A novel R416C mutation in human DMT1 (SLC11A2) displays pleiotropic effects on function and causes microcytic anemia and hepatic iron overload

Blood Cells, Molecules, and Diseases

Volumn 36, Issue 3, 2006, Pages 347-354

  Lam Yuk Tseung, Steven ^a   Camaschella, Clara ^b   Iolascon, Achille ^c   Gros, Philippe ^a  

^a MCGILL UNIVERSITY   (Canada)

^b VITA SALUTE SAN RAFFAELE UNIVERSITY   (Italy)

^c UNIVERSITY OF NAPLES FEDERICO II   (Italy)

Author keywords

DMT1; Iron overload; Iron transport; Microcytic anemia; Nramp2; SL2HA2

Indexed keywords

MEMBRANE PROTEIN; NATURAL RESISTANCE ASSOCIATED MACROPHAGE PROTEIN 2; ORGANIC CATION TRANSPORTER 2;

AMINO ACID SUBSTITUTION; ANIMAL MODEL; ARTICLE; CELL SURFACE; ENDOSOME; GENE MUTATION; HETEROZYGOSITY; IRON OVERLOAD; KIDNEY CELL; MICROCYTIC ANEMIA; MOUSE; NONHUMAN; PLEIOTROPY; PRIORITY JOURNAL; PROTEIN PROCESSING;

AMINO ACID SUBSTITUTION; ANEMIA; ANIMALS; CATION TRANSPORT PROTEINS; CELL LINE; HUMANS; IRON OVERLOAD; LIVER DISEASES; MICE; POINT MUTATION; PROTEIN PROCESSING, POST-TRANSLATIONAL; PROTEIN TRANSPORT; SWINE;

EID: 33646849617     PISSN: 10799796     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bcmd.2006.01.011     Document Type: Article

References (22)

1. Hentze M.W., Muckenthaler M.U., and Andrews N.C. Balancing acts: molecular control of mammalian iron metabolism. Cell 117 (2004) 285-297
2. Canonne-Hergaux F., Gruenheid S., Ponka P., and Gros P. Cellular and subcellular localization of the Nramp2 iron transporter in the intestinal brush border and regulation by dietary iron. Blood 93 (1999) 4406-4417
3. Canonne-Hergaux F., Zhang A.S., Ponka P., and Gros P. Characterization of the iron transporter DMT1 (NRAMP2/DCT1) in red blood cells of normal and anemic mk/mk mice. Blood 98 (2001) 3823-3830
4. Gunshin H., et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388 (1997) 482-488
5. Fleming M.D., et al. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat. Genet. 16 (1997) 383-386
6. Fleming M.D., Romano M.A., Su M.A., Garrick L.M., Garrick M.D., and Andrews N.C. Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proc. Natl. Acad. Sci. U. S. A. 95 (1998) 1148-1153
7. Gunshin H., Fujiwara Y., Custodio A.O., Direnzo C., Robine S., and Andrews N.C. Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J. Clin. Invest. 115 (2005) 1258-1266
8. Priwitzerova M., et al. Severe hypochromic microcytic anemia caused by a congenital defect of the iron transport pathway in erythroid cells. Blood 103 (2004) 3991-3992
9. Mims M.P., et al. Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload. Blood 105 (2005) 1337-1342
10. Lam-Yuk-Tseung S., Mathieu M., and Gros P. Functional characterization of the E399D DMT1/NRAMP2/SLC11A2 protein produced by an exon 12 mutation in a patient with microcytic anemia and iron overload. Blood Cells, Mol. Dis. 35 (2005) 212-216
11. Gunshin H., Jin J., Fujiwara Y., Andrews N.C., Mims M., and Prchal J. Analysis of the E399D mutation in SLC11A2. Blood 106 (2005) 2221-2222
12. Priwitzerova M., Nie G., Sheftel A.D., Pospisilova D., Divoky V., and Ponka P. Functional consequences of the human DMT1 (SLC11A2) mutation on protein expression and iron uptake. Blood 106 (2005) 3985-3987
13. Iolascon A., d'Apolito M., Servedio V., Cimmino F., Piga A., and Camaschella C. Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2). Blood 107 (2006) 349-354
14. Lam-Yuk-Tseung S., Govoni G., Forbes J., and Gros P. Iron transport by Nramp2/DMT1: pH regulation of transport by 2 histidines in transmembrane domain 6. Blood 101 (2003) 3699-3707
15. Picard V., Govoni G., Jabado N., and Gros P. Nramp 2 (DCT1/DMT1) expressed at the plasma membrane transports iron and other divalent cations into a calcein-accessible cytoplasmic pool. J. Biol. Chem. 275 (2000) 35738-35745
16. Lam-Yuk-Tseung S., Touret N., Grinstein S., and Gros P. Carboxyl-terminus determinants of the iron transporter DMT1/SLC11A2 isoform II (-IRE/1B) mediate internalization from the plasma membrane into recycling endosomes. Biochemistry 44 (2005) 12149-12159
17. Gruenheid S., Canonne-Hergaux F., Gauthier S., Hackam D.J., Grinstein S., and Gros P. The iron transport protein NRAMP2 is an integral membrane glycoprotein that colocalizes with transferrin in recycling endosomes. J. Exp. Med. 189 (1999) 831-841
18. Cellier M., et al. Nramp defines a family of membrane proteins. Proc. Natl. Acad. Sci. U. S. A. 92 (1995) 10089-10093
19. Touret N., Furuya W., Forbes J., Gros P., and Grinstein S. Dynamic traffic through the recycling compartment couples the metal transporter Nramp2 (DMT1) with the transferrin receptor. J. Biol. Chem. 278 (2003) 25548-25557
20. Beaumont C., Delaunay J., Hetet G., de Montalembert A., and Grandchamp G.J. Two new human DMT1 mutations in a compound heterozygous patient with mircocytic anemia and low iron stores (Poster). 47th American Society of Hematology (ASH) Meeting, Atlanta, GA, USA (2005) December 10-13
21. Cotten J.F., and Welsh M.J. Cystic fibrosis-associated mutations at arginine 347 alter the pore architecture of CFTR. Evidence for disruption of a salt bridge. J. Biol. Chem. 274 (1999) 5429-5435
22. L. Guan, H.R. Kaback, Lessons from lactose permease, Annu. Rev. Biophys. Biomol. Struct. (in press) (Electronic publication ahead of print).