Researchers Discover a Genetic Cause for Primary Iron Overload
By Jason Socrates
Three studies to be published in the November/December issue
of the scientific journal Blood Cells, Molecules, & Diseases
describe the discovery of a genetic mutation that could be
responsible for causing the metabolic disorder, primary iron
overload, common among people of African descent.
Professor Ernest Beutler, who is chair of The Scripps Research
Institute (TSRI) Department of Molecular and Experimental
Medicine and professor in The Skaggs Institute for Chemical
Biology at TSRI, led one of the studies and is coauthor of
Beutler and his colleagues and an independent study by Italian
and U.S. researchers found a polymorphism or genetic variation
in a gene that increases levels of an iron storage protein
in the body. Mutations to this gene occur almost exclusively
within African populations and appear to explain the disproportionate
number of African-Americans with primary iron overload.
"There are probably multiple causes [of primary iron overload
disease], and we have found one of them," says Beutler.
Primary iron overload is a metabolic disorder in which excessive
amounts of iron are deposited in the liver, pancreas, and
other organs. This disease can lead to cirrhosis of the liver,
diabetes, other metabolic problems, and cardiovascular disease.
The severe form of the disease can be lethal.
Iron overload was recognized to be relatively common among
Africans in the 1920s. For years, scientists thought that
the disease was caused by environmental factors, such as increased
dietary iron. In recent years, some scientists suggested that
genetic factors are involved as well.
Now Beutler and his colleagues are reporting the discovery
of a genetic variation in a gene called SCL40A1, which
encodes the protein ferroportin 1, used by the body to transport
iron. Mutations to this gene cause the levels of the iron
storage protein, ferritin, to rise and lead to accumulation
of iron in macrophagesthe scavenger cells of the body.
An Italian-U.S. group led by Antonello Pietrangelo of the
University of Modena first discovered the ferroportin 1 mutation
in several patients from southern Africa and the United States
who have primary iron overload (1). Working with the Health
Appraisal Center at the Kaiser Permanente Medical Care Program
in San Diego, Beutler and his colleagues examined the DNA
and clinical data of hundreds of African-American men and
women and found independently that the same mutant form of
the ferroportin 1 protein is associated with increased iron
levels and suggest that it is one of the causes of primary
iron overload in African-Americans (2). When Professors Pietrangelo
and Beutler discovered through correspondence that they had
independently found the same mutation they decided to publish
their results together in the same journal.
Another paper by James C. Barton of the Southern Iron Disorders
Center and the University of Alabama at Birmingham (3) and
his colleagues, including Beutler, characterizes the genes
and symptoms of 23 African-American patients who have primary
iron overload disease. This study found the same mutation
in some of the patients, which supports Beutler's conclusion
that this mutation is one of the causes of primary iron overload
in African-Americans. Barton's paper also concludes that primary
iron overload disease is not the result of a single mutation
of a single gene.
All three articles will be published in the November/December
issue of Blood Cells, Molecules, & Diseases. The journal
can be accessed online by journal subscribers at: http://www.elsevier.com/locate/issn/10799796.
1) The article "Iron overload in Africans
and African-Americans and a common mutation in the SCL40A1
(ferroportin 1) gene" is authored by Victor R. Gordeuk, Angela
Caleffi, Elena Corradini, Francesca Ferrara, Russell A. Jones,
Oswaldo Castro, Onyinye Onyekwere, Rick Kittles, Elisa Pignatti,
Giuliana Montosi, Cinzia Garuti, Innocent T. Gangaidzo, Z.A.R.
Gomo, Victor M. Moyo, Tracey A. Rouault, Patrick MacPhail,
and Antonello Pietrangelo.
2) The article "Ferroportin 1 (SCL40A1)
variant associated with iron overload in African-Americans"
is authored by Ernest Beutler, James C. Barton, Vincent J.
Felitti, Terri Gelbart, Carol West, Pauline L. Lee, Jill Waalen,
and Chris Vulpe.
3) The article "Genotypic and phenotypic
heterogeneity of African Americans with primary iron overload"
is authored by James C. Barton, Ronald T. Acton, Charles A.
Rivers, Luigi F. Bertoli, Terri Gelbart, Carol West, and Ernest
The research was funded by the National
Institutes of Health, the Stein Endowment Fund, and The Skaggs
Institute for Research.
Professor Ernest Beutler has been investigating
primary iron overload, a metabolic disorder common among people
of African descent. Photo by Jeff Tippett.