Matriptase-2 mutations in iron-refractory iron deficiency anemia patients provide new insights into protease activation mechanisms
Autor/a
Ramsay, Andrew J.
Quesada, Victor
Sanchez, Mayka
Garabaya, Cecilia
Sardà, María P.
Baiget, Montserrat
Remacha, Angel
Velasco, Gloria
López-Otín, Carlos
Fecha de publicación
2009ISSN
0964-6906
Resumen
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.
Tipo de documento
Artículo
Versión del documento
Versión publicada
Lengua
English
Materias (CDU)
61 - Medicina
Palabras clave
Fenotip
Mutació del ferro
Anèmia per deficiència de ferro
Endopeptidases
Exons
Pèptid
Hidrolases
Hepcidina
Proteòlisi
Cognició social i avaluació emocional
Fenotipo
Mutación del hierro
Deficiencia de hierro
Anemia
Endopeptidasas
Exones
Péptido
Hidrolasas
Hepcidina
Proteólisis
Cognición social y evaluación emocional
Phenotype
Iron mutation
Iron deficiency
Anemia
Endopeptidases
Exons
Peptide
Hydrolases
Hepcidin
Proteolysis
Social cognition and emotional assessment
Páginas
10
Publicado por
Oxford University Press
Colección
18; 19
Publicado en
Human Molecular Genetics
Citación
Ramsay, Andrew J.; Quesada, Victor; Sanchez, Mayka [et al.]. Matriptase-2 mutations in iron-refractory iron deficiency anemia patients provide new insights into protease activation mechanisms. Human Molecular Genetics, 2009, 18(19), p. 3673-3683. Disponible en: <https://academic.oup.com/hmg/article/18/19/3673/2386335?login=true>. Fecha de acceso: 31 ene. 2024. DOI: 10.1093/hmg/ddp315
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