title: A novel TMPRSS6 mutation that prevents protease auto-activation causes IRIDA.
abstract: IRIDA (iron-refractory iron-deficiency anaemia) is a rare autosomal-recessive disorder hallmarked by hypochromic microcytic anaemia, low transferrin saturation and high levels of the iron-regulated hormone hepcidin. The disease is caused by mutations in the transmembrane serine protease TMPRSS6 (transmembrane protease serine 6) that prevent inactivation of HJV (haemojuvelin), an activator of hepcidin transcription. In the present paper, we describe a patient with IRIDA who carries a novel mutation (Y141C) in the SEA domain of the TMPRSS6 gene. Functional characterization of the TMPRSS6(Y141C) mutant protein in cultured cells showed that it localizes to similar subcellular compartments as wild-type TMPRSS6 and binds HJV, but fails to auto-catalytically activate itself. As a consequence, hepcidin mRNA expression is increased, causing the clinical symptoms observed in this IRIDA patient. The present study provides important mechanistic insight into how TMPRSS6 is activated.
authors: Department of Pediatric Oncology, Haematology and Immunology, University Hospital of Heidelberg, Germany.
authors: Sandro
authors: S
authors: Altamura
authors: Flavia
authors: F
authors: D'Alessio
authors: Barbara
authors: B
authors: Selle
authors: Martina U
authors: MU
authors: Muckenthaler
mesh_terms: D000595:Amino Acid Sequence; D018798:Anemia, Iron-Deficiency / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000652:urine; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000652:urine; D001483:Base Sequence; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D004789:Enzyme Activation; D005260:Female; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010802:Phylogeny; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics; D016415:Sequence Alignment; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D023181:Antimicrobial Cationic Peptides; D058851:GPI-Linked Proteins; C578702:HAMP protein, human; C481006:HJV protein, human; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D008565:Membrane Proteins; D012333:RNA, Messenger; D012697:Serine Endopeptidases; C504318:TMPRSS6 protein, human