Our recent study demonstrated that defects in p110delta result in B-cell immunodeficiency that is very similar to that observed in BTK-deficient mice. We revealed that the p110delta fit the B-cell signal transduction complex and played a non-redundant role in the development and function of B cells. In humans, most children with primary B-cell immunodeficiency have mutations in the BTK, whereas a few have defects in the components of the B-cell signal transduction complex. But little is known about the genetic variation of p110delta in children with defects in B-cell immunodeficiency of unknown aetiology. Sixteen patients from 15 unrelated families and 112 normal controls underwent sequence analysis to identify genetic variations of the p110delta. Allele frequency in each group was also analysed and compared. We identified five single base-pair polymorphic nucleotide exchanges in both patient and control groups with similar allele frequencies, which did not contribute to the immunodeficiency. Three of them are novel (m.953A>G, m.1200C>T and m.1561A>G), and the m.953A>G and m.1561A>G nucleotide exchanges are non-synonymous (N253S and T456A, respectively). The novel m.1561A>G was in complete linkage disequilibrium with the known m.873A>G in our study of Taiwanese group. In addition, one novel single base-pair missense mutation, m.3256G>A (E1021K), was identified in one boy with typical clinical features of primary B-cell immunodeficiency and could not be found in either his family or the normal control population. By atomic structural analysis of the amino acid as well as the alignment comparison between species, it resulted in the replacement of the negative-charged amino acid E with the positive-charged amino acid K at codon 1021, located in the highly conservative and important catalytic functional domain. Our findings could shed light on further understanding the polymorphisms of p110delta in B-cell immunodeficiency and different populations. Moreover, the 3256G>A missense mutation raised the attention and warranted further extensive analysis to elucidate the role of p110delta in human immunodeficiency.

译文

我们最近的研究表明,p110delta的缺陷导致b细胞免疫缺陷,这与BTK缺陷小鼠中观察到的非常相似。我们揭示了p110delta符合b细胞信号转导复合物,并且在b细胞的发育和功能中起着非冗余的作用。在人类中,大多数患有原发性b细胞免疫缺陷的儿童在BTK中存在突变,而少数儿童在b细胞信号转导复合物的成分中存在缺陷。但是,对于病因不明的b细胞免疫缺陷儿童中p110delta的遗传变异知之甚少。来自15个无关家庭和112个正常对照的16名患者进行了序列分析,以鉴定p110delta的遗传变异。还对各组的等位基因频率进行了分析和比较。我们在患者组和对照组中鉴定出五个具有相似等位基因频率的单碱基对多态性核苷酸交换,这对免疫缺陷没有贡献。其中三个是新颖的 (m.953A>G,m.1200C>T和m.1561A>G),而m.953A>G和m.1561A>G核苷酸交换是非同义的 (分别为N253S和T456A)。在我们对台湾组的研究中,新颖的m.1561A>G与已知的m.873A>G完全处于连锁不平衡状态。此外,在一名具有原发性b细胞免疫缺陷典型临床特征的男孩中鉴定出一个新的单碱基对错义突变m.3256G>A (E1021K),在其家人或正常对照人群中均找不到。通过氨基酸的原子结构分析以及物种之间的比对比较,它导致负电荷氨基酸E被密码子1021位的正电荷氨基酸K取代,位于高度保守和重要的催化功能域。我们的发现可能有助于进一步了解b细胞免疫缺陷和不同人群中p110delta的多态性。此外,3256G>A错义突变引起了人们的注意,并需要进一步广泛的分析来阐明p110delta在人类免疫缺陷中的作用。

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