Fourth International Symposium on Neuroacanthocytosis

Abstracts from the Fourth International Symposium on Neuroacanthocytosis

July 1-2, 2008
London and Oxford

Chairs: Prof. Kailash Bhatia, MD, FRCP, Institute of Neurology, University College London; Prof. Anthony P. Monaco, MD, PhD, Wellcome Trust Centre for Human Genetics, University of Oxford

Organizers: Antonio Velayos-Baeza, PhD; Susanne Schneider, MD; Glenn Irvine

7-1 Recent progress on Kell and XK: Functional aspects of the two proteins learned from knockout mouse models
S. Lee
New York Blood Center, New York, NY, USA

Absence of XK protein, the McLeod phenotype, is responsible for red cell acanthocytosis and late onset forms of neuromuscular abnormalities. On red cells, XK, a putative membrane transporter, forms a heterodimer with Kell, an endothelin-converting enzyme-3 (ET-3) and Kell/XK is anchored, by binding with 4.1R, to the cytoskeleton forming a XK(Kell)/ 4.1R/actin/spectrin multi-protein complex. ET-3 exerts multiple functions primarily through activation of ETB receptor which is coupled with various alpha subunits of heterotrimeric G protein. Neither the functions of XK nor the role played by Kell in the XK/Kell complex have been defined. The expressions of Kell and XK on the red cell surface, are affected by absence of either partner protein; absence of XK (McLeod red cells) reduces Kell expression and absence of Kell (Kell Null red cells) reduces XK expression. In non-erythroid tissues, where XK expression exceeds Kell (or no Kell is expressed), XK may function differently from XK/Kell in red cells. In order to understand the function of XK alone (mainly non-erythroid) and of the erythroid XK/Kell/4.1R complex (also present in non-erythroid tissues), we studied knockout mouse models, lacking Xk, Kel or both Xk and Kel (Xk-KO, Kel-KO and Xk/Kel-double KO) and compared them to wild-type mice. Scanning skeletal muscles of the knockout mice, we found some abnormalities (internalized nuclei, angulated fibers and splitting fibers), in Xk-KO and Xk/Kel-KO mice and very mild changes in Kel-KO. Sciatic nerves, anterior horns of lumbar spinal cord and related nerve roots of all three knockout mice showed axonal neuropathy with variable degrees of secondary demyelination (Xk/Kel-double KO>Kel-KO>Xk-KO). Ion transport studies of the red cells of the knockout mice showed that their functions are affected in all three knockout mice lines. These results, taken together with other behavioral, motor function studies indicate that Kell and XK are functionally coupled and imply that Kell and XK may both participate in McLeod pathology and that absence of XK in the XK(Kell)/4.1R complex is a contributing factor to McLeod pathology.