Mutations in the adaptor-binding domain and associated linker region of p110δ cause Activated PI3K-δ Syndrome 1 (APDS1)

Heurtier, Lucie; Lamrini, Hicham; Chentout, Loïc; Deau, Marie-Céline; Bouafia, Amine; Rosain, Jérémie; Plaza, Jean-Marc; Parisot, Mélanie; Dumont, Benoît; Turpin, Delphine; Merlin, E.; Moshous, Despina; Aladjidi, Nathalie; Neven, Bénédicte; Pïcard, Capucine; Cavazzana, Marina; Fischer, Alain; Durandy, Anne; Kracker, Sven

doi:10.3324/haematol.2017.167601

Cited by 38 publications

(17 citation statements)

References 15 publications

(21 reference statements)

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“…Patients' cells were significantly less efficient than those of controls (by 30%-40%) in dampening AKT phosphorylation ( Figure 7, C and D). An elevated frequency of ribosomal protein S6 phosphorylation in B lymphocytes (as a consequence of increased PI3K/AKT/mTOR activation) has been observed in activated PI3Kδ syndromes (APDS1 and -2) caused by a gain-of-function PI3Kδ-signaling mutation (19). We also observed a higher frequency of phosphorylated ribosomal protein S6 in ARHGEF1-deficient B cells than in healthy donor cells (Supplemental Figure 10).…”

Section: Resultssupporting

confidence: 70%

Loss of ARHGEF1 causes a human primary antibody deficiency

Bouafia¹,

Lofek²,

Bruneau³

et al. 2019

Journal of Clinical Investigation

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Section: Resultssupporting

confidence: 70%

Loss of ARHGEF1 causes a human primary antibody deficiency

Bouafia¹,

Lofek²,

Bruneau³

et al. 2019

Journal of Clinical Investigation

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“…Analogous activating mutations in PIK3CD encoding p110δ (E1021K, E525K, N334K) have been identified in approximately 100 patients worldwide (Lucas et al, 2016), with distinct mutations affecting other domains discovered recently (Heurtier et al, 2017). Affected individuals suffer from a dominant immunodeficiency disorder termed Activated PI3K-Delta Syndrome (APDS).…”

Section: The Pi3k Signaling Networkmentioning

confidence: 99%

The PI3K Pathway in Human Disease

Fruman

Chiu

Hopkins

et al. 2017

Cell

1,893

1,658

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Phosphoinositide 3-kinase (PI3K) activity is stimulated by diverse oncogenes and growth factor receptors, and elevated PI3K signaling is considered a hallmark of cancer. Many PI3K pathway-targeted therapies have been tested in oncology trials, resulting in regulatory approval of one isoform-selective inhibitor (idelalisib) for treatment of certain blood cancers, and a variety of other agents at different stages of development. In parallel to PI3K research by cancer biologists, investigations in other fields have uncovered exciting and often unpredicted roles for PI3K catalytic and regulatory subunits in normal cell function and in disease. Many of these functions impinge upon oncology by influencing the efficacy and toxicity of PI3K-targeted therapies. Here we provide a perspective on the roles of class I PI3Ks in the regulation of cellular metabolism and in immune system functions, two topics closely intertwined with cancer biology. We also discuss recent progress developing PI3K-targeted therapies for treatment of cancer and other diseases.

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“…The immunological phenotype includes perturbed T and B cell maturation and increased activation of the AKT/S6/mTOR pathway [2,3]. To date, the majority of affected patients present a recurrence of monoallelic mutations in p110δ, with a limited number of novel ones reported since the identification of this disorder [2,3,[5][6][7]. We report on a female patient affected with adult onset hypogammaglobulinemia with lymphopenia harbouring a novel gain of function mutation in p110δ.…”

Section: To the Editormentioning

confidence: 97%