Novel mutation in addition to functional TMPRSS6 gene polymorphisms originate an IRIDA-like phenotype in an African child

Faleiro, Bárbara D.; Maia, Raquel; Batalha, Sara; Mendonça, Joana; Machado, Miguel P.; Vieira, Luís; Lavinha, João; Faustino, Paula

http://hdl.handle.net/10400.18/6728

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Iron-refractory iron deficiency anemia (IRIDA) is a rare autosomal recessive anemia often unresponsive to oral iron intake and partially responsive to parenteral iron treatment. The disease originates from mutations in TMPRSS6 gene, encoding Matriptase 2, a transmembrane serine protease that plays an essential role in down-regulating hepcidin. Once TMPRSS6 is mutated, the corresponding protein is absent or inactive at the hepatocyte membrane leading to uncontrolled high levels of hepcidin and impaired iron absorption. This study aimed to investigate a 4-year-old boy of sub-Saharan ancestry (Mozambique/Angola), presenting with microcytic hypochromic anemia, low transferrin saturation, normal ferritin, and having a partial response to intravenous iron treatment. He is a -α3.7-thalassemia carrier. TMPRSS6 was screened for variants by Next-Generation Sequencing using Nextera XT libraries in a MiSeq platform (Illumina). Genetic variants found were validated by Sanger sequencing. In silico analyses were performed in HSF, SIFT, Poly-Phen2 and Missense3D softwares. A novel missense mutation (c.871G>A) was found in heterozygosity, in TMPRSS6 exon 8. In silico analysis indicates the conserved amino acid change (G291S) may be damaging to the protein stability. Due to its location in the CUB1 domain, it may also affect the enzyme activation and substrate recognition. Additionally, 3 SNPs previously associated with a greater risk of developing iron deficiency anemia (K253E, V736A and Y739Y) were also identified in TMPRSS6. Although IRIDA is known as an autosomal recessive disease, we conclude that, in this case, the result of a digenic inheritance of the novel damaging mutation (c.871G>A; G291S) and the 3 common modulating SNPs in the same gene and a co-inheritance of the α-thalassemia HBA deletion may lead to an IRIDA-like phenotype. Further functional studies of the mutated protein as well as family studies should be conducted.