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Rare PIK3CD Variant Linked to Immunodeficiency, Recurrent Respiratory Infections

NEW YORK (GenomeWeb News) – A rare mutation in the PIK3CD gene is shared among a number of unrelated patients with a primary immunodeficiency, researchers led by the University of Cambridge's Sergey Nejentsev reported in Science today.

People with primary immunodeficiencies are susceptible to infections, including recurrent respiratory infections, and Nejentsev and his colleagues turned to exome sequencing to search for mutations behind the PID of some 35 patients with such recurrent infections. They homed in on a variant in the PIK3CD gene that was originally found in four patients from two families.

"This mutation was not present in the other exomes and was the only rare variant shared among all patients in these two unrelated families," Nejentsev and his colleagues wrote.

The mutation, the researchers reported, leads to changes in how the catalytic subunit of phosphoinositide 3-kinase δ, encoded by the PIK3CD gene, associates with membranes as well as its kinase activity.

Because of this, the researchers dubbed this particular primary immunodeficiency activated PI3K-δ syndrome. Further, the researchers noted that certain p110δ inhibitors could be treatments for the disease.

To uncover that PIK3CD variant, Nejentsev and his colleagues performed exome sequencing on 35 PID patients from the UK. After noticing that four patients had the same heterozygous G to A mutation in the PIK3CD gene, the researchers confirmed that finding using Sanger sequencing and also found the mutation in an additional four affected family members.

The researchers also developed a genotyping assay for the mutation, which they used to screen a further 3,346 controls, about two-thirds of whom were from the UK and one-third from the rest of the world. They found no healthy carriers of the PIK3CD mutation. In addition, from a cohort of 134 PID patients from the UK and Ireland, they uncovered a further five patients with the mutation.

Nejentsev and his colleagues also suspected that there might be a connection between this mutation and hyper-IgM syndrome as the mutation appears frequently in PID patients, and one patient with the mutation had previously been diagnosed with the syndrome. By examining a French cohort of 15 hyper-IgM patients from 13 families, they uncovered an additional three patients as well as another affected family member with the PIK3CD mutation.

Overall, the researchers found 17 patients with the PIK3CD mutation.

The mutation, the researchers noted, encodes an amino acid substitution, changing a glutamic acid for a lysine in p110δ, the catalytic subunit of the PI3Kδ protein. The PI3Kδ protein is a heterodimeric lipid kinase that phosphorylates phosphatidylinositol 4,5-bisphosphate to generate phosphatidylinositol 3,4,5-trisphosphate, also known as PIP3, which is a second messenger molecule.

Using site-directed mutagenesis, Nejentsev and his colleagues introduced the mutation into p110δ, and by expressing both the mutated and wild-type versions, they found that the p110δ protein with the mutated catalytic subunit had increased basal PIP3 levels by about six fold. Stimulating PIP3production increased the activity of both the mutant and wild-type proteins, though the mutant production levels were still three-fold higher than the wild type.

The mutation is located in the part of the kinase that interacts with the cell membrane, the researchers noted, and through fluorescence resonance energy transfer assays, they determined that the mutant p110δ has a higher affinity for lipid vesicles than the wild type does.

"These results suggest that stronger binding to membranes contributes to the increased activity of the mutant p110δE1021K protein," the researchers said.

PI3Kδ is primarily expressed in cells derived from the hematopoietic lineage, such as T cells and B cells. Using a high-performance mass spectrometry-based assay, the researchers found that CD4+ and CD8+ T cells isolated from patients had higher PIP3 levels before and after the samples were stimulated, as compared to controls.

Iin both T cells and B cells with mutated PI3Kδ, the researchers noted that stimulation also led to levels of phosphorylated AKT, a downstream mediator of PIP3 levels.

While PI3Kδ is also expressed in neutrophils, they found no difference in PIP3 levels between control and mutated cells after stimulation.

"Thus, the effect of the E1021K mutation on the PI3Kδ activity may be cell-type or stimulus-specific, or may be compensated for by effects of other PI3K isoforms or PTEN," they noted.

Nejentsev and his colleagues also named this condition activated PI3K-δ syndrome, or APDS.

When they tested PIP3 production by mutant and wild-type p110δ, the researchers also looked at the effects of two selective PI3Kδ inhibitors on that production, finding that they reduced the activity of both wild-type and mutant PI3Kδ. One selective PI3Kδ inhibitor, GS-1101, they noted, is in clinical trials for the treatment of chronic lymphocytic leukemia.

"The possibility of treating APDS patients with p110δ inhibitors should therefore be considered," the researchers added.

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