Molecular Basis of Dominantly Inherited Kidd-null Phenotype

Yale University, New Haven CT

Investigators

Abstract

DESCRIPTION (provided by applicant): 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.