The novel SLC40A1 (T419I) variant results in a loss-of-function phenotype and may provide insights into the mechanism of large granular lymphocytic leukemia and pure red cell aplasia
Hongfei Wu, Xiang Ren, M. Ge, Peiyuan Dong, Shichong Wang, Hui-ming Yi, Xingxin Li, J. Huo, Xuan Zheng, Mengying Gao, Jin-bo Huang, Jing Zhang, Min Wang, P. Jin, N. Nie, Y. Shao, Yizhou Zheng
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引用次数: 0
Abstract
Abstract Variants in the solute carrier family 40 member 1 (SLC40A1) gene are the molecular basis of ferroportin disease, which is an autosomal dominant hereditary hemochromatosis. Here, we present a patient with pure red cell aplasia (PRCA) and large granular lymphocytic leukemia (LGLL) associated with an extremely high levels of serum ferritin and iron overload syndrome. Whole exon sequencing revealed a novel heterozygous variant in SLC40A1 (p.T419I), which was found in his daughter as well. A series of functional studies in vitro of the T419I variant in ferroportin were conducted and the results revealed a reduced capacity of iron export from cells without changes in protein localization and its sensitivity to hepcidin. Intracellular iron storage in mutated cells was significantly higher than that of wild-type. These findings suggest that the novel variant p.T419I can cause the classical form of ferroportin disease and an elevated intracellular iron level indicates a potential novel pathogenic mechanism underlying PRCA and LGLL.