Activated PI3Kδ syndrome, an immunodeficiency disorder, leads to sensorimotor deficits recapitulated in a murine model

Ines Serra, Olivia R Manusama, Fabian M P Kaiser, Izi Izumi Floriano, Lucas Wahl, Christian van der Zalm, Hanna IJspeert, P Martin van Hagen, Nico J M van Beveren, Sandra M Arend, Klaus Okkenhaug, Johan J M Pel, Virgil A S H Dalm, Aleksandra Badura*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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The phosphoinositide-3-kinase (PI3K) family plays a major role in cell signaling and is predominant in leukocytes. Gain-of-function (GOF) mutations in the PIK3CD gene lead to the development of activated PI3Kδ syndrome (APDS), a rare primary immunodeficiency disorder. A subset of APDS patients also displays neurodevelopmental delay symptoms, suggesting a potential role of PIK3CD in cognitive and behavioural function. However, the extent and nature of the neurodevelopmental deficits has not been previously quantified. Here, we assessed the cognitive functions of two APDS patients, and investigated the causal role of the PIK3CD GOF mutation in neurological deficits using a murine model of this disease. We used p110δE1020K knock-in mice, harbouring the most common APDS mutation in patients. We found that APDS patients present with visuomotor deficits, exacerbated by autism spectrum disorder comorbidity, whereas p110δE1020K mice exhibited impairments in motor behaviour, learning and repetitive behaviour patterning. Our data indicate that PIK3CD GOF mutations increase the risk for neurodevelopmental deficits, supporting previous findings on the interplay between the nervous and the immune system. Further, our results validate the knock-in mouse model, and offer an objective assessment tool for patients that could be incorporated in diagnosis and in the evaluation of treatments.

Original languageEnglish
Article number100377
JournalBrain, behavior, & immunity - health
Publication statusPublished - Dec 2021

Bibliographical note

We thank Peter Katsikis for providing splenocytes of WT and Pik3cd−/- animals; Roxanne ter Haar and Elize Haasdijk for the biotechnical assistance; and Chris de Zeeuw for helpful comments and histological reagents. This work has been funded by the Stichting Sophia Kinderziekenhuis Fonds (grant no. S15-07 Genes and Immunity in SCID- F.M.P.K.), the Medical Research Council (MR/M012328/2) (K.O.) and the Dutch Research Council (NWO, ZonMw) Talent Programme Vidi (Vidi/ZonMw/917.18.380,2018) (A.B.). We declare that PMH has received grants and research support from Takeda, CSL Behring, Abbvie, Lamepro, Novartis Nederland, and honoraria or consultation fees from UCB Pharma. The other authors have no conflict of interest to declare.

© 2021 The Authors.


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