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Blood, 5 February 2009, Vol. 113, No. 6, pp. 1350-1357. Prepublished online as a Blood First Edition Paper on October 17, 2008; DOI 10.1182/blood-2008-07-171140. This Article Full Text (PDF) Supplemental Methods and Figures Supplemental Methods and Figures All Versions of this Article: blood-2008-07-171140v1 113/6/1350    most recent Alert me when this article is cited Alert me if a correction is posted 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 Bruce, L. J Articles by Stewart, G. W Search for Related Content PubMed PubMed Citation Articles by Bruce, L. J Articles by Stewart, G. W Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 25, 2008 Accepted September 24, 2008 The monovalent cation leak in over-hydrated stomatocytic red blood cells results from amino acid substitutions in the Rh associated glycoprotein (RhAG) Lesley J Bruce*, Helene Guizouarn, Nicholas M Burton, Nicole Gabillat, Joyce Poole, Joanna F Flatt, R Leo Brady, Franck Borgese, Jean Delaunay, and Gordon W Stewart Bristol Institute for Transfusion Sciences, National Blood Service, Bristol, United Kingdom Laboratoire de biologie et physiopathologie des systemes integres, FRE3094 CNRS-Universite de Nice, Nice, France Department of Biochemistry, University of Bristol, Bristol, United Kingdom Hematologie, Hopital de Bicetre, APHP; Faculte de Medecine Paris-Sud, Univ Paris-Sud, Paris, France Department of Medicine, University College London, London, United Kingdom * Corresponding author; email: lesley.bruce{at}nbs.nhs.uk. Over-hydrated hereditary stomatocytosis (OHSt) is a rare dominantly-inherited hemolytic anemia characterized by a profuse membrane leak to monovalent cations. Here we show that OHSt red cell membranes contain slightly reduced amounts of Rh-associated glycoprotein (RhAG), a putative gas channel protein. DNA analysis revealed that the OHSt patients have one of two heterozygous mutations (t182g, t194c) in RHAG leading to substitutions of two highly conserved amino acids (Ile61Arg, Phe65Ser). Unexpectedly, expression of wild-type RhAG in Xenopus laevis oocytes induced a monovalent cation leak; expression of the mutant RhAG proteins induced a leak about six times greater than wild-type. RhAG belongs to the ammonium transporter family of proteins that form pore-like structures. We have modeled RhAG on the homologous Nitrosomonas europaea Rh50 protein and shown that these mutations are likely to lead to an opening of the pore. Although the function of RhAG remains controversial, this first report of functional RhAG mutations supports a role for RhAG as a cation pore. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Mairhofer, M. Steiner, U. Salzer, and R. Prohaska Stomatin-like Protein-1 Interacts with Stomatin and Is Targeted to Late Endosomes J. Biol. Chem., October 16, 2009; 284(42): 29218 - 29229. [Abstract] [Full Text] [PDF] J. F. Flatt and L. J. Bruce The hereditary stomatocytoses Haematologica, August 1, 2009; 94(8): 1039 - 1041. [Full Text] [PDF] G. C. Kodippili, J. Spector, C. Sullivan, F. A. Kuypers, R. Labotka, P. G. Gallagher, K. Ritchie, and P. S. Low Imaging of the diffusion of single band 3 molecules on normal and mutant erythrocytes Blood, June 11, 2009; 113(24): 6237 - 6245. [Abstract] [Full Text] [PDF]

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