iron
stores. As iron stores exceed the body's capacity for effective
chelation, free iron accumulates. Unbound iron is highly toxic, owing
to its participation in the generation of free radicals and reactive
oxygen intermediates. These molecules provoke peroxidation of membrane
lipids leading to cellular injury, ultimately resulting in severe
damage to the liver, heart, joints, and endocrine organs. Liver damage
may be exacerbated by alcohol consumption or viral hepatitis. The onset
of the disease is insidious, and the initial manifestations are often
nonspecific symptoms, including fatigue and arthropathy. If untreated,
hemochromatosis invariably progresses and is ultimately fatal. However,
if diagnosed before end stage organ damage, phlebotomy is an effective
and life-saving treatment. Red blood cells are removed at regular intervals to deplete iron stores, and bone marrow erythropoiesis compensates effectively.
The cloning of the causative gene in HHC represents a true tour de
force of modern molecular biology. In the mid-1980s the fortuitous
discovery of an increased frequency of the HLA-A3 allele in
hemochromatosis patients quickly allowed investigators to demonstrate linkage between the phenotype and the HLA complex on human chromosome 6p.18 However, despite this lucky start, nearly 12 years
elapsed before the gene was found. Premier human genetics labs around the world devoted years to the effort, but were foiled by severe linkage disequilibrium in the candidate genomic region. Finally, using
a novel approach, a small biotech company, Mercator Genetics (now
called Progenitor, Menlo Park, CA), found a compelling
candidate gene.19
On the basis of the HLA-A3 association, the Mercator group assumed a
strong "founder effect" in hemochromatosis. They postulated that
a unique mutation had occurred in the remote past in one ancestor
common to most (but not all) affected patients. On the basis of this
assumption, they analyzed polymorphic genetic markers throughout a
large candidate region to determine which alleles were most frequently
present in hemochromatosis patients. Assuming that the original
mutation arose on a single chromosome from a single individual, it
should be associated with a particular set of alleles of nearby
polymorphic markers. They took advantage of the fact that alleles of
markers close to the gene were more likely to have been maintained in
modern hemochromatosis patients, whereas alleles of more remote markers
would have changed through historical recombination events. They
performed this analysis looking first at the frequency of occurrence of
polymorphic alleles of each marker. Only later did they examine the
pattern of alleles in each individual (haplotype), using the haplotype
analysis as a means of deducing historic recombination events. This
strategy allowed a more precise localization of the causative gene than had previously been possible using linkage studies alone, because information could be assimilated from a large number of individuals who
were not known to be related to each other. After narrowing the
candidate interval to 250 kb, the Mercator group performed an
exhaustive screen for genes within the region, using cDNA selection, exon trapping, and direct genomic sequencing. A single gene emerged as
the only plausible candidate for the disease gene. It encodes a
protein, HFE (originally called HLA-H), that resembles atypical HLA
class I molecules, consistent with the localization of the gene near
the HLA cluster.19 This explained an earlier finding that
mice lacking  2-microglobulin, a protein associated with HLA class I
molecules, developed iron overload resembling that of patients with
hemochromatosis.20,21 However, how an atypical class I-like
molecule could affect iron homeostasis remained a mystery. Recently,
targeted disruption of the HFE gene has provided confirmation of the
identity of this gene as the HHC locus and proved that HHC results from
a loss of protein function. Zhou et al22 found that HFE
knockout mice develop iron overload with features similar to human HHC
patients.
Two point mutations have been found within HFE in hemochromatosis
patients, but only one of these (Cys282Tyr) has been definitively associated with hemochromatosis and corresponds to the founder mutation.19,23-25 It is thought to have arisen in a single
individual, approximately 60 to 70 generations in the
past.26 It is most prevalent in individuals of western
European descent and rare in individuals of African descent. The
discovery of the Cys282Tyr mutation in HFE has had enormous impact on
the diagnosis of hemochromatosis, offering a simple polymerase chain
reaction (PCR)-based genotyping assay that will identify
most (but not all) patients unambiguously. This will complement the use
of iron saturation measurements and supplant HLA typing in the majority
of HHC patients and allow identification of young homozygotes and
heterozygous carriers without biochemical evidence of iron overload.
However, it is still important to consider the entire clinical context
as a significant proportion of hemochromatosis patients lack the
Cys282Tyr mutation, and individuals have been reported who are
homozygous for Cys282Tyr but do not show clinical evidence of
hemochromatosis.27
A second HFE polymorphism, His63Asp, has been found in more diverse
ethnic backgrounds and may represent an older mutation.28 Its clinical significance is less clear, and there are conflicting data
as to whether it contributes to iron overload in Cys282Tyr/His63Asp compound heterozygotes (reviewed in Cuthbert29).
The functional role of HFE in iron metabolism remains obscure, but
several recent clues have emerged. The crystal structure of normal HFE
protein strongly resembles that of class I MHC molecules. Similar to
class I molecules, HFE interacts with 2-microglobulin through a
domain termed  3 that resembles an Ig constant-like domain.30 However, in contrast to true class I proteins,
HFE is not capable of binding short peptides, because the portion of
the protein similar to the peptide binding groove in class I molecules
has been narrowed. Studies in cells transfected with HFE expression
constructs have shown that the Cys282Tyr mutation interferes with
binding of 2-microglobulin and consequently prevents normal membrane
localization of HFE.31,32 This suggests that normal HFE
attenuates iron absorption through some activity on the cell surface.
Three recent studies have reported evidence of a physical interaction
between HFE and TfR. TfR was initially found to colocalize with HFE
protein by immunohistochemical analysis of human placental syncytiotrophoblasts and to associate with the HFE/2-microglobulin complex.33 This was confirmed by a more complete
biochemical analysis that indicated that normal HFE protein bound to
TfR and decreased its affinity for diferric transferrin, whereas
Cys282Tyr HFE did not bind to TfR.34 Interestingly, the
His63Asp mutant form of HFE also bound to TfR, but did not decrease its
affinity for transferrin. This is the first functional evidence that
the His63Asp mutation is physiologically significant. Finally, HFE protein covalently linked to a biosensor chip has a high measured affinity for binding TfR at pH 7.5, similar to the pH of the cell surface, but not at pH 6.0, which is similar to the pH within transferrin cycle endosomes.30 A complex forms with a
stoichiometry of one TfR homodimer per HFE molecule. The stoichiometry
of transferrin in the quarternary complex has not yet been determined.
Figure 1 summarizes our current
understanding of HFE/TfR interactions.
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| Fig 1.
The TfR-HFE complex. The structure of the ternary complex
formed by transferrin, TfR, and HFE has not yet been elucidated fully.
This cartoon represents our current understanding. (A) Wild-type HFE
protein, associated with 2-microglobulin, binds to TfR with high
affinity and decreases binding of diferric transferrin.34
(B) C282Y HFE protein does not associate with 2-microglobulin and
therefore is not expressed in mature form on the cell surface, leaving
TfR free to bind transferrin. (C) H63D HFE protein is expressed on the
cell surface, but it does not decrease TfR affinity for transferrin to
the same extent as wild-type HFE does.
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Despite this progress, it is still not known how HFE regulates iron
transport. It is unlikely that HFE acts as an iron transporter directly. It was formerly believed that dietary iron entered the intestinal cell through the transferrin cycle. This hypothesis has been
disproved experimentally. The transferrin gene is not expressed in
intestinal cells, and transferrin found in the lumen is derived from
plasma.35 It is unlikely that plasma transferrin entering
bile performs a chelating function in the intestinal lumen, because it
is fully saturated with iron before it leaves the biliary
system.36 Furthermore, hypoxia, which greatly increases iron absorption, has no effect on intestinal transferrin
levels.37 Experiments indicate that endogenous transferrin
cannot donate iron to intestinal mucosal cells, and TfRs have been
found on basolateral surface, rather than at the brush border
membrane.38,39
However, it is possible that TfR is involved in the transfer of iron
across the basolateral (serosal) surface of the absorptive, epithelial
enterocyte. Intestinal cells show regulated expression of basolateral
TfR that increases in iron deficiency and decreases in iron
overload.40 However, surface TfR activity is most prominent in crypt cells and decreases with differentiation of the absorptive epithelium. More differentiated cells demonstrate a redistribution of
TfRs from the surface to intracellular sites.41 This makes it unlikely that the TfR is directly responsible for basolateral iron
transfer.41 At least two interpretations remain that are not mutually exclusive. It is possible that TfRs are important for
supplying iron to rapidly developing enterocyte precursors in the
crypts. Alternatively, they may serve to transduce some sort of signal
from the body to the future absorptive cells to communicate the need
for iron absorption. This latter interpretation is particularly
interesting in light of the recently discovered interaction of HFE and
TfRs.
Several lines of evidence indicate that patients with HHC
have increased iron transfer at the basolateral surface of the
absorptive cell.42-44 A larger portion of a oral
radiolabeled iron dose is retained in HHC patients than in normal
individuals. This indicates that iron taken up by the
enterocytes is efficiently transferred to the plasma and not held
within the enterocytes as ferritin, to be lost through mucosal
sloughing. These findings suggest that mutations in HFE somehow promote
basolateral iron export, perhaps because of a failure to interact with
the TfR.
However, it remains to be shown that normal HFE interacts with TfR in
intestinal cells. The HFE/TfR interaction has been demonstrated in the
placenta and in transfected cells; in both cases, TfR was expressed at
very high levels. Furthermore, normal HFE protein was detected in an
intracellular, paranuclear compartment in small intestine cells, and it
was exclusively found in the crypts.45 Although it is
intriguing to postulate that HFE interacts with TfR in intestinal cells
in a regulatory fashion, presumably to transduce information from
circulating mediators as to the state of body iron stores, it is not
clear that HFE and TfR are present in the same subcellular location.
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IDENTIFICATION OF THE INTESTINAL IRON TRANSPORTER, Nramp2 (DCT1) |
Another big piece in the iron overload puzzle came 1 year after HFE was
discovered, when two groups, using two quite different approaches,
simultaneously reported the identification of an intestinal iron
transporter. Both used iron-deficient rodents as experimental models.
Microcytic anemia mice (gene symbol mk) have an autosomal
recessive defect in iron metabolism that includes marked impairment of
intestinal iron transport.46-48 They have no abnormalities
in Tf, TfR, ferritin, or the RNA binding iron regulatory proteins. The
phenotype suggested that the causative mutation was likely to be in an
intestinal transporter functioning at the brush
border.48-50 Using a positional cloning strategy, Fleming
et al51 localized the mk mutation to the
Nramp2 gene on mouse chromosome 15 and found a glycine to
arginine (Gly185Arg) missense mutation unique to animals with the
mk phenotype. Nramp2 had been an orphan protein with no known
function cloned based on its homology to Nramp1, a molecule involved in
macrophage host defense.52,53
In parallel experiments, Gunshin et al54 searched for an
intestinal iron transporter using a Xenopus oocyte expression cloning system and found a single cDNA that stimulated iron transport. This
cDNA encoded rat Nramp2 (referred to as DCT-1 in their
report). They went on to show that Nramp2(DCT1) transported a variety
of other heavy metals as well, including cobalt, manganese, lead, zinc,
and copper, and that protons were cotransported. These data concurred
with earlier physiology studies that indicated that the human
intestinal iron transporter also transports other
metals.16,17,55 Iron-deficient rats showed a dramatic
increase in the amount of Nramp2(DCT1) mRNA in small intestine
enterocytes, consistent with a role for Nramp2(DCT1) as a major iron
transport protein. Taken together, the genetic and biochemical
characterizations of Nramp2(DCT1) make a compelling argument that it is
the primary intestinal transporter involved in apical iron uptake.
Mammalian cells transfected with Nramp2 cDNA expression
constructs have markedly increased iron uptake as compared with control transfectants. Transfection of Nramp2 cDNA carrying the
mk mutation confers minimal iron uptake capability, indicating
that the Gly185Arg mutation is highly deleterious to Nramp2(DCT1)
function.56 Surprisingly, a second mutant animal with
autosomal recessive iron deficiency, the Belgrade rat (gene symbol
b), also carries a mutation in Nramp2 (DCT1).57 Homozygous mutant b rats have a
well-characterized defect in the transferrin cycle in erythroid cells,
as well as defective intestinal iron transport.58-64 Their
phenotype resembles that of mk mice in having defects at both
levels, but the intestinal abnormality was better studied in mk
animals, and the erythroid abnormality was better understood in
b animals. The identification of a mutation within the b
Nramp2 gene confirms that Nramp2(DCT1) is not only important in
intestinal iron absorption, but also for erythroid use
(Fig 2). Nramp2(DCT1) functions in export
of iron from Tf cycle endosomes. Remarkably, the b mutation
results in exactly the same amino acid change (Gly185Arg) as the
mk mutation. This alteration in Nramp2(DCT1) protein seems to
be the unique cause of the mk-like phenotype in rodents.
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| Fig 2.
Critical steps in mammalian iron transport. Key iron
transport steps are diagrammed, showing the route dietary iron follows
from the intestinal lumen to the cytoplasm of an erythroid precursor
cell. Nramp2(DCT1) acts as an iron transporter at two steps. It is
required for transfer of iron across the intestinal brush border and
for export of iron from transferrin cycle endosomes in the bone marrow.
The function of Hfe is not well understood, but it appears to regulate
basolateral iron transfer from enterocyte to plasma. Transferrin (Tf)
chelates circulating iron in plasma.
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The mk and b phenotypes are severe, suggesting that
Nramp2(DCT1) function is essential for normal intestinal iron
transport, at least in mice and rats. It has not yet been determined
whether Nramp2(DCT1) expression or activity is altered in patients with HHC. There is compelling evidence that Nramp2(DCT1) acts as the apical
transporter that brings iron into enterocytes, and HHC seems to affect
basolateral iron transport (Fig 2). However, it is possible that HHC
patients have increased Nramp2(DCT1) function consequent to more rapid
export of iron from enterocytes or as a result of an altered regulatory
mechanism. This will need to be investigated. However, whether or not
HHC alters Nramp2(DCT1) function, the mk and b animal
models suggests that Nramp2(DCT1) would be an ideal target for
pharmacological blockade of iron absorption. It may be possible to
develop drugs that could be administered orally to specifically block
Nramp2(DCT1) function in patients with iron overload disorders. At
present, hemochromatosis patients must undergo phlebotomy every few
weeks to maintain a slightly iron-deficient state. Perhaps an oral,
nonabsorbable agent might be developed that could inhibit Nramp2(DCT1)
without systemic side effects. Such a drug could offer a significant
improvement in the quality of life for patients with hemochromatosis.
It might also find uses in treating siderosis associated with
thalassemia and other metal intoxication disorders such as lead
poisoning.
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FUTURE DIRECTIONS |
Although great strides have been made towards understanding iron
transport and associated disorders, many questions remain. Despite
intensive investigation and its tantalizing association with the TfR,
it is still unclear how HFE functions in normal individuals. To date,
only two functionally significant mutations in HFE have been
discovered; is it possible that additional mutations will be found that
contribute to iron overload or iron deficiency disorders? What is the
etiology of iron overload in patients without Cys282Tyr mutations?
Nramp2(DCT1) is not only expressed in intestinal cells; it is expressed
in most if not all tissues and seems to be particularly actively
expressed in certain brain structures.54 What role does it
play in iron uptake in the central nervous system? Does its function
contribute to the pathology associated with increased metal deposition
in patients with Parkinson's disease, Alzheimer's disease, and other
conditions?65 Are there human patients with mutations in
Nramp2(DCT1)?
It now seems likely that the role of Nramp1 in host defense also
involves movement of metal ions. Nramp1 is expressed exclusively in
macrophages and is localized to phagolysosomes.53,66 Normal Nramp1 causes an attenuation of replication of a variety of ferrophilic intracellular pathogens, including several Mycobacteria
species, Leishmania, and Salmonella
typhimurium. A point mutation in Nramp1 leads to
rampant pathogen proliferation, but no alteration of normal host
killing mechanisms.53 Nramp1 carrying this mutation is
undetectable in macrophages.66 These observations strongly suggest that Nramp1 may act by removing a necessary metal, presumably iron, from the intracellular compartment containing the invaders, thus
starving them of an essential nutrient.
What function does Nramp1 serve in normal, uninfected cells?
Intriguingly, it is expressed exclusively in reticuloendothelial macrophages. These cells play a fundamental role in iron metabolism, by
phagocytosing effete red blood cells, breaking down their hemoglobin, and recycling iron to transferrin for delivery back to the
erythron.67 The bulk of iron used for erythropoiesis has
passed through this recycling pathway. Perhaps Nramp1 plays a special
role in this process. Accordingly, it has been established that various
inflammatory cytokines that are associated with anemia of chronic
disease68 also affect the regulation of
Nramp1.69 One might speculate that the failure of normal
iron recycling in anemia of chronic disease might be a consequence of
alterations in the expression or activity of Nramp1. This needs to be
investigated.
Nramp2(DCT1) is abundantly expressed in the proximal tubules and
collecting ducts of the kidney, suggesting that it might be involved in
metal reabsorption.54 This raises the intriguing possibility that there may be a potential excretory system for iron
after all and that it is overcome by constitutive reabsorption. If so,
it is conceivable that reabsorption could be blocked pharmacologically, resulting in a urinary iron leak. This type of therapeutic maneuver could be invaluable in dealing with patients with siderosis due to a
chronic transfusion requirement, for example, in patients with
myelodysplastic syndromes or thalassemia major.
The severe mk and b phenotypes indicate that
Nramp2(DCT1) is a key transmembrane iron transporter, at least in
intestinal cells and erythroid cells. Nramp2(DCT1) may be involved in
iron transport in other cell types as well. Nonetheless, there is
indisputable biochemical evidence for multiple iron transport
activities in mammalian cells, and there are clearly several iron
transporters operating in yeast. Database searches to date have not
shown additional mammalian Nramp-like proteins; it appears likely that
other mammalian iron transport molecules will be unrelated. One
candidate molecule, SFT (stimulator of Fe transport), was recently
isolated in an expression cloning screen using K562 erythroleukemia
cell mRNA.70 This molecule appears to promote iron uptake,
but there is no direct evidence that it is, itself, an iron
transporter. A high-affinity transmembrane iron transporter found in
yeast, FTR1, is clearly important for iron homeostasis in that
organism, but it has no known mammalian homolog at this
time.71
Finally, there are two other iron overload disorders, not yet mentioned
in this review, that are still poorly understood. African iron
overload, also known as Bantu siderosis, is a prevalent condition in
sub-Saharan Africa that leads to massive iron accumulation and ensuing
complications.72 The phenotype of African iron overload differs subtly from that of HHC on a pathologic level, as iron first
accumulates in reticuloendothelial cells. Furthermore, though there is
a genetic predisposition, African iron overload is not linked to the
HLA complex.73 It is not yet known whether
African-Americans have an increased susceptibility to iron overload as
a result of this same gene. A different disorder, neonatal
hemochromatosis, is a devastating iron loading disease of the perinatal
period that results in liver failure and almost certain death in
affected patients. Liver transplant is apparently futile, because iron has been shown to accumulate in the donor organ.74 Future
efforts must be directed towards working out the pathogenesis of these diseases and using our new knowledge in their treatment.
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FOOTNOTES |
Submitted March 25, 1998;
accepted May 20, 1998.
N.C.A. is an Assistant Investigator of the Howard Hughes Medical
Institute. J.E.L. is supported by a National Institutes of Health
(NIH) K08 award. Some studies described in this review are
funded by NIH R01 DK53813 to N.C.A.
Address reprint requests to Nancy C. Andrews, MD, PhD, Howard Hughes
Medical Institute, Enders 720, Children's Hospital, 300 Longwood Ave,
Boston, MA 02115; e-mail: andrews_n{at}a1.tch.harvard.edu.
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ACKNOWLEDGMENT |
The authors thank Mark Fleming for stimulating discussions and for help
in preparing Fig 2.
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Introduction
References
Introduction