Molecular mechanisms of the defective hepcidin inhibition in TMPRSS6 mutations associated with iron-refractory iron deficiency anemia.
Matriptase-2 is a transmembrane serine protease that negatively regulates hepcidin expression by cleaving membrane-bound hemojuvelin. Matriptase-2 has a complex ectodomain, including a C-terminal serine protease domain and its activation requires an autocatalytic cleavage. Matriptase-2 mutations have been reported in several patients with iron-refractory iron deficiency anemia. Here we describe a patient with 2 missense mutations in the second class A low-density lipoprotein receptor (LDLRA) domain. Functional studies of these 2 mutations and of a previously reported mutation in the second C1r/C1s, urchin embryonic growth factor and bone morphogenetic protein 1 (CUB) domain were performed. Transfection of mutant cDNAs showed that membrane targeting of the 2 LDLRA mutants was impaired, with Golgi retention of the variants. The activating cleavage was absent for the LDLRA mutants and reduced for the CUB mutant. All 3 mutated proteins were still able to physically interact with hemojuvelin but only partially repressed hepcidin expression compared with wild-type matriptase-2. Our results underline the importance of LDLRA and CUB domains of matriptase-2.
Silvestri
Laura
L
Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy.
Guillem
Flavia
F
Pagani
Alessia
A
Nai
Antonella
A
Oudin
Claire
C
Silva
Muriel
M
Toutain
Fabienne
F
Kannengiesser
Caroline
C
Beaumont
Carole
C
Camaschella
Clara
C
Grandchamp
Bernard
B
D018798:Anemia, Iron-Deficiency / Q000188:drug therapy / Q000235:genetics*; D023181:Antimicrobial Cationic Peptides / Q000037:antagonists & inhibitors*; D002648:Child; D006367:HeLa Cells; D064451:Hepcidins; D006801:Humans; D007501:Iron / Q000627:therapeutic use; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008954:Models, Biological; D009154:Mutation / Q000502:physiology; D012697:Serine Endopeptidases / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D017211:Treatment Failure
D023181:Antimicrobial Cationic Peptides; C578702:HAMP protein, human; D064451:Hepcidins; D008565:Membrane Proteins; D007501:Iron; D012697:Serine Endopeptidases; C504318:TMPRSS6 protein, human