The V736A TMPRSS6 polymorphism influences liver iron concentration in nontransfusion‐dependent thalassemias

Abstract

To the Editor: TMPRSS6 is a transmembrane serine protease expressed mainly in the liver that plays an important role during erythropoiesis. TMPRSS6 loss-of-function mutations result in the over-expression of hepcidin, impaired intestinal iron absorption and ironrefractory iron deficiency anemia (IRIDA). Tmprss6 deletion has been shown to improve iron overload and anemia in murine models of beta-thalassemia intermedia, and the siRNA-or antisense oligonucleotide-mediated suppression of Tmprss6 mRNA expression has been demonstrated to increase the hepcidin level, leading to diminished iron uptake and recycling as well as improved erythropoiesis and anemia in beta thalassemic animals [1,2].TMPRSS6 polymorphisms have been implicated in iron metabolism in both animal and human studies. The common rs855791 polymorphism (NM_153609.3:c.2207C>T) causes a nonsynonymous valine to alanine change (p.V736A), and the T allele (encoding valine) has been associated with lower hemoglobin and ferritin concentrations as well as increased serum transferrin receptor and transferrin concentrations in all populations [3]. Moreover, this polymorphism influences iron overload in hereditary hemochromatosis as well as the development of nonalcoholic fatty liver disease [4,5] and it has been associated with iron deficiency anemia in women of reproductive ages [6].The mechanism of action of TMPRSS6 is still unclear. Some studies have indicated that TMPRSS6 polymorphisms directly affect hepcidin transcription, while others have suggested that the polymorphisms may addictionally influence iron homeostasis by mechanisms independent of hepcidin expression. The latter theory could explain why rs855791 has not been found to be significantly associated with serum hepcidin in some studies [3].In this study, we evaluated the influence of rs855791 on liver iron concentration (LIC) in patients with different levels of ineffective erythropoiesis: mild and severe thalassemia intermedia (TI) and Hemoglobin H (HbH) disease patients, which are clinically distinct forms of the so-called nontransfusion-dependent thalassemias (NTDTs), a term used to label patients who do not require regular transfusion for survival. We classified TI in agreement with the extent of imbalance between the alpha and non alpha globin chains. Accordingly, it was considered as mild in case of coinheritance of heterozygous beta thalassemia and, respectively, triple or quadruple alpha globin gene arrangement, delta/beta 0 thalassemia, and mild or silent beta mutation. It was considered as severe in case of homozygosity or compound heterozygosity for beta 0 mutations.In patients with NTDTs, the increased intestinal absorption of iron caused by ineffective erythropoiesis is the main cause of iron overload, which can become clinically relevant by the age of 10 years. Iron overload is associated with liver dysfunction and vascular, bone, and endocrine morbidities and is therefore an important challenge in terms of diagnosis, monitoring, and treatment. Moreover, although much more rarely tha...

Functional diversity of TMPRSS6 isoforms and variants expressed in hepatocellular carcinoma cell lines

“…This variant is mainly found in African populations 33 and is associated with lower haemoglobin levels 34 , 35 . Moreover, it has been found to be detrimental in patients suffering from non-transfusion-dependent thalassemias 36 and identified in patients with iron deficiency anaemia (IDA), a milder form of IRIDA partially responsive to iron treatment, suggesting the polymorphism has a protective effect 11 , 37 . On the other hand, valine at position 736 (V736) has been identified as beneficial in non-alcoholic fatty liver disease (OMIM %613282) 38 .…”

“…Using HEK293 cells as a cellular model, we show that the common V736A polymorphism variant identified in Hep3B cells does not affect TMPRSS6 cell surface expression or its catalytic activity when compared to TMPRSS6 WT. Because V736A has been associated with higher susceptibility to hepatic iron accumulation in thalassemia patients 36 and lower hepcidin levels in normal individuals 35 , and because of the predicted entropy gain assessed by our structural bioinformatics analysis 47 , 48 , we expected higher catalytic activity of the V736A variant. It is possible that the gain of function is subtle and could not be measured in our cellular enzymatic assay.…”

Functionally impaired isoforms regulate TMPRSS6 proteolytic activity

“…Of note, TMPRSS6 SNP rs855791 encodes for valine to alanine change at position 736 within the proteolytic domain of TMPRSS6 isoform 2. Interestingly, this variant, which is found in Hep3B cells 18 is associated with higher susceptibility to hepatic iron accumulation in thalassemia patients [ 39 ] and lower hepcidin levels in healthy individuals [ 40 ]. These results suggest a gain-of-function for the V736A variant, that could lead to increased TfR1 cell surface shedding, but the molecular mechanism involved still needs to be determined.…”