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.

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.

• Authors: Hongfei Wu, Xiang Ren, Meili Ge, Peiyuan Dong, Shichong Wang, Huiming Yi, Xingxin Li, Jiali Huo, Xuan Zheng, Mengying Gao, Jinbo Huang, Jing Zhang, Min Wang, Peng Jin, Neng Nie, Yingqi Shao, Yizhou Zheng
• Journal: Blood science (Baltimore, Md.) (Blood Sci) Vol. 4 Issue 1 Pg. 29-37 (Jan 2022) ISSN: 2543-6368 [Electronic] United States
• PMID: 35399544 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the Chinese Medical Association (CMA) and Institute of Hematology, Chinese Academy of Medical Sciences & Peking Union Medical College (IHCAMS).