Matriptase-2 mutations in iron-refractory iron deficiency anemia patients provide new insights into protease activation mechanisms
Author
Ramsay, Andrew J.
Quesada, Victor
Sanchez, Mayka
Garabaya, Cecilia
Sardà, María P.
Baiget, Montserrat
Remacha, Angel
Velasco, Gloria
López-Otín, Carlos
Publication date
2009ISSN
0964-6906
Abstract
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.
Document Type
Article
Document version
Published version
Language
English
Subject (CDU)
61 - Medical sciences
Keywords
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
Pages
10
Publisher
Oxford University Press
Collection
18;19
Is part of
Human Molecular Genetics
Citation
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
This item appears in the following Collection(s)
- Ciències de la Salut [732]
Rights
© 2024 Oxford University Press