Molecular Basis of Dominantly Inherited Kidd-null Phenotype

描述（由申请人提供）：Kidd抗原系统，包括Jka和Jkb抗原，在输血医学中非常重要，因为暴露个体的所有免疫都可能引起严重的急性和延迟溶血性输血反应以及新生儿溶血性疾病。由于SLC14A1基因（编码具有Jka和Jkb抗原的蛋白质）的双等位基因突变，无基德血型通常作为隐性遗传性状遗传。基德-零表型与显性遗传[In(Jk)]相同的原因尚未确定，尽管它在1965年首次被描述。我们建议确定从未描述过的基德null表型的分子原因。由SLC14A1基因编码并显示Kidd抗原的蛋白是尿素转运蛋白UT-B1。Kidd- null表型不仅与输血风险有关，还与由于肾脏中尿素转运蛋白表达减少而导致的浓缩尿能力异常有关。通过与西班牙实验室的合作，Krause实验室可以接触到迄今为止所描述的最广泛的In（Jk）人群。到目前为止，我们已经使用分子方法将受影响的位点定位到19q13.11-13.2的5 Mbp区域，LOD评分为9.6。通过深度测序，我们在ZNF850基因中发现了一个潜在的有害突变，该突变删除了84 bp，导致整个zing finger结构域的丢失。相同的del84 ZNF850突变存在于所有受影响的个体中，而在所有测试的对照中不存在（2010年6月）。在本项目中，我们将测试del84 ZNF850是否负责在红系分化的原代人细胞中抑制Kidd抗原的表达，如果不是，我们将进一步分析感兴趣的5Mbp区域，以确定导致该表型的遗传异常。我们将确定Kidd抗原表达在in （Jk）细胞中被阻断的机制，我们将阐明19号染色体上的遗传异常导致in （Jk）表型的分子机制。获得的数据将与输血医学、肾脏生理学相关，并可能阐明蛋白质特异性细胞内运输的新特异性机制。

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.