RESUMO
Mutations leading to abrogation of matriptase-2 proteolytic activity in humans are associated with an iron-refractory iron deficiency anemia (IRIDA) due to elevated hepcidin levels. Here we describe two novel heterozygous mutations within the matriptase-2 (TMPRSS6) gene of monozygotic twin girls exhibiting an IRIDA phenotype. The first is the frameshift mutation (P686fs) caused by the insertion of the four nucleotides CCCC in exon 16 (2172_2173insCCCC) that is predicted to terminate translation before the catalytic serine. The second mutation is the di-nucleotide substitution c.467C>A and c.468C>T in exon 3 that causes the missense mutation A118D in the SEA domain of the extracellular stem region of matriptase-2. Functional analysis of both variant matriptase-2 proteases has revealed that they lead to ineffective suppression of hepcidin transcription. We also demonstrate that the A118D SEA domain mutation causes an intra-molecular structural imbalance that impairs matriptase-2 activation. Collectively, these results extend the pattern of TMPRSS6 mutations associated with IRIDA and functionally demonstrate that mutations affecting protease regions other than the catalytic domain may have a profound impact in the regulatory role of matriptase-2 during iron deficiency.
Assuntos
Anemia Ferropriva/enzimologia , Anemia Ferropriva/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Mutação , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Adolescente , Sequência de Aminoácidos , Sequência de Bases , Ativação Enzimática , Éxons , Feminino , Mutação da Fase de Leitura , Humanos , Masculino , Proteínas de Membrana/química , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Linhagem , Estrutura Terciária de Proteína , Alinhamento de Sequência , Serina Endopeptidases/químicaRESUMO
Our aim was to establish the reference values of the new parameter reticulocyte hemoglobin equivalent (RET-He) and to investigate its role in differentiating between iron deficiency anemia and anemia of chronic diseases. We found that RET-He was useful for diagnosing iron deficiency anemia. A cut-off point of 25 pg provided a specificity of 0.81 and a sensitivity of 0.76.