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Scientists at Scripps discover a genetic cause for primary iron overload

Scripps Research Institute

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, M.D., 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 another.

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 macrophages--the scavenger cells of the body.

An Italian-U.S. group led by Dr. 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:

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 Beutler.

The research was funded by the National Institutes of Health, the Stein Endowment Fund, and The Skaggs Institute for Research.

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