Activated <scp>PI</scp>3Kδ syndrome type 2: Two patients, a novel mutation, and review of the literature

Olbrich, Peter; Lorenz, Myriam Ricarda; Daball, Paola Cura; Lucena, José Manuel; Rensing‐Ehl, Anne; Sánchez, Berta; Führer, Marita; Camacho-Lovillo, Marisol; Melon, Marta; Schwarz, Klaus; Neth, Olaf; Speckmann, Carsten

doi:10.1111/pai.12585

Cited by 50 publications

(46 citation statements)

References 14 publications

(38 reference statements)

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“…The description given in the legend of ▶ Fig. 1 is similar to respective descriptions of SHORT syndrome [1,9,10,12], but SHORT defining characteristics are absent from our patients. Other examples are known with hypomorphic and hypermorphic mutations in the same gene (or the same signaling pathway) that lead to different clinical phenotypes, but show some phenotypic overlap nevertheless.…”

Section: Resultssupporting

confidence: 79%

Variant PIK3R1 Hypermorphic Mutation and Clinical Phenotypes in a Family with Short Statures, Mild Immunodeficiency and Lymphoma

et al. 2017

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Heterozygous point mutations in the GT splice donor consensus sequence of exon 11 of the PIK3R1 gene (coding for p85α, p55α, and p50α regulatory subunits of PI3K) lead to exon skipping and thereby to an aberrant protein that leaves PI3K hyperactivated. Several patients with this particular variant of PI3 kinase delta syndrome (APDS) suffering from sinopulmonary infections and lymphoproliferation have been described. (Whole exome) sequencing, evaluation of cellular and clinical phenotypes. We here report a family with a new heterozygous mutation in this gene, a 9 bp deletion (c.1418_1425+1del) that, however, leads to the same skipping of exon 11. The clinical phenotypes of their members partly overlap features of patients of other reports. We found a new mutation in PIK3R1 and show how broad the resulting clinical spectrum can be.

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Section: Resultssupporting

confidence: 79%

Variant PIK3R1 Hypermorphic Mutation and Clinical Phenotypes in a Family with Short Statures, Mild Immunodeficiency and Lymphoma

et al. 2017

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“…immunodeficiency patients have been identified with either APDS1 or APDS2 mutations (27,28). Patients with APDS exhibit a heterogeneous set of clinical features, including symptoms of both immune deficiency and immune dysfunction (5).…”

Section: Discussionmentioning

confidence: 99%

“…However, in a cohort study of APDS2 patients with germline mutations resulting in a Δ434-475 p85α, the main increased oncogenic risk appeared to be lymphoma (34), with so far no evidence that patients with the APDS2 splice variant have any increased cancer risk outside the immune system. The only nonimmune defect so far identified is growth retardation (27), which has also been identified in SHORT syndrome, a disorder that is caused by heterozygous mutations in PIK3R1 that prevent RTK binding, leading to altered PI3K signaling (4).…”

Section: Discussionmentioning

confidence: 99%

Conformational disruption of PI3Kδ regulation by immunodeficiency mutations in PIK3CD and PIK3R1

Dornan

Siempelkamp

Jenkins

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

102

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Activated PI3K Delta Syndrome (APDS) is a primary immunodeficiency disease caused by activating mutations in either the leukocyte-restricted p110δ catalytic () subunit or the ubiquitously expressed p85α regulatory () subunit of class IA phosphoinositide 3-kinases (PI3Ks). There are two classes of APDS: APDS1 that arises from p110δ mutations that are analogous to oncogenic mutations found in the broadly expressed p110α subunit and APDS2 that occurs from a splice mutation resulting in p85α with a central deletion (Δ434-475). As p85 regulatory subunits associate with and inhibit all class IA catalytic subunits, APDS2 mutations are expected to similarly activate p110α, β, and δ, yet APDS2 largely phenocopies APDS1 without dramatic effects outside the immune system. We have examined the molecular mechanism of activation of both classes of APDS mutations using a combination of biochemical assays and hydrogen-deuterium exchange mass spectrometry. Intriguingly, we find that an APDS2 mutation in p85α leads to substantial basal activation of p110δ (>300-fold) and disrupts inhibitory interactions from the nSH2, iSH2, and cSH2 domains of p85, whereas p110α is only minimally basally activated (∼2-fold) when associated with mutated p85α. APDS1 mutations in p110δ (N334K, E525K, E1021K) mimic the activation mechanisms previously discovered for oncogenic mutations in p110α. All APDS mutations were potently inhibited by the Food and Drug Administration-approved p110δ inhibitor idelalisib. Our results define the molecular basis of how and mutations result in APDS and reveal a potential path to treatment for all APDS patients.

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“…Patients with GOF mutations in either of these genes appear to largely phenocopy each other, despite the fact that p85α is ubiquitously expressed and can pair with p110α and p110β in addition to p110δ. There is some evidence for effects of the PIK3R1 mutation outside the immune system (for example, short stature, Box 1)74, but detailed analyses of the effects of this p85α defect on p110α or p110β have not yet been reported. The biochemical and clinical symptoms of patients with APDS1 ( PIK3CD mutations) or APDS2 ( PIK3R1 mutations) are similar, suggesting that the pathological features of both syndromes are a consequence of aberrant and hyperactive PI3Kδ signalling1–4.…”

Section: Alterations In Pi3kδ Signalling Leads To Pids In Humansmentioning

confidence: 99%

“…Growth retardation is common in patients with APDS2 6, 73, 74 but does not seem to be a feature of APDS1 and may relate to the association of heterozygous mutations in PIK3R1 with SHORT syndrome (short stature, hyperextensibility of joints, hernia, ocular depression, Rieger anomaly and teething delay)88–91.…”

Section: Clinical Features Of Apdsmentioning

confidence: 99%

PI3Kδ and primary immunodeficiencies

et al. 2016

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Primary immunodeficiencies are inherited disorders of the immune system, often caused by the mutation of genes required for lymphocyte development and activation. Recently, several studies have identified gain-of-function mutations in the phosphoinositide 3-kinase (PI3K) genes PIK3CD (which encodes p110δ) and PIK3R1 (which encodes p85α) that cause a combined immunodeficiency syndrome, referred to as activated PI3Kδ syndrome (APDS) or p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency (PASLI). Paradoxically, both loss-of-function and gain-of-function mutations that affect these genes lead to immunosuppression, albeit via different mechanisms. Here, we review the roles of PI3Kδ in adaptive immunity, describe the clinical manifestations and mechanisms of disease in APDS and highlight new insights into PI3Kδ gleaned from these patients, as well as implications of these findings for clinical therapy.

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Activated PI3Kδ syndrome type 2: Two patients, a novel mutation, and review of the literature

Cited by 50 publications

References 14 publications

Variant PIK3R1 Hypermorphic Mutation and Clinical Phenotypes in a Family with Short Statures, Mild Immunodeficiency and Lymphoma

Variant PIK3R1 Hypermorphic Mutation and Clinical Phenotypes in a Family with Short Statures, Mild Immunodeficiency and Lymphoma

Conformational disruption of PI3Kδ regulation by immunodeficiency mutations in PIK3CD and PIK3R1

PI3Kδ and primary immunodeficiencies

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