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- The role of TMPRSS6 gene variants in different types of iron deficiency anaemia - from the rare severe hereditary IRIDA to the common mild acquired IDAPublication . Gonçalves, Lúcia; Nobre Jesus, Gustavo; Afonso, Celina; Vieira, Albertina; Maia, Raquel; Correia, Leonor; Faustino, PaulaObjective: Iron-refractory iron-deficiency anaemia (IRIDA) is a rare autosomal-recessive disease characterized by severe hypochromic microcytic anemia, low serum iron and transferrin saturation, normal-high ferritin and inappropriate high levels of the hormone hepcidin. Patients are unresponsive to iron oral treatment and present a slow persistent response to intravenous iron injections. The disease is caused by loss-of-function mutations in the TMPRSS6 gene which encodes the matriptase-2 (MT2), a negative regulator of hepcidin transcription. In those patients, high hepcidin levels prevent iron absorption in the duodenum and iron recycling by macrophages. Furthermore, it has been suggested that common variants in TMPRSS6 might modulate haematological phenotype and iron status. Therefore, the objective of this work was to search for severe genetic variants in TMPRSS6 in order to elucidate IRIDA-like phenotypes in some patients and to evaluate whether the SNP rs855791 influences iron deficiency anaemia (IDA) susceptibility in women. Patients and Methods: Sequencing analyses of the TMPRSS6 gene were performed in 6 cases presenting IRIDA-like phenotypes. Additionally, the SNP rs855791 (p.V736A) was characterized, using an allele specific amplification approach, in 25 women presenting IDA and in 89 women normal controls. Results: Sequencing analyses of TMPRSS6 in the IRIDA-suspected cases revealed the presence of a previously described pathogenic variant (c.757A>G, p.K253E), a novel splicing variant (whose functional effect is under study) and 3 other common variants. Concerning SNPs study, the frequency distribution of the rs8855791 genotypes showed a statistically association with women hemoglobin, serum iron level and transferrin saturation, being the proportion of CC homozygotes significantly lower in IDA patients. Conclusion: Several degrees of iron deficiency anaemia can be attributed to genetic variants of TMPRSS6 gene and a relation genotype/phenotype can be established. Moreover, SNPs within the gene which give rise to a partial impairment of MT2 are able to modulate susceptibility to IDA. This suggests that TMPRSS6 has a role in iron-related common disorders in which it may act as a gene modifier.