The Kidd antigen system, which includes the Jka and Jkb antigens, is of great importance in transfusion medicine because all immunization of exposed individuals can cause severe acute and delayed hemolytic transfusion reactions as well as hemolytic disease of the newborn. The Kidd---null blood group is most often inherited as a recessive genetic trait due to bi-allelic mutations in the SLC14A1 gene, which encodes the protein that has the Jka and Jkb antigens. The cause of the identical Kidd-null phenotype with dominant inheritance [In(Jk)] has not yet been defined, though it was first described in 1965. We are proposing to identify the never before described molecular cause of the Kidd-null phenotype. The protein encoded by the SLC14A1 gene, and displaying the Kidd antigens, is the urea transporter UT-B1. The Kidd---null phenotype is associated not only with transfusion risk, but also with abnormalities in the ability to concentrate urine due to decrease expression of this urea transporter in the kidney. In collaboration with laboratories in Spain, the Krause laboratory has access to the most extensive population with In(Jk) ever described. To date, we have used molecular approaches to map the affected locus to a 5 Mbp region in 19q13.11-13.2 with an LOD score of 9.6. Using deep sequencing, we have identified a potential deleterious mutation in the ZNF850 gene, which deletes 84 bp resulting in loss of an entire zing finger domain. The identical del84 ZNF850 mutation is present in all affected individuals, and is absent from all controls tested (n>2000). In the present project, we will test whether del84 ZNF850 is responsible for inhibition of Kidd antigen expression on primary human cells differentiated down the erythroid lineage, and if not, we will further analyze the 5Mbp region of interest to identify he genetic abnormality that causes this phenotype. We will determine the mechanism by which Kidd antigen expression is blocked in In(Jk) cells, and we will elucidate the molecular mechanism by which the genetic abnormalities on chromosome 19 cause the In(Jk) phenotype. The data obtained will have relevance to transfusion medicine, renal physiology, and will likely also elucidate novel specific mechanisms for protein-specific intracellular trafficking.

Public Health Relevance

Patients may need to receive red blood cells after extensive bleeding or if they have a disease or treatment regimen that causes them to produce too few red blood cells. When a patient receives a red blood cells infusion, there is a risk that the patiet will develop an immune response against the donated cells, and the consequences to this immune response can range from being relatively minimal to life threatening. One life threatening event that can happen is called an acute hemolytic transfusion reaction (AHTR). These immune responses can also cause problems to the developing fetus or newborn. This is called hemolytic disease of the newborn (HDN). The Kidd antigen system is important because it is one of the major causes of AHTR and HDN. We are proposing to identify the never before described genetic basis of the 'Inhibitor of Kidd,' which causes some people to lack Kidd antigens on their red blood cells. The goal of the proposed study is to better understand the Kidd antigen system, and to use this understanding to prevent severe transfusion reactions.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-VH-F (55))
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Thomas, John
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Yale University
Schools of Medicine
New Haven
United States
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