The Colton blood group system, despite the knowledge known about its genetics and biochemistry, has remained a relatively uncomplicated system. In 1967, Heisto et al. reported three examples of a similar antibody against a high frequency antigen they named Co^a (Colton) after one of the antibody producers. (Unfortunately, like the Lutheran blood group system, the authors misread the name of the individual chosen, as the original individual's name was in-fact Calton). Giles et al., in 1970, identified the antithetical antibody, anti-Co^b, and the blood group system was established. Co^a is present on the red cells in 99.9 % of most populations, with a slightly lower incidence in Northern Europeans. Alternatively, Co^b is present in 8 to 10 % of Northern Europeans with much lower incidence in other populations. The Co (a-b-) phenotype, the anticipated "null" phenotype, was reported by Rogers et al. in 1974 and Co_null cells have reduced water permeability. This made the system somewhat similar to other systems known at that time in that the "null phenotype" individual had produced an antibody of a single specificity that reacted with cells of all Colton phenotypes except Co (a-b-). Thus, this indicated a third antigen, Co3, present on all cells having either Colton allele. Moulds et al. (1973) and Swanson et al. (1978) had reported the possibility of a rare silent allele from separate family studies.

Antibodies to the Colton antigens have caused both mild and moderate hemolytic transfusion reactions and mild hemolytic disease of the newborn, except in one severe case due to anti-Co3. In this case the antibody titer was greater than 32,000 and the baby was supported by intrauterine and post-delivery maternal transfusions.

As a blood group system, Colton had been of limited clinical interest except for suggestions of linkage with monosomy 7, weaker expression with certain chromosomal 7 rearrangements and congenital dyserythropoietic anemia. Then, through a series of excellent studies by Agre et al. (1991), Smith et al. (1994) and Preston et al. (1994), Colton antigens were found to be located on the channel forming integral protein (CHIP-1). CHIP-1 is a product of the AQPI (Aquaporin-1) gene located on the short arm of chromosome 7 at 7p14. This 269 amino acid membrane glycoprotein has six a -helices forming a trapezoid-like cylinder. There is a branched rod-like structure within the cylinder that transverses the membrane and likely contains a least one a -helix. The function of this protein is essentially a regulated water channel through the membrane. An amino acid change of Ala⁴⁵ to Val⁴⁵ represents the difference between Co^a and Co^b, respectively. The location of Co3 on CHIP-1 is unknown.

Investigation of blood from three unrelated Co (a-b-) individuals revealed that the serological aberration was due to three separate causes: a frame shift after Gly¹⁰⁴, a deletion of exon 1 and a Leu³⁸ (instead of a Pro³⁸) causing a stop. These three individuals lacked or had a very low amount of CHIP-1. The CHIP-1 protein (hence the Colton blood group antigens) is located on a variety of surfaces including epithelia, endothelium, descending tubules and apical surfaces of proximal tubules in addition to red blood cells. However, the Co(a-b-) individuals do not appear to have any health related problems related to the loss of this protein.