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Gene Review

XK  -  X-linked Kx blood group

Homo sapiens

Synonyms: KX, Kell complex 37 kDa component, Kx, Kx antigen, MCLDS, ...
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Disease relevance of XK

  • Almost total absence of Kell antigens from the RBCs of a German man with no symptoms of neuroacanthocytosis could not be due to the Kell-null phenotype, Ko, because his RBCs had very weak expression of Kx antigen and his three children were Kp(a + b+) [1].
  • These findings contribute to the understanding of the physiology of XK and Kell proteins, and the pathogenetic mechanisms of acanthocytosis, myopathy, and striatal neurodegeneration in McLeod syndrome [2].
  • The expanding range of muscle pathology reported in McLeod syndrome, to which this case adds, may reflect variable involvement of the XK gene on chromosome Xp21, or of the adjacent loci of Duchenne muscular dystrophy and chronic granulomatous disease [3].
  • Absence of XK, the McLeod phenotype, is associated with acanthocytic red blood cells (RBCs), and with late-onset forms of muscular dystrophy and nerve abnormalities [4].
  • We present six males (aged 29 to 60 years), with proven XK mutations, to discuss the chorea associated with McLeod syndrome [5].

High impact information on XK

  • The mRNA expression pattern of one of them, designated as XK, correlates closely to the McLeod phenotype [6].
  • Nucleotide sequence analysis of XK from two unrelated McLeod patients has identified point mutations at conserved splice donor and acceptor sites [6].
  • Lastly, the rate of invasion of Kx null erythrocytes by P. falciparum was significantly lower than Kx-expressing erythrocytes [7].
  • McLeod syndrome, characterized by acanthocytosis and the absence of a red-blood-cell Kell antigen (Kx), is a multisystem disorder involving a late-onset myopathy, splenomegaly, and neurological defects [8].
  • A combination of the effects of rare genotypes at the XK and KEL blood group loci results in absence of Kell system antigens from the red blood cells [1].

Biological context of XK

  • Expression of the Kell system antigens is partially governed by XK, an X-linked gene that encodes the Kx protein; absence of Kx results in reduced Kell antigen expression [1].
  • Sequencing of his XK gene showed a single base change within the donor splice consensus sequence of intron 2 [1].
  • Although the E327K missense mutation was associated with the immunohematologic characteristics of McLeod syndrome, the mutated XK protein seemed to be largely functional [2].
  • In addition, no subclinical involvement was discovered on the basis of normal muscle histology with a physiologic pattern of XK and Kell immunohistochemistry, normal cerebral MRI, and quantified PET [2].
  • CONCLUSION: Known disease-causing XK gene mutations comprised deletions, nonsense, or splice-site mutations predicting absent or truncated XK protein devoid of the Kell-protein binding site [2].

Anatomical context of XK

  • A rare phenotype termed Kell null (Ko) is characterized by the absence of Kell protein and Kell antigens from the red cell membrane and diminished amounts of XK protein [9].
  • The mechanism of Kell/XK assembly was studied in transfected COS cells co-expressing Kell and XK proteins [10].
  • Time course studies combined with endonuclease-H treatment and cell fractionation showed that Kell and XK are assembled in the endoplasmic reticulum [10].
  • Kell and XK transcripts are expressed in multipotent progenitor cells and these cells express Kell surface antigens [11].
  • XK protein was absent from the RBC membranes [12].

Associations of XK with chemical compounds

  • Kell, a type II membrane glycoprotein, is a zinc endopeptidase, while XK, which has 10 transmembrane domains, is a putative membrane transporter [9].
  • The single extracellular cysteine 347 of XK was also mutated [13].
  • A single disulphide bond, Kell Cys 72-XK Cys 347, links Kell to XK [14].
  • This unmasking of the Kx antigenic site is near maximal using 2 microM DTT [15].
  • Lack of Kx, the McLeod phenotype, is associated with red cell acanthocytosis, elevated levels of serum creatine phosphokinase and late onset forms of muscular and neurological defects [14].

Other interactions of XK

  • XPLAC, like XK, has 3 exons and is located on X chromosome at q22.1, while XTES has 4 exons and is located at 22q11 [16].
  • Identification of two new members, XPLAC and XTES, of the XK family [16].
  • This illustrates the variable phenotype of XK mutations and suggests the possibility that CAPN3 heterozygotes may have their condition caused by nonallelic mutations in other unrelated genes [17].
  • We examined the XK gene in three patients with neuroacanthocytosis, one of whom had cardiomyopathy, and his symptoms were very similar to those of McLeod syndrome [18].
  • The physiological functions of Kell and XK have not been fully elucidated but Kell is a zinc endopeptidase with endothelin-3-converting enzyme activity and XK has the structural characteristics of a membrane transporter [14].

Analytical, diagnostic and therapeutic context of XK


  1. A combination of the effects of rare genotypes at the XK and KEL blood group loci results in absence of Kell system antigens from the red blood cells. Daniels, G.L., Weinauer, F., Stone, C., Ho, M., Green, C.A., Jahn-Jochem, H., Offner, R., Monaco, A.P. Blood (1996) [Pubmed]
  2. McLeod phenotype associated with a XK missense mutation without hematologic, neuromuscular, or cerebral involvement. Jung, H.H., Hergersberg, M., Vogt, M., Pahnke, J., Treyer, V., Röthlisberger, B., Kollias, S.S., Russo, D., Frey, B.M. Transfusion (2003) [Pubmed]
  3. Unusual muscle pathology in McLeod syndrome. Barnett, M.H., Yang, F., Iland, H., Pollard, J.D. J. Neurol. Neurosurg. Psychiatr. (2000) [Pubmed]
  4. The Kell blood group system: Kell and XK membrane proteins. Lee, S., Russo, D., Redman, C.M. Semin. Hematol. (2000) [Pubmed]
  5. The chorea of McLeod syndrome. Danek, A., Tison, F., Rubio, J., Oechsner, M., Kalckreuth, W., Monaco, A.P. Mov. Disord. (2001) [Pubmed]
  6. Isolation of the gene for McLeod syndrome that encodes a novel membrane transport protein. Ho, M., Chelly, J., Carter, N., Danek, A., Crocker, P., Monaco, A.P. Cell (1994) [Pubmed]
  7. Domain III of Plasmodium falciparum apical membrane antigen 1 binds to the erythrocyte membrane protein Kx. Kato, K., Mayer, D.C., Singh, S., Reid, M., Miller, L.H. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  8. Fine mapping of the McLeod locus (XK) to a 150-380-kb region in Xp21. Ho, M.F., Monaco, A.P., Blonden, L.A., van Ommen, G.J., Affara, N.A., Ferguson-Smith, M.A., Lehrach, H. Am. J. Hum. Genet. (1992) [Pubmed]
  9. Molecular defects underlying the Kell null phenotype. Lee, S., Russo, D.C., Reiner, A.P., Lee, J.H., Sy, M.Y., Telen, M.J., Judd, W.J., Simon, P., Rodrigues, M.J., Chabert, T., Poole, J., Jovanovic-Srzentic, S., Levene, C., Yahalom, V., Redman, C.M. J. Biol. Chem. (2001) [Pubmed]
  10. Intracellular assembly of Kell and XK blood group proteins. Russo, D., Lee, S., Redman, C. Biochim. Biophys. Acta (1999) [Pubmed]
  11. Onset of expression of the components of the Kell blood group complex. Pu, J.J., Redman, C.M., Visser, J.W., Lee, S. Transfusion (2005) [Pubmed]
  12. First example of anti-Kx in a person with the McLeod phenotype and without chronic granulomatous disease. Russo, D.C., Oyen, R., Powell, V.I., Perry, S., Hitchcock, J., Redman, C.M., Reid, M.E. Transfusion (2000) [Pubmed]
  13. Association of XK and Kell blood group proteins. Russo, D., Redman, C., Lee, S. J. Biol. Chem. (1998) [Pubmed]
  14. Kell, Kx and the McLeod syndrome. Redman, C.M., Russo, D., Lee, S. Baillière's best practice & research. Clinical haematology. (1999) [Pubmed]
  15. Unmasking of Kx antigen by reduction of disulphide bonds on normal and McLeod red cells. Branch, D.R., Sy Siok Hian, A.L., Petz, L.D. Br. J. Haematol. (1985) [Pubmed]
  16. Identification of two new members, XPLAC and XTES, of the XK family. Calenda, G., Peng, J., Redman, C.M., Sha, Q., Wu, X., Lee, S. Gene (2006) [Pubmed]
  17. A family with McLeod syndrome and calpainopathy with clinically overlapping diseases. Starling, A., Schlesinger, D., Kok, F., Passos-Bueno, M.R., Vainzof, M., Zatz, M. Neurology (2005) [Pubmed]
  18. Analysis of the McLeod syndrome gene in three patients with neuroacanthocytosis. Shizuka, M., Watanabe, M., Aoki, M., Ikeda, Y., Mizushima, K., Okamoto, K., Itoyama, Y., Abe, K., Shoji, M. J. Neurol. Sci. (1997) [Pubmed]
  19. A murine monoclonal antibody against Kx protein which reacts also with beta-spectrin. Carbonnet, F., Blanchard, D., Hattab, C., Cochet, S., Petit-Leroux, Y., Loirat, M.J., Cartron, J.P., Bertrand, O. Transfusion medicine (Oxford, England) (2000) [Pubmed]
  20. Biochemical studies on McLeod phenotype red cells and isolation of Kx antigen. Redman, C.M., Marsh, W.L., Scarborough, A., Johnson, C.L., Rabin, B.I., Overbeeke, M. Br. J. Haematol. (1988) [Pubmed]
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