Gordeuk Victor R, Caleffi Angela, Corradini Elena, Ferrara Francesca, Jones Russell A, Castro Oswaldo, Onyekwere Onyinye, Kittles Rick, Pignatti Elisa, Montosi Giuliana, Garuti Cinzia, Gangaidzo Innocent T, Gomo Z A R, Moyo Victor M, Rouault Tracey A, MacPhail Patrick, Pietrangelo Antonello
Howard University College of Medicine, Washington, DC 20059, USA.
Blood Cells Mol Dis. 2003 Nov-Dec;31(3):299-304. doi: 10.1016/s1079-9796(03)00164-5.
The product of the SLC40A1 gene, ferroportin 1, is a main iron export protein. Pathogenic mutations in ferroportin 1 lead to an autosomal dominant hereditary iron overload syndrome characterized by high serum ferritin concentration, normal transferrin saturation, iron accumulation predominantly in macrophages, and marginal anemia. Iron overload occurs in both the African and the African-American populations, but a possible genetic basis has not been established. We analyzed the ferroportin 1 gene in 19 unrelated patients from southern Africa (N = 15) and the United States (N = 4) presenting with primary iron overload. We found a new c. 744 C-->T (Q248H) mutation in the SLC40A1 gene in 4 of these patients (3 Africans and 1 African-American). Among 22 first degree family members, 10 of whom were Q248H heterozygotes, the mutation was associated with a trend to higher serum ferritin to amino aspartate transferase ratios (means of 14.8 versus 4.3 microg/U; P = 0.1) and lower hemoglobin concentrations (means of 11.8 versus 13.2 g/dL; P = 0.1). The ratio corrects serum ferritin concentration for alcohol-induced hepatocellular damage. We also found heterozygosity for the Q248H mutation in 7 of 51 (14%) southern African community control participants selected because they had a serum ferritin concentration below 400 microg/L and in 5 of 100 (5%) anonymous African-Americans, but we did not find the change in 300 Caucasians with normal iron status and 25 Caucasians with non-HFE iron overload. The hemoglobin concentration was significantly lower in the African community controls with the Q248H mutation than in those without it. We conclude that the Q248H mutation is a common polymorphism in the ferroportin 1 gene in African populations that may be associated with mild anemia and a tendency to iron loading.
SLC40A1基因的产物铁转运蛋白1是一种主要的铁输出蛋白。铁转运蛋白1中的致病性突变会导致常染色体显性遗传性铁过载综合征，其特征为血清铁蛋白浓度升高、转铁蛋白饱和度正常、铁主要在巨噬细胞中蓄积以及轻度贫血。非洲人群和非裔美国人群中均会出现铁过载，但尚未确定其可能的遗传基础。我们分析了来自非洲南部（N = 15）和美国（N = 4）的19例原发性铁过载的非亲缘患者的铁转运蛋白1基因。我们在其中4例患者（3名非洲人和1名非裔美国人）中发现了SLC40A1基因新的c. 744 C→T（Q248H）突变。在22名一级家庭成员中，其中10人为Q248H杂合子，该突变与血清铁蛋白与天冬氨酸转氨酶比值升高趋势相关（均值分别为14.8与4.3μg/U；P = 0.1）以及血红蛋白浓度降低（均值分别为11.8与13.2 g/dL；P = 0.1）。该比值可校正酒精性肝细胞损伤所致的血清铁蛋白浓度。我们还在51名非洲南部社区对照参与者中的7名（14%）中发现了Q248H突变杂合子，这些参与者因血清铁蛋白浓度低于400μg/L而被选中，在100名匿名非裔美国人中的5名（5%）中也发现了该突变，但在300名铁状态正常的白种人和25名非HFE铁过载的白种人中未发现该变化。具有Q248H突变的非洲社区对照者的血红蛋白浓度显著低于无该突变者。我们得出结论，Q248H突变是非洲人群中铁转运蛋白1基因的常见多态性，可能与轻度贫血和铁负荷倾向相关。
