title: Haematologic data, iron parameters and molecular findings in two new cases of iron-refractory iron deficiency anaemia.
abstract: Matriptase-2 (Tmprss6), a type II transmembrane serine protease, has an essential role in iron homoeostasis as a hepcidin regulator. Recently, patients with TMPRSS6 mutations and suffering from iron-refractory iron deficiency anaemia (IRIDA) have been reported. We describe two new cases of IRIDA, one patient of Swiss origin and the second of Italian origin. The first case results from a large deletion of 1054 nucleotides corresponding to an in frame deletion of 30 amino acid residues in the low-density lipoprotein receptor-1/-2 (LDLR-1/-2) domains and from a missense mutation in CUB1 (S304L). In the second case, a homozygous G-->C mutation in the last nucleotide of exon 15 and which modified the consensus sequence of the 5' splice donor site of intron 15 (AGgt-->ACgt) was identified. Both patients had a high hepcidin level and low serum iron and transferrin saturation compared to age-matched controls. Continuous perfusion of i.v. iron 4 h/d x 5 d in the first case resulted in a significant rise in haemoglobin. These new cases of IRIDA illustrate the importance of LDLR-1/-2 and CUB1 domains in matriptase-2 function as well as the role of matriptase-2 in hepcidin regulation. Furthermore a deletional form of TMPRSS6 (in LDLR-1/-2 domains) resulting in IRIDA is described for the first time. These cases reinforce the belief that patients suffering from IRIDA have no specific geographical or ethnic distribution and are sporadic secondary to different mutations of the matriptase-2 gene.
authors.affiliation: Geneva University Hospitals, Switzerland. Isabelle.Tchou@unige.ch
authors.forename: Isabelle
authors.initials: I
authors.lastname: Tchou
authors.forename: Myriam
authors.initials: M
authors.lastname: Diepold
authors.forename: Pierre-Antonio
authors.initials: PA
authors.lastname: Pilotto
authors.forename: Dorine
authors.initials: D
authors.lastname: Swinkels
authors.forename: Marguerite
authors.initials: M
authors.lastname: Neerman-Arbez
authors.forename: Photis
authors.initials: P
authors.lastname: Beris
mesh_terms: D000595:Amino Acid Sequence; D018798:Anemia, Iron-Deficiency / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D023181:Antimicrobial Cationic Peptides / Q000097:blood* / Q000502:physiology; D002097:C-Reactive Protein / Q000032:analysis; D003241:Consanguinity; D016384:Consensus Sequence; D003951:Diagnostic Errors; D004351:Drug Resistance; D004909:Erythrocyte Indices; D005091:Exons / Q000235:genetics; D064451:Hepcidins; D006801:Humans; D007223:Infant; D007438:Introns / Q000235:genetics; D007501:Iron / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use; D007558:Italy; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D017434:Protein Structure, Tertiary; D022821:RNA Splice Sites / Q000235:genetics; D017384:Sequence Deletion; D012697:Serine Endopeptidases / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D013557:Switzerland; D013789:Thalassemia / Q000175:diagnosis
chemical_list: D023181:Antimicrobial Cationic Peptides; C578702:HAMP protein, human; D064451:Hepcidins; D008565:Membrane Proteins; D022821:RNA Splice Sites; D002097:C-Reactive Protein; D007501:Iron; D012697:Serine Endopeptidases; C504318:TMPRSS6 protein, human