Germline biallelic PIK3CG mutations in a multifaceted immunodeficiency with immune dysregulation

Thian, Marini; Hoeger, Birgit; Kamnev, Anton; Poyer, Fiona; Bal, Sevgi Köstel; Caldera, Michael; Jiménez-Heredia, Raúl; Huemer, Jakob; Pickl, Winfried F.; Groß, Miriam; Ehl, Stephan; Lucas, Carrie L.; Menche, Jörg; Hutter, Caroline; Attarbaschi, Andishe; Dupré, Loı̈c; Boztuğ, Kaan

doi:10.3324/haematol.2019.231399

Cited by 23 publications

(15 citation statements)

References 19 publications

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“…Recently-reported gene defects have been found for most categories of inborn errors of immunity, including novel causes of: SCID ( PAX1 [ 5 , 6 ], SLP76 [ 7 ]); CID ( MCM10 [ 8 ], IL6ST [ 9 – 11 ]); Predominantly antibody deficiencies ( FNIP1 [ 14 , 15 ], PIK3CG [ 16 , 17 ], CTNNBL1 [ 18 ], TNFSF13 [ 19 ]); Autoinflammatory diseases ( SOCS1 [ 20 – 22 ], TET2 [ 23 ], CEBPE [ 24 ], CDC42 [ 33 – 39 ], LSM11 , RNU7–1 [ 32 ], STAT2 [ 40 , 41 ], RIPK1 [ 42 , 43 ], NCKAP1L [ 44 – 46 ]), UBA1 (somatic mutations) [ 47 ]; and Susceptibility to infection with specific pathogens ( MAPK8 [ 31 ]; TBX21 [ 25 ], IFNG [ 26 ], NOS2 [ 28 ], SNORA31 [ 29 ], ATG4A , MAP1LC3B2 [ 30 ]) (Table 1 ). …”

Section: Novel Causes Of Inborn Errors Of Immunitymentioning

confidence: 99%

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The Ever-Increasing Array of Novel Inborn Errors of Immunity: an Interim Update by the IUIS Committee

et al. 2021

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The most recent updated classification of inborn errors of immunity/primary immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee, was published in January 2020. Within days of completing this report, it was already out of date, evidenced by the frequent publication of genetic variants proposed to cause novel inborn errors of immunity. As the next formal report from the IUIS Expert Committee will not be published until 2022, we felt it important to provide the community with a brief update of recent contributions to the field of inborn errors of immunity. Herein, we highlight studies that have identified 26 additional monogenic gene defects that reach the threshold to represent novel causes of immune defects.

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Section: Novel Causes Of Inborn Errors Of Immunitymentioning

confidence: 99%

“…Predominantly antibody deficiencies ( FNIP1 [ 14 , 15 ], PIK3CG [ 16 , 17 ], CTNNBL1 [ 18 ], TNFSF13 [ 19 ]);…”

Section: Novel Causes Of Inborn Errors Of Immunitymentioning

confidence: 99%

The Ever-Increasing Array of Novel Inborn Errors of Immunity: an Interim Update by the IUIS Committee

et al. 2021

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“…It would be expected that these mutations are activating, although this has not been fully explored. Intriguingly, p110γ loss-of-function mutations in the C-terminal regulatory motif (R1021P, N1085S) have been identified in patients with immunodeficiencies ( Takeda et al, 2019 ; Thian et al, 2020 ; Figure 1B ). PI3K mediated diseases being caused by both activating and inactivating mutations highlights the critical role of maintaining appropriate PI P 3 levels for human health.…”

Section: Introductionmentioning

confidence: 99%

Disease-related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveal a path to selective inhibitors

Rathinaswamy

Gaieb

Fleming

et al. 2021

eLife

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Class I Phosphoinositide 3-kinases (PI3Ks) are master regulators of cellular functions, with the class IB PI3K catalytic subunit (p110g) playing key roles in immune signalling. p110g is a key factor in inflammatory diseases, and has been identified as a therapeutic target for cancers due to its immunomodulatory role. Using a combined biochemical/biophysical approach, we have revealed insight into regulation of kinase activity, specifically defining how immunodeficiency and oncogenic mutations of R1021 in the C-terminus can inactivate or activate enzyme activity. Screening of inhibitors using HDX-MS revealed that activation loop-binding inhibitors induce allosteric conformational changes that mimic those in the R1021C mutant. Structural analysis of advanced PI3K inhibitors in clinical development revealed novel binding pockets that can be exploited for further therapeutic development. Overall this work provides unique insights into regulatory mechanisms that control PI3Kg kinase activity, and shows a framework for the design of PI3K isoform and mutant selective inhibitors.

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“…The PI3Kg isoform is critical to maintain immune system function, and plays important roles in the regulation of the tumour microenvironment [7,66]. Bi-allelic loss of function mutations in PI3Kg are a driver of human immunodeficiencies, and multiple inactivating mutations located in the C-terminal regulatory motif of the kinase domain have been described [46,47]. Initial results linking deletion of PI3Kg to the development of colon cancer [67] have been disputed [68], and recent studies suggest that tumour growth and metastasis is attenuated in PI3Kg deficient mice [30,69] and IPI-549 treated animals [29].…”

Section: Discussionmentioning

confidence: 99%

“…It would be expected that these mutations are activating, although this has not been fully explored. Intriguingly, PI3Kg loss of function mutations in the C-terminal regulatory motif (R1021P, N1085S) have been identified in patients with immunodeficiencies [46,47] (Fig. 1B+C).…”

Section: Introductionmentioning

confidence: 95%

Disease related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveals a path to selective inhibitors

Rathinaswamy

Gaieb

Fleming

et al. 2020

Preprint

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Class I Phosphoinositide 3-kinases (PI3Ks) are master regulators of cellular functions, with the p110γ subunit playing a key role in immune signalling. PI3Kγ is a key factor in inflammatory diseases, and has been identified as a therapeutic target for cancers due to its immunomodulatory role. Using a combined biochemical/biophysical approach, we have revealed insight into regulation of kinase activity, specifically defining how immunodeficiency and oncogenic mutations of R1021 in the c-terminus can inactivate or activate enzyme activity. Screening of small molecule inhibitors using HDX-MS revealed that activation loop binding inhibitors induce allosteric conformational changes that mimic those seen for the R1021C mutant. Structural analysis of clinically advanced PI3K inhibitors revealed novel binding pockets that can be exploited for further therapeutic development. Overall this work provides unique insight into the regulatory mechanisms that control PI3Kγ kinase activity, and shows a framework for the design of PI3K isoform and mutant selective inhibitors.

show abstract

Germline biallelic PIK3CG mutations in a multifaceted immunodeficiency with immune dysregulation

Cited by 23 publications

References 19 publications

The Ever-Increasing Array of Novel Inborn Errors of Immunity: an Interim Update by the IUIS Committee

The Ever-Increasing Array of Novel Inborn Errors of Immunity: an Interim Update by the IUIS Committee

Disease-related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveal a path to selective inhibitors

Disease related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveals a path to selective inhibitors

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