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A genetic
cause for Iron Deficiency
Newswise — The
discovery of a gene for a rare form of
inherited iron deficiency may provide clues
to iron deficiency in the general population
– particularly iron deficiency that doesn’t
respond to iron supplements - and suggests a
new treatment approach.
The finding was
published online by the journal Nature
Genetics on April 13.
Iron deficiency is the
most common nutritional deficiency and the
leading cause of anemia in the United
States.(1) Most cases are easily reversed
with oral iron supplements, but over the
years, Mark Fleming, MD, DPhil, interim
Pathologist-in-Chief at Children’s Hospital
Boston, and pediatric hematologist Nancy
Andrews, MD, PhD, formerly of Children’s and
now Dean of Duke University School of
Medicine, had been referred a number of
children with iron deficiency anemia who
didn’t respond to oral supplements, and only
poorly to intravenous iron.
The cause of their
condition – termed iron-refractory
iron-deficiency anemia (IRIDA) –was a
mystery. The children all had good diets,
and none had any condition that might
interfere with iron absorption or cause
chronic blood loss, the most common causes
of iron deficiency. All had evidence of
anemia from a very early age, and many also
had siblings with iron deficiency anemia.
Seeing reports of several similarly
afflicted families in the medical
literature, Fleming and Andrews were
convinced that genetics was a factor.
“After nearly 15 years,
we finally had enough families that we could
begin to think about positionally cloning
the gene for the disorder,” says Fleming.
Fleming and Andrews,
experts in iron metabolism, and their
colleagues Karin Finberg, MD, PhD, and
Matthew Heeney, MD, studied five extended
families with more than one chronically
iron-deficient member. They found a variety
of mutations in a gene called TMPRSS6 (the
acronym stands for transmembrane serine
protease S6) in all of these families, as
well as several patients without a family
history of the disorder.
Although IRIDA is quite
rare, the authors believe it might be the
extreme end of a broad continuum of disease,
since TMPRSS6 mutations varied widely in the
five families and caused different degrees
of iron deficiency and anemia.
“Our observations
suggest that more common forms of iron
deficiency anemia may have a genetic
component,” says Andrews.
All patients in the
study apparently had recessive mutations,
since their parents did not have iron
deficiency anemia. The investigators now
want to determine whether people with just a
single abnormal copy of TMPRSS6 have subtler
alterations in iron absorption that might
not otherwise have come to the attention of
a hematologist.
Although the mechanism
is still unknown, deficiency of the TMPRSS6
protein causes the body to produce too much
hepcidin, a hormone that inhibits iron
absorption by the intestine. Normally,
hepcidin is produced to protect the body
against iron overload – but patients with
IRIDA make large amounts of hepcidin even
though they are iron deficient. “People with
this disorder make too much hepcidin,
putting the brakes on iron absorption
inappropriately,” Fleming says.
In addition, patients
with TMPRSS6 mutations cannot make new red
blood cells efficiently because the iron
needed to make them comes from macrophages,
and hepcidin causes macrophages to hold on
to iron. This explains the patients’ poor
response to intravenous iron – the iron is
trapped in macrophages and cannot be used
for red blood cell production.
The fact that TMPRSS6
regulates hepcidin may open up new avenues
for therapy, the researchers say. For
example, blocking TMPRSS6 may help patients
with iron overload disorders make more
hepcidin in order to limit intestinal iron
absorption. Conversely, stimulating TMPRSS6
may have therapeutic benefit in certain
patients with anemia, particularly those in
which hepcidin is overproduced.
The study was supported
by the National Institutes of Health.
Reference
1) Centers for Disease Control and
Prevention. Iron deficiency – United States,
1999–2000. MMWR 2002;51:897–899.
Founded in 1869 as a
20-bed hospital for children, Children’s
Hospital Boston today is the nation’s
leading pediatric medical center, the
largest provider of health care to
Massachusetts children, and the primary
pediatric teaching hospital of Harvard
Medical School. In addition to 377 pediatric
and adolescent inpatient beds and
comprehensive outpatient programs,
Children’s houses the world’s largest
research enterprise based at a pediatric
medical center, where its discoveries
benefit both children and adults. More than
500 scientists, including eight members of
the National Academy of Sciences, 11 members
of the Institute of Medicine and 12 members
of the Howard Hughes Medical Institute
comprise Children’s research community.
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