Hosseini-Maaf Bahram, Letts James A, Persson Mattias, Smart Elizabeth, LePennec Pierre-Yves, Hustinx Hein, Zhao Zhihon, Palcic Monica M, Evans Stephen V, Chester M Alan, Olsson Martin L
Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University and Blood Center, Lund University Hospital, Lund, Sweden.
Transfusion. 2007 May;47(5):864-75. doi: 10.1111/j.1537-2995.2007.01203.x.
Four amino-acid-changing polymorphisms differentiate the blood group A and B alleles. Multiple missense mutations are associated with weak expression of A and B antigens but the structural changes causing subgroups have not been studied.
Individuals or families having serologically weak B antigen on their red cells were studied. Alleles were characterized by sequencing of exons 1 through 7 in the ABO gene. Single crystal X-ray diffraction, three-dimensional-structure molecular modeling, and enzyme kinetics showed the effects of the B allele mutations on the glycosyltransferases.
Seven unrelated individuals with weak B phenotypes possessed seven different B alleles, five of which are new and result in substitution of highly conserved amino acids: M189V, I192T, F216I, D262N, and A268T. One of these (F216I) was due to a hybrid allele resulting from recombination between B and O(1v) alleles. The two other alleles were recently described in other ethnic groups and result in V175M and L232P. The first crystal-structure determination (A268T) of a subgroup glycosyltransferase and molecular modeling (F216I, D262N, L232P) indicated conformational changes in the enzyme that could explain the diminished enzyme activity. The effect of three mutations could not be visualized since they occur in a disordered loop.
The genetic background for B(w) phenotypes is very heterogeneous but usually arises through seemingly random missense mutations throughout the last ABO exon. The targeted amino acid residues, however, are well conserved during evolution. Based on analysis of the resulting structural changes in the glycosyltransferase, the mutations are likely to disrupt molecular bonds of importance for enzymatic function.
四个氨基酸改变的多态性区分了血型A和B等位基因。多个错义突变与A和B抗原的弱表达相关，但导致亚群的结构变化尚未得到研究。
对红细胞上血清学表现为弱B抗原的个体或家庭进行研究。通过对ABO基因外显子1至7进行测序来鉴定等位基因。单晶X射线衍射、三维结构分子建模和酶动力学显示了B等位基因突变对糖基转移酶的影响。
7名具有弱B表型的无关个体拥有7种不同的B等位基因，其中5种是新的，导致高度保守氨基酸的替代：M189V、I192T、F216I、D262N和A268T。其中一个（F216I）是由于B和O(1v)等位基因之间重组产生的杂合等位基因。另外两个等位基因最近在其他种族群体中被描述，导致V175M和L232P。亚群糖基转移酶的首次晶体结构测定（A268T）和分子建模（F216I、D262N、L232P）表明酶的构象变化可以解释酶活性的降低。由于三个突变发生在无序环中，其影响无法显现。
B(w)表型的遗传背景非常异质，但通常是通过整个ABO最后一个外显子中看似随机的错义突变产生的。然而，目标氨基酸残基在进化过程中高度保守。基于对糖基转移酶产生的结构变化的分析，这些突变可能破坏对酶功能重要的分子键。
