doi: 10.1111/j.1744-313X.2006.00627.x © 2006 The Authors Journal compilation © 2006 Blackwell Publishing Ltd, International Journal of Immunogenetics 33, 361–369 361 Blackwell Publishing Ltd Identification of variations in the human phosphoinositide 3-kinase p110δ gene in children with primary B-cell immunodeficiency of unknown aetiology S.-T. Jou,* Y.-H. Chien,* Y.-H. Yang,* T.-C. Wang,† S.-D. Shyur,† C.-C. Chou,* M.-L. Chang,‡ D.-T. Lin,* K.-H. Lin* & B.-L. Chiang* Summary Our recent study demonstrated that defects in p110δ result in B-cell immunodeficiency that is very similar to that observed in BTK-deficient mice. We revealed that the p110δ fit the B-cell signal transduction complex and played a non-redundant role in the development and func- tion 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 p110δ 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 p110δ. 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 disequi- librium 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 struc- tural 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 p110δ in B-cell immunodeficiency and different populations. Moreover, the 3256G>A mis- sense mutation raised the attention and warranted further extensive analysis to elucidate the role of p110δ in human immunodeficiency. Introduction Antibody deficiencies are the most common types of pri- mary immunodeficiency among children. Recognition of the pathogenesis of impaired immunity is very important not only for proper treatment to prevent recurrent or life- threatening infections, but also for carrier detection, prenatal diagnosis, and possible gene therapy. Remarkable advances in molecular genetics during the past few years have established the use of the mouse knock- out model to search for genes involved in the pathogenesis of primary immunodeficiency in humans (Buckley, 2000). The heterogeneity of genetic defects along the same sign- alling pathway may lead to the same immunodeficient phenotypes in humans. The mice with knocked-out B-cell linker protein (BLNK) gene had phenotypes with defects in B-cell function (Pappu et al., 1999) that were similar to those of Bruton’s tyrosine kinase (Btk) knockout mice (Khan et al., 1995; Kerner et al., 1995). The immuno- logical research was propelled forward by the discovery in 1993 that mutations in Btk were the cause of primary B-cell immunodeficiency diseases in both mice (Xid, for X-linked immunodeficiency) and humans (XLA, for X-linked agammaglobulinemia) (Tsukada et al., 1993; Vetrie et al., 1993). Because only about 85% of patients with primary B-cell immunodeficiency are males with XLA and have mutations in Btk (Conley et al., 1998), the nature of the gene defects in many patients with primary B-cell immunodeficiency remains unknown. Conley et al. (1998) hypothesized and then proved that the mutations in BLNK gave rise to primary B-cell immunodeficiency not only in mice but in humans by characterizing the human genomic BLNK structure and mutation analysis (Minegishi et al., 1999). * Department of Paediatrics, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan, † Department of Paediatrics, Mackay Memorial Hospital, 92 Section 2, Chung-Shan North Road, Taipei 104, Taiwan and ‡ Department of Paediatrics, Chang Gung Children’s Hospital, 5 Fu Hsing Street, Kweishan 333 Taoyuan, Taiwan Received 16 June 2006; accepted 11 July 2006 Correspondence: Bor-Luen Chiang, Department of Paediatrics, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan. Tel: 886-2-23123456 ext 7302; Fax: 886-2-23934749; E-mail: gicmbor@ha.mc.ntu.edu.tw