Several of the blood group systems have a relationship with another system; e.g. ABO and H or Rh and LW. The same holds true for the Kx system, which is associated with the Kell system. This relationship was discovered when the McLeod phenotype was first found. The McLeod phenotype has both weakened Kell as well as Kx antigens and occurs in males. The red cell phenotype is only one aspect of a syndrome now known as the McLeod syndrome which includes a variety of muscular and neurological defects, elevated serum creatine phosphokinase and acanthocytic red blood cells. In addition to the McLeod association, the null phenotype for the Kell system (K_o) has increased amounts of Kx leading early investigators to suggest that Kx was a precursor substrate for the Kell genes to act upon.

Since the McLeod phenotype was found in males and could be further associated with the X-linked disease chronic granulomatous disease, it was relatively easy to assign this gene to the sex chromosome (X). Hence the designation Xk. The specific chromosomal location is Xp21.1. The Xk gene encodes a protein of 37,000 molecular weight and is predicted to span the membrane 10 times. It is widely expressed in the body occurring in the fetal liver, adult skeletal muscle, pancreas, brain and heart. The Kell glycoprotein co-precipitated with Kx when immunoprecipitation studies were performed in order to isolate the Kx protein. This suggested that there might be a functional association; indeed, recent studies suggest that Kx may act as a chaperone or transport protein. Kx can be phosphorylated invitro and this may be a regulatory mechanism for the protein.

XK is an approximate 440-amino acid protein that is predicted to traverse the membrane 10 times. The XK Cys346 is disulfide-linked to Kell Cys72, a linkage site close to the membrane surface.