title: Matriptase-2 mutations in iron-refractory iron deficiency anemia patients provide new insights into protease activation mechanisms.
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.
authors: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.
authors: Andrew J
authors: AJ
authors: Ramsay
authors: Victor
authors: V
authors: Quesada
authors: Mayka
authors: M
authors: Sanchez
authors: Cecilia
authors: C
authors: Garabaya
authors: María P
authors: MP
authors: Sardà
authors: Montserrat
authors: M
authors: Baiget
authors: Angel
authors: A
authors: Remacha
authors: Gloria
authors: G
authors: Velasco
authors: Carlos
authors: C
authors: López-Otín
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D018798:Anemia, Iron-Deficiency / Q000201:enzymology* / Q000235:genetics*; D001483:Base Sequence; D004789:Enzyme Activation; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D012697:Serine Endopeptidases; C467801:matriptase 2