The protein Matriptase-2 damaged by a novel missense mutation in the TMPRSS6 gene originates an IRIDA-like phenotype in an African child

Iron-refractory iron deficiency anemia (IRIDA) is a rare autosomal recessive anemia usually unresponsive to oral iron intake and partially responsive to parenteral iron treatment. This disease is the result of mutations in TMPRSS6 gene, encoding Matriptase-2, a transmembrane serine protease that plays a key role in down-regulating hepcidin, allowing iron bioavailability for erythropoiesis. 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 investigates the case of 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. The subject 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 software. In order to run a Missense3D analysis, we predicted a 3D Structure for matriptase-2 in the software Phyre2. 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 noted as an autosomal recessive disease, we infer that, in this case, the result of a digenic inheritance of the novel damaging mutation (c.871G>A; G291S) and 3 common modulating SNPs in the same gene in addition to the co-inheritance of the α-thalassemia allele, may add up to an IRIDA-like phenotype. Further functional studies of the mutated protein as well as family studies should be conducted. INSA_2013DGH910 e GenomePT (POCI-01-0145-FEDER-022184) info:eu-repo/semantics/publishedVersion