MOLECULAR GENETICS OF RED CELL RH ANTIGENS

Rh抗原存在于红细胞膜的Rh多肽中，形成 这是人类最复杂的多态之一。它们在临床上是 重要的是，这是血液中最常见的血型不合的原因 新生儿输血和溶血性疾病。他们似乎是 必需的膜成分，因为红细胞不含所有的Rh抗原 (Rh/空表型)表现为口腔细胞增多症，体内存活时间缩短， 多发性膜异常。我们的目标是揭开 Rh系统的结构/功能关系，并描绘了 其表型多样性的遗传机制。具体目标是： 1)克隆和定位整个RH基因座，建立物理秩序 以及其基因成员的转录方向。2)确定 不同Rh抗原和表型的分子基础 DNA重组和其他遗传机制如何调节基因结构 并引起抗原性变异。3)研究一种新的Rh基因的表达 可表征d(D-阴性)单倍型的转录本 确定导致其激活的机制。4)学习 Rh基因的差异剪接及其在发病中的作用 以及Rh基因在红系发育过程中的表达调控。5)至 确定Rh/Null和Rhmod基因，并确定初级 缺陷存在于Rh基因本身或与Rh相关的候选基因中。 拟议的研究承诺提供对结构/功能的洞察 Rh蛋白与致病遗传机制的关系 最多态的人类系统。所获得的知识将加深我们的 对输血和输血相关临床问题的认识 为临床服务使用提供了依据 输血医学中的分子方法。

Rh antigens reside in Rh polypeptides of the red cell membrane and form one of the most complex polymorphisms in humans. They are clinically important, accounting for the most common incompatibility found in blood transfusion and hemolytic disease of the newborn. They appear to be essential membrane components because red cells devoid of all Rh antigens (Rh/null phenotype) manifest stomatocytosis, shortened in vivo survival, and multiple membrane abnormalities. Our objectives are to unravel the structure/function relationships of the Rh system and delineate the genetic mechanisms for its phenotypic diversity. The specific aims are: 1) To clone and map the entire RH locus and establish the physical order and transcriptional direction of its gene members. 2) To determine the molecular basis of different Rh antigens and phenotypes with emphasis on how DNA recombination and other genetic mechanisms modulate gene structure and cause antigenic variation. 3) To study the expression of a novel Rh transcript that may characterize the d (D-negative) haplotypes and determine the mechanism that results in its activation. 4) To study differential splicing of the Rh genes and determine its role in the onset and regulation of Rh gene expression during erythroid development. 5) To identify the Rh/null and Rhmod genes and determine whether the primary defect is in the Rh genes themselves or in the Rh-related candidate genes. The proposed studies promise to provide insights into structure/function relationships of Rh proteins and the genetic mechanisms leading to one of the most polymorphic human systems. The knowledge gained will deepen our understanding of clinical problems associated with blood transfusion and hemolytic reactions and provide a basis for the clinical service to use molecular approaches in transfusion medicine.