Novel TMPRSS6 mutations associated with Iron-refractory Iron Deficiency Anemia (IRIDA)

Luigia De Falco, Francesca Totaro, Antonella Nai, Alessia Pagani, Domenico Girelli, Laura Silvestri, Carmelo Piscopo, Natascia Campostrini, Carlo Dufour, Fahd Al Manjomi, Milen Minkov, Dennis G. Van Vuurden, Aurora Feliu, Antonis Kattamis, Clara Camaschella, Achille Iolascon

Research output: Contribution to journalArticle

47 Citations (Scopus)

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. In this paper we describe 12 IRIDA patients belonging to 7 unrelated families and identify 10 (9 novel) TMPRSS6 mutations spread along the gene sequence: 5 missense, 1 non sense and 4 frameshift. The frameshift and non sense mutations are predict to result in truncated protein lacking the catalytic domain. The causal role of missense mutations (Y141C, I212T, R271Q, S304L and C510S) is demonstrated by in silico analysis, their absence in 100 control chromosomes and the high conservation of the involved residues. The C510S mutation in the LDLRA domain in silico model causes an intra-molecular structural imbalance that impairs matriptase-2 activation. We also assessed the in vitro effect on hepcidin promoter and the proteolytic activity of I212T and R271Q variants demonstrating a reduced inhibitory effect for the former mutation, but surprisingly a normal function for R271Q which appears a silent mutation in vitro. Based on mRNA expression studies I212T could also decrease the total amount of protein produced, likely interfering with mRNA stability. Collectively, our results extend the pattern of TMPRSS6 mutations associated with IRIDA and propose a model of causality for some of the novel missense mutation.

Original languageEnglish
JournalHuman Mutation
Volume31
Issue number5
DOIs
Publication statusPublished - May 2010

Fingerprint

Mutation
Hepcidins
Missense Mutation
Computer Simulation
RNA Stability
Human Activities
Causality
Iron-Refractory Iron Deficiency Anemia
Catalytic Domain
Proteins
Chromosomes
Messenger RNA
Genes
In Vitro Techniques
matriptase 2

Keywords

  • IRIDA
  • Iron metabolism
  • Microcytic anemia
  • TMPRSS6

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

De Falco, L., Totaro, F., Nai, A., Pagani, A., Girelli, D., Silvestri, L., ... Iolascon, A. (2010). Novel TMPRSS6 mutations associated with Iron-refractory Iron Deficiency Anemia (IRIDA). Human Mutation, 31(5). https://doi.org/10.1002/humu.21243

Novel TMPRSS6 mutations associated with Iron-refractory Iron Deficiency Anemia (IRIDA). / De Falco, Luigia; Totaro, Francesca; Nai, Antonella; Pagani, Alessia; Girelli, Domenico; Silvestri, Laura; Piscopo, Carmelo; Campostrini, Natascia; Dufour, Carlo; Al Manjomi, Fahd; Minkov, Milen; Van Vuurden, Dennis G.; Feliu, Aurora; Kattamis, Antonis; Camaschella, Clara; Iolascon, Achille.

In: Human Mutation, Vol. 31, No. 5, 05.2010.

Research output: Contribution to journalArticle

De Falco, L, Totaro, F, Nai, A, Pagani, A, Girelli, D, Silvestri, L, Piscopo, C, Campostrini, N, Dufour, C, Al Manjomi, F, Minkov, M, Van Vuurden, DG, Feliu, A, Kattamis, A, Camaschella, C & Iolascon, A 2010, 'Novel TMPRSS6 mutations associated with Iron-refractory Iron Deficiency Anemia (IRIDA)', Human Mutation, vol. 31, no. 5. https://doi.org/10.1002/humu.21243
De Falco, Luigia ; Totaro, Francesca ; Nai, Antonella ; Pagani, Alessia ; Girelli, Domenico ; Silvestri, Laura ; Piscopo, Carmelo ; Campostrini, Natascia ; Dufour, Carlo ; Al Manjomi, Fahd ; Minkov, Milen ; Van Vuurden, Dennis G. ; Feliu, Aurora ; Kattamis, Antonis ; Camaschella, Clara ; Iolascon, Achille. / Novel TMPRSS6 mutations associated with Iron-refractory Iron Deficiency Anemia (IRIDA). In: Human Mutation. 2010 ; Vol. 31, No. 5.
@article{6b6a14794ed542ec886e194794e748c8,
title = "Novel TMPRSS6 mutations associated with Iron-refractory Iron Deficiency Anemia (IRIDA)",
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. In this paper we describe 12 IRIDA patients belonging to 7 unrelated families and identify 10 (9 novel) TMPRSS6 mutations spread along the gene sequence: 5 missense, 1 non sense and 4 frameshift. The frameshift and non sense mutations are predict to result in truncated protein lacking the catalytic domain. The causal role of missense mutations (Y141C, I212T, R271Q, S304L and C510S) is demonstrated by in silico analysis, their absence in 100 control chromosomes and the high conservation of the involved residues. The C510S mutation in the LDLRA domain in silico model causes an intra-molecular structural imbalance that impairs matriptase-2 activation. We also assessed the in vitro effect on hepcidin promoter and the proteolytic activity of I212T and R271Q variants demonstrating a reduced inhibitory effect for the former mutation, but surprisingly a normal function for R271Q which appears a silent mutation in vitro. Based on mRNA expression studies I212T could also decrease the total amount of protein produced, likely interfering with mRNA stability. Collectively, our results extend the pattern of TMPRSS6 mutations associated with IRIDA and propose a model of causality for some of the novel missense mutation.",
keywords = "IRIDA, Iron metabolism, Microcytic anemia, TMPRSS6",
author = "{De Falco}, Luigia and Francesca Totaro and Antonella Nai and Alessia Pagani and Domenico Girelli and Laura Silvestri and Carmelo Piscopo and Natascia Campostrini and Carlo Dufour and {Al Manjomi}, Fahd and Milen Minkov and {Van Vuurden}, {Dennis G.} and Aurora Feliu and Antonis Kattamis and Clara Camaschella and Achille Iolascon",
year = "2010",
month = "5",
doi = "10.1002/humu.21243",
language = "English",
volume = "31",
journal = "Human Mutation",
issn = "1059-7794",
publisher = "John Wiley and Sons Inc.",
number = "5",

}

TY - JOUR

T1 - Novel TMPRSS6 mutations associated with Iron-refractory Iron Deficiency Anemia (IRIDA)

AU - De Falco, Luigia

AU - Totaro, Francesca

AU - Nai, Antonella

AU - Pagani, Alessia

AU - Girelli, Domenico

AU - Silvestri, Laura

AU - Piscopo, Carmelo

AU - Campostrini, Natascia

AU - Dufour, Carlo

AU - Al Manjomi, Fahd

AU - Minkov, Milen

AU - Van Vuurden, Dennis G.

AU - Feliu, Aurora

AU - Kattamis, Antonis

AU - Camaschella, Clara

AU - Iolascon, Achille

PY - 2010/5

Y1 - 2010/5

N2 - 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. In this paper we describe 12 IRIDA patients belonging to 7 unrelated families and identify 10 (9 novel) TMPRSS6 mutations spread along the gene sequence: 5 missense, 1 non sense and 4 frameshift. The frameshift and non sense mutations are predict to result in truncated protein lacking the catalytic domain. The causal role of missense mutations (Y141C, I212T, R271Q, S304L and C510S) is demonstrated by in silico analysis, their absence in 100 control chromosomes and the high conservation of the involved residues. The C510S mutation in the LDLRA domain in silico model causes an intra-molecular structural imbalance that impairs matriptase-2 activation. We also assessed the in vitro effect on hepcidin promoter and the proteolytic activity of I212T and R271Q variants demonstrating a reduced inhibitory effect for the former mutation, but surprisingly a normal function for R271Q which appears a silent mutation in vitro. Based on mRNA expression studies I212T could also decrease the total amount of protein produced, likely interfering with mRNA stability. Collectively, our results extend the pattern of TMPRSS6 mutations associated with IRIDA and propose a model of causality for some of the novel missense mutation.

AB - 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. In this paper we describe 12 IRIDA patients belonging to 7 unrelated families and identify 10 (9 novel) TMPRSS6 mutations spread along the gene sequence: 5 missense, 1 non sense and 4 frameshift. The frameshift and non sense mutations are predict to result in truncated protein lacking the catalytic domain. The causal role of missense mutations (Y141C, I212T, R271Q, S304L and C510S) is demonstrated by in silico analysis, their absence in 100 control chromosomes and the high conservation of the involved residues. The C510S mutation in the LDLRA domain in silico model causes an intra-molecular structural imbalance that impairs matriptase-2 activation. We also assessed the in vitro effect on hepcidin promoter and the proteolytic activity of I212T and R271Q variants demonstrating a reduced inhibitory effect for the former mutation, but surprisingly a normal function for R271Q which appears a silent mutation in vitro. Based on mRNA expression studies I212T could also decrease the total amount of protein produced, likely interfering with mRNA stability. Collectively, our results extend the pattern of TMPRSS6 mutations associated with IRIDA and propose a model of causality for some of the novel missense mutation.

KW - IRIDA

KW - Iron metabolism

KW - Microcytic anemia

KW - TMPRSS6

UR - http://www.scopus.com/inward/record.url?scp=77951822044&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77951822044&partnerID=8YFLogxK

U2 - 10.1002/humu.21243

DO - 10.1002/humu.21243

M3 - Article

C2 - 20232450

AN - SCOPUS:77951822044

VL - 31

JO - Human Mutation

JF - Human Mutation

SN - 1059-7794

IS - 5

ER -