Altered germinal center reaction and abnormal B cell peripheral maturation in PI3KR1-mutated patients presenting with HIGM-like phenotype

Dominant Splice Site Mutations in PIK3R1 Cause Hyper IgM Syndrome, Lymphadenopathy and Short Stature

“…Altogether, these observations suggest that amino acids 435–474 in PIK3R1 are important for its stability and also restrain PI3K activity. Its deletion may lead to constitutive activation of PI3K/Akt/mTOR signaling, which is consistent with recent reports of patients with similar mutations [6–8]. …”

“…Despite this apparent limited allelic heterogeneity for PIK3R1 immunodeficiency, the findings in the four patients presented here continue to highlight the heterogeneity of the clinical and immunologic abnormalities of the patients who have PIK3RI Δ434_475 essential splice mutations [6–8]. The clinical features of the four patients reported here are uniform and similar to some but not all of those described by Deau et al [6] and Lucas et al [7].…”

“…Four unrelated patients were found by next generation sequencing to have the same de novo heterozygous mutation in an essential donor splice site of PIK3R1 (NM_181523.2:c.1425 + 1G > A) found in three prior reports [6–8]. All four had the Hyper IgM syndrome, lymphadenopathy and short stature, and one also had a clinical diagnosis of SHORT syndrome.…”

“…Including the 12 patients in the three earlier reports [6–8] all sixteen known cases of PIK3R1 immunodeficiency have had mutations at this essential donor splice site (NM_181523.2:c.1425 + 1G > A/C/T). Despite this apparent limited allelic heterogeneity for PIK3R1 immunodeficiency, the findings in the four patients presented here continue to highlight the heterogeneity of the clinical and immunologic abnormalities of the patients who have PIK3RI Δ434_475 essential splice mutations [6–8].…”

“…The resulting clinical problems included respiratory infections, Epstein Barr virus and/or cytomegalovirus infections, antibody deficiency, lymphadenopathy and lymphoma susceptibility. More recently, dominant mutations in the gene encoding PIK3R1, the p85α regulatory subunit for PIK3CD, were also found to result in constitutive hyperactivation of that pathway and immunodeficiency [6–8]. Currently, the dominant PIK3R1 mutations linked to constitutive hyperactivation have been restricted to mutations of essential donor splice sites in intron 11, resulting in the exclusion of exon 11 ( PIK3RI Δ434_475 ) [6, 7, 9].…”