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Blood, 1 September 2004, Vol. 104, No. 5, pp. 1526-1533. Prepublished online as a Blood First Edition Paper on May 20, 2004; DOI 10.1182/blood-2004-02-0731. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-02-0731v1 104/5/1526    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Touret, N. Articles by Grinstein, S. Search for Related Content PubMed PubMed Citation Articles by Touret, N. Articles by Grinstein, S. Related Collections Red Cells Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  RED CELLS Molecular and cellular mechanisms underlying iron transport deficiency in microcytic anemia Nicolas Touret, Natalia Martin-Orozco, Paul Paroutis, Wendy Furuya, Steven Lam-Yuk-Tseung, John Forbes, Philippe Gros, and Sergio Grinstein From the Programme in Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada; and the Department of Biochemistry, McGill University, Montreal, QC, Canada. A mutation of the iron transporter Nramp2 (DMT1, Slc11a2) causes microcytic anemia in mk mice and in Belgrade rats by impairing iron absorption in the duodenum and in erythroid cells, causing severe iron deficiency. Both mk and Belgrade animals display a glycine-to-arginine substitution at position 185 (G185R) in the fourth predicted transmembrane domain of Nramp2. To study the molecular basis for the loss of function of Nramp2G185R, we established cell lines stably expressing extracellularly tagged versions of wild-type (WT) or mutated transporters. Like WT Nramp2, the G185R mutant was able to reach the plasmalemma and endosomal compartments, but with reduced efficiency. Instead, a large fraction of Nramp2G185R was detected in the endoplasmic reticulum, where it was unstable and was rapidly degraded by a proteasome-dependent mechanism. Moreover, the stability of the mutant protein that reached the plasma membrane was greatly reduced, further diminishing its surface density at steady state. Last, the specific metal transport activity of plasmalemmal Nramp2G185R was found to be significantly depressed, compared with its WT counterpart. Thus, a singlepoint mutation results in multiple biosynthetic and functional defects that combine to produce the impaired iron deficiency that results in microcytic anemia. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: The Nramp2 G185R mutant iron transporter: defective in many ways Robert E. Fleming Blood 2004 104: 1237-1238. [Full Text] [PDF] This article has been cited by other articles: S. Lam-Yuk-Tseung, V. Picard, and P. Gros Identification of a Tyrosine-based Motif (YGSI) in the Amino Terminus of Nramp1 (Slc11a1) That Is Important for Lysosomal Targeting J. Biol. Chem., October 20, 2006; 281(42): 31677 - 31688. [Abstract] [Full Text] [PDF] A. Iolascon, M. d'Apolito, V. Servedio, F. Cimmino, A. Piga, and C. Camaschella Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2) Blood, January 1, 2006; 107(1): 349 - 354. [Abstract] [Full Text] [PDF] B. Mackenzie and M. D. Garrick Iron Imports. II. Iron uptake at the apical membrane in the intestine Am J Physiol Gastrointest Liver Physiol, December 1, 2005; 289(6): G981 - G986. [Abstract] [Full Text] [PDF] M. Priwitzerova, G. Nie, A. D. Sheftel, D. Pospisilova, V. Divoky, and P. Ponka Functional consequences of the human DMT1 (SLC11A2) mutation on protein expression and iron uptake Blood, December 1, 2005; 106(12): 3985 - 3987. [Abstract] [Full Text] [PDF] M. P. Mims, Y. Guan, D. Pospisilova, M. Priwitzerova, K. Indrak, P. Ponka, V. Divoky, and J. T. Prchal Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload Blood, February 1, 2005; 105(3): 1337 - 1342. [Abstract] [Full Text] [PDF]

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