Haematologica, Vol 94, Issue 8, 1049-1059 doi:10.3324/haematol.2008.002873
Copyright © 2009 by Ferrata Storti Foundation
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Red Cell Disorders

A novel erythroid anion exchange variant (Gly796Arg) of hereditary stomatocytosis associated with dyserythropoiesis

Achille Iolascon1, Luigia De Falco1, Franck Borgese2, Maria Rosaria Esposito1, Rosa Anna Avvisati1, Pietro Izzo3, Carmelo Piscopo1, Helene Guizouarn2, Andrea Biondani5, Antonella Pantaleo4, Lucia De Franceschi5

1 Chair of Medical Genetics, Department of Biochemistry and Medical Biotechnologies, University Federico II, Naples and CEINGE-Advanced Biotechnologies, Naples, Italy
2 Laboratoire de Biologie et Physiopathologie des Systèmes Intégrés, FRE3094, CNRS-Université de Nice, Bâtiment de Sciences Naturelles, Nice, France
3 Istituto di Patologia Medica, Università di Bari, Bari, Italy
4 Dipartimento di Biochimica, Università di Torino, Italy
5 Department of Clinical and Experimental Medicine, Section of Internal Medicine, University of Verona, Verona, Italy

Correspondence: Achille Iolascon, MD, PhD, CEINGE- Advanced Biotechnologies, Via Comunale Margherita 482, 80145 Naples, Italy., E-mail:iolascon{at}ceinge.unina.it

Background: Stomatocytoses are a group of inherited autosomal dominant hemolytic anemias and include overhydrated hereditary stomatocytosis, dehydrated hereditary stomatocytosis, hereditary cryohydrocytosis and familial pseudohyperkalemia.

Design and Methods: We report a novel variant of hereditary stomatocytosis due to a de novo band 3 mutation (p. G796R-band3 CEINGE) associated with a dyserythropoietic phenotype. Band 3 genomic analysis, measurement at of hematologic parameters and red cell indices and morphological analysis of bone marrow were carried out. We then evaluated the red cell membrane permeability and ion transport systems by functional studies of the patient’s erythrocytes and Xenopus oocytes transfected with mutated band 3. We analyzed the red cell membrane tyrosine phosphorylation profile and the membrane association of the tyrosine kinases Syk and Lyn from the Src-family-kinase group, since the activity of the membrane cation transport pathways is related to cyclic phosphorylation-dephosphorylation events.

Results: The patient showed mild hemolytic anemia with circulating stomatocytes together with signs of dyserythropoiesis. Her red cells displayed increased Na+ content with decreased K+content and abnormal membrane cation transport activities. Functional characterization of band 3 CEINGE in Xenopus oocytes showed that the mutated band 3 is converted from being an anion exchanger (Cl–, HCO3–) to being a cation pathway for Na+ and K+. Increased tyrosine phosphorylation of some red cell membrane proteins was observed in diseased erythrocytes. Syk and Lyn membrane association was increased in the patient’s red cells compared to in normal controls, indicating perturbation of phospho-signaling pathways involved in cell volume regulation events.

Conclusions: Band 3 CEINGE alters function from that of anion exchange to cation transport, affects the membrane tyrosine phosphorylation profile, in particular of band 3 and stomatin, and its presence during red cell development likely contributes to dyserythropiesis.

Key words: stomatocytosis, anion exchanger, dyserythropoiesis, tyrosine phosphorylation, Src family kinase.


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