From Blood Group Antigens
to Renal Failure

By Zoe L. Larned, M.D., and
Thomas L. Ortel, M.D., Ph.D

The RAPH blood group system consists of only one antigen, MER2, which has been localized to chromosome 11 (11p15.5). MER2 has a quantitatively variable expression in individuals and is found expressed on erythrocytes in 92% of Caucasians (MER2+). While MER2 is not found to be expressed on erythrocytes in 8% of Caucasians (MER2-), this is primarily accounted for by individual quantitative variability with many having levels below detection. However, four individuals have been identified who are considered true MER2- and actually produce antibody to MER2 (anti-MER2).

What has been particularly interesting about the discovery of human anti-MER2 are the resulting studies that utilized this antibody, and the subsequently developed monoclonal antibody form, to help gain further understanding of its relationship to the CD151 protein. The CD151 protein, also localized to chromosome 11p15.5, is a member of the transmembrane 4 (tetraspanin) superfamily. This is a family of cell surface proteins that are thought to have several roles in mediating signal transduction including: cell adhesion, cell growth, and differentiation. The CD151 protein has been found in a variety of tissues including the endothelium, skin, renal glomeruli, and proximal and distal tubules.

The above discoveries were then utilized by Dr. Vanja Karamatic Crew and colleagues to investigate the relationship between a common finding of renal failure in 3 of the 4 previously identified anti- MER2 individuals (Plenary Session, Sunday, December 7, 2003, 1:15 p.m.). All three of these individuals were Asians of Indian descent who developed renal failure in childhood secondary to membranous glomerulonephritis. Two of these individuals also had epidermolysis bullosa and neurosensory deafness while this clinical history was not available for the third patient. Upon examination of their CD151 gene, all were found to have CD151 mutations (homozygosity for G383 insertion in exon 5 leading to translation of a truncated CD151 protein). These results offered a pathophysiologic explanation for their finding of renal failure and skin disease since CD151 is found in renal tissues and skin. An additional patient, also with a known antiMER2 but without end stage renal disease, was determined to have a different CD151 gene mutation, resulting from an amino acid substitution. In this case, he was a healthy blood donor found to be homozygous for G533A in exon 6. This is an area where protein:protein recognition is felt to play a role, although his mutation has not appeared to cause any clinical sequelae.

With the increasing utilization of microarray technology, CD151 protein is one of many being recognized for its possible role in a variety of disease processes and its potential as a therapeutic target, for example, in multiple myeloma. (Poster Session: Myeloma Genetics and Gene Expression Sunday, December 7, 2003 5:45 p.m.). The importance of MER2 is not yet fully understood, although its role in transfusion appears to be minimal. For example, there is data showing that some of the 4 anti-MER2 patients currently identified have been successfully transfused with normal donor blood without evidence of transfusion reactions.