European Hematology Association - Mutations in PIGA Cause a New Form of Juvenile Hemochromatosis

THE HAGUE, Netherlands, June 11, 2021 /PRNewswire/ -- The iron overload disorder hereditary hemochromatosis is the most common genetic disorder in the Caucasian population. If untreated, iron overload causes progressive organ damage in ageing patients, including heart failure, diabetes, liver cirrhosis and cancer. In addition to the frequent late-onset subtype of hemochromatosis, rare forms have been described with severe iron accumulation in children. Our work identifies a novel subtype of juvenile hemochromatosis due to mutations in the phosphatidylinositol glycan class A (PIGA) gene, which anchors proteins to the cell membrane. Systemic iron overload and PIGA mutations were diagnosed in three juvenile patients with neurological deficits. We applied CRISPR/Cas-mediated gene deletion of PIGA in a liver cell line to investigate the pathomechanism of iron overload. We show that PIGA deletion prevents cell membrane attachment of hemojuvelin, a protein involved in facilitating the formation of an active bone morphogenetic receptor complex that signals to increase hepcidin, an hepatic hormone regulating systemic iron levels. Therefore, the lack of PIGA reduces hepcidin expression, thus contributing to the iron overload observed in our patients. Furthermore, ceruloplasmin, a ferroxidase involved in cellular iron export is also GPI-anchored. PIGA deletion severely decreases ceruloplasmin levels, which may contribute to intracellular iron accumulation and release of toxic forms of iron, further aggravating the iron overload.

Taken together, our results identify a novel form of juvenile hereditary hemochromatosis and its molecular mechanism by demonstrating that the function of two GPI-anchored proteins involved in maintaining iron homeostasis, hemojuvelin and ceruloplasmin, is impaired by PIGA mutations. This new link advocates for the need for clinical assessment of potential iron overload in patients with germline PIGA mutations.

The results of this study will be presented by Dr. Oriana Marques in the Presidential Symposium.

Presenter: Dr. Oriana Marques

Affiliation: Universitätsklinikum Heidelberg, Heidelberg, Germany

Abstract: #S100 PIGA GERMLINE MUTATIONS CAUSE DECREASED HEPCIDIN EXPRESSION AND A NOVEL SUBTYPE OF HEREDITARY HEMOCHROMATOSIS

About the EHA Annual Congress: Every June, EHA organizes its Annual Congress in a major European city. This year, due to the persisting COVID19 pandemic, EHA organizes a virtual Congress for the second time. The Congress is aimed at health professionals working in or interested in the field of hematology.

Website: www.ehaweb.org

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