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

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...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Primary immunodeficiency PID PIK3CD APDS ASD Mouse Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/27d8b652350244c4b767f51c4c9d81e3
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spelling	oai:doaj.org-article:27d8b652350244c4b767f51c4c9d81e32021-11-04T04:40:03ZActivated PI3Kδ syndrome, an immunodeficiency disorder, leads to sensorimotor deficits recapitulated in a murine model2666-354610.1016/j.bbih.2021.100377https://doaj.org/article/27d8b652350244c4b767f51c4c9d81e32021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2666354621001800https://doaj.org/toc/2666-3546The 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.Ines SerraOlivia R. ManusamaFabian M.P. KaiserIzi Izumi FlorianoLucas WahlChristian van der ZalmHanna IJspeertP. Martin van HagenNico J.M. van BeverenSandra M. ArendKlaus OkkenhaugJohan J.M. PelVirgil A.S.H. DalmAleksandra BaduraElsevierarticlePrimary immunodeficiencyPIDPIK3CDAPDSASDMouseNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENBrain, Behavior, & Immunity - Health, Vol 18, Iss , Pp 100377- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Primary immunodeficiency PID PIK3CD APDS ASD Mouse Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	Primary immunodeficiency PID PIK3CD APDS ASD Mouse Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 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 Activated PI3Kδ syndrome, an immunodeficiency disorder, leads to sensorimotor deficits recapitulated in a murine model
description	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.
format	article
author	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
author_facet	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
author_sort	Ines Serra
title	Activated PI3Kδ syndrome, an immunodeficiency disorder, leads to sensorimotor deficits recapitulated in a murine model
title_short	Activated PI3Kδ syndrome, an immunodeficiency disorder, leads to sensorimotor deficits recapitulated in a murine model
title_full	Activated PI3Kδ syndrome, an immunodeficiency disorder, leads to sensorimotor deficits recapitulated in a murine model
title_fullStr	Activated PI3Kδ syndrome, an immunodeficiency disorder, leads to sensorimotor deficits recapitulated in a murine model
title_full_unstemmed	Activated PI3Kδ syndrome, an immunodeficiency disorder, leads to sensorimotor deficits recapitulated in a murine model
title_sort	activated pi3kδ syndrome, an immunodeficiency disorder, leads to sensorimotor deficits recapitulated in a murine model
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/27d8b652350244c4b767f51c4c9d81e3
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Activated PI3Kδ syndrome, an immunodeficiency disorder, leads to sensorimotor deficits recapitulated in a murine model

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