Class I phosphoinositide-3-kinases (PI3Ks) convert phosphoinositol-4, 5-bisphosphate to phosphoinositol-3, 4, 5-trisphosphate, a lipid second messenger produced mainly at plasma membranes where it recruits and activates pleckstrin homology domain-containing proteins, including the well known protein kinase AKT. Class IA PI3Ks are heterodimers composed of a catalytic subunit (p110a, p110β or p110δ) and a regulatory subunit (p85a, p85β or p85g, p50a and p55a). The catalytic subunits consist of an adaptor-binding domain (ABD), a Ras-binding domain (RBD), a protein kinase C homology-2 (C2) domain, a helical domain and a kinase domain. All of the class IA regulatory subunits contain two Src homology 2 domains, nSH2 and cSH2, separated by a coiled-coil domain known as inter-SH2 domain (iSH2). 1 The p110δ catalytic subunit encoded by the PIK3CD gene is predominantly expressed in leukocytes. So far, six heterozygous germline gain-of-function mutations affecting either C2, helical or kinase domains of p110δ have been described to be responsible for the autosomal dominant “Activated PI3K-δ Syndrome 1”(APDS1): N334K, C416R, E525K, E525A, E1021K and E1025G2-6 (Figure 1A, B). A clinically and biologically similar disease “Activated PI3K-δ Syndrome 2”(APDS2) is caused by mutations in the PIK3R1 gene encoding the regulatory subunit p85a, p55a and p50a: splice site mutations responsible for amino acid

434-475 deletion. 7, 8 Both diseases-although heterogeneous-share a common phenotype characterized mainly by recurrent respiratory tract infections since childhood, bronchiectasis, lymphoproliferative disorder, and predisposition to development of B-cell lymphoma as main clinical complications. 9 Biologically, APDS patients present with hypogammaglobulinemia and B-cell lymphopenia with an increased percentage of transitional B cells and decreased naive T-cell counts, especially T CD4+ cells. Here, we report three unrelated patients with novel heterozygous mutations in PIK3CD (E81K and G124D) located in the ABD and the ABD-RBD linker region of p110δ as cause for APDS1. These two gain-of-function mutations thus affect domains not previously shown to be important in the increased p110δ activity characteristic of this syndrome.

The patients were born at term and presented with recurrent upper and lower respiratory tract infections since childhood. For patient 1 (P1), a 13-year-old boy, no relevant family history was reported. He presented with hypogammaglobulinemia with decreased IgG and IgA but normal IgM serum levels (Table 1). Current complications include bronchiectasis, a lymphoproliferative syndrome with splenomegaly and hepatic fibrosis responsible for portal hypertension associated with gastrointestinal bleedings. P2, a 10-year-old boy, presented with recurrent otitis media and sinusitis since his first year of life. He had an adenoidectomy at 3 years of age. He presented with high IgM but normal IgG and IgA serum levels (Table 1). The serum levels of IgG2 (0.23; N: 0.56) and IgG4 (< 0.002; N: 0.018) subclasses were low. P3, a 9-year-old girl, presented with growth retardation since 6 months of age (currently-