Gain-of-function mutation in PIK3R1 in a patient with a narrow clinical phenotype of respiratory infections

Martínez-Saavedra, María Teresa; García-Gómez, Sonia; Acosta, Ana Domínguez; Quintana, Juan Jesús Mendoza; Páez, Jesús Poch; Reino, Eduardo J. Garcia; Camps, Gracián; Martı́nez-Barricarte, Rubén; Itan, Yuval; Boisson, Bertrand; Sánchez-Ramón, Silvia; Regueiro, José R.; Casanova, Jean‐Laurent; Rodríguez-Gallego, Carlos; Diego, Rebeca Pérez de

doi:10.1016/j.clim.2016.09.011

Cited by 17 publications

(7 citation statements)

References 12 publications

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“…6,7 The nomenclature APDS2 started being used to discriminate these patients from those carrying mutations in PIK3CD. Although almost all patients with APDS2 reported to date have exon-skipping mutations resulting in a central deletion of amino acid residues 434 to 475 of p85a, 6,7,11,[21][22][23][24][25][26][27] more recently, a heterozygous missense mutation in the iSH2 domain of PIK3R1 has been shown to cause APDS2. 20 These LOF PIK3R1 mutations disrupt interaction of the 2 subunits and lead to a loss of inhibition of the catalytic subunit p110d by p85, therefore behaving as PI3Kd GOF mutations.…”

Section: Immunodeficiency Caused By Overactivation Of the Pi3kd Pathwmentioning

confidence: 99%

PI3K pathway defects leading to immunodeficiency and immune dysregulation

Nunes-Santos

Uzel

Rosenzweig

2019

Journal of Allergy and Clinical Immunology

114

103

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The phosphatidylinositol 3-kinase (PI3K) signaling pathway is involved in a broad range of cellular processes, including growth, metabolism, differentiation, proliferation, motility, and survival. The PI3Kd enzyme complex is primarily present in the immune system and comprises a catalytic (p110d) and regulatory (p85a) subunit. Dynamic regulation of PI3Kd activity is required to ensure normal function and differentiation of immune cells. In the last decade, discovery of germline mutations in genes involved in the PI3Kd pathway (PIK3CD, PIK3R1, or phosphatase and tensin homolog [PTEN]) proved that both overactivation and underactivation (gain of function and loss of function, respectively) of PI3Kd lead to impaired and dysregulated immunity. Although a small group of patients reported to underactivate PI3Kd show predominantly humoral defects and autoimmune features, more than 200 patients have been described with overactivation of PI3Kd, presenting with a much more complex phenotype of combined immunodeficiency and immune dysregulation. The clinical and immunologic characterization, as well as current pathophysiologic understanding and specific therapies for PI3K pathway defects leading to immunodeficiency and immune dysregulation, are reviewed here.

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Section: Immunodeficiency Caused By Overactivation Of the Pi3kd Pathwmentioning

confidence: 99%

PI3K pathway defects leading to immunodeficiency and immune dysregulation

Nunes-Santos

Uzel

Rosenzweig

2019

Journal of Allergy and Clinical Immunology

114

103

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“…While a few isolated cases have been identified who are completely asymptomatic ( 20 ) or who have severe extrapulmonary manifestations but minimal or no respiratory symptomatology ( 21 ), recurrent respiratory tract infections are reported near universally in APDS; indeed, they may be the sole manifestation of the disease ( 16 ), and they may be both very frequent and severe ( 5 ). Unfortunately, however, differences in definitions and nomenclature make direct comparisons between published studies challenging at times.…”

Section: Respiratory Infections In Apdsmentioning

confidence: 99%

“…Improvements in sinopulmonary infection have been reported following hematopoietic stem cell transplantation, with the majority of surviving patients no longer requiring immunoglobulin therapy ( 50 ); however, this procedure carries a significant mortality and will not alleviate established structural lung damage such as bronchiectasis. Early identification of patients with APDS ( 16 ) may allow transplantation before the development of such complications; however, the clinical heterogeneity makes prediction of future disease severity challenging.…”

Section: Management Of the Respiratory Manifestations Of Apdsmentioning

confidence: 99%

“…Subsequently, patients with a highly reminiscent clinical phenotype who did not harbor APDS-associated PIK3CD mutations were found instead to have exon-skipping mutations in the Class 1A regulatory PI3K subunit p85α encoded by PIK3R1 [e.g., Ref. ( 10 – 16 )]; these mutations disrupt the inhibitory interactions with the catalytic subunit of PI3Kδ ( 17 ), increasing both basal and stimulated activation. The resulting clinical syndrome, termed APDS2 (or PASLI-R1), phenocopies many of the APDS1 disease manifestations but with a higher incidence of growth retardation and in some cases, overlap with SHORT syndrome [short stature, hyperextensibility, hernia, ocular depression, Rieger anomaly, and teething delay ( 14 , 18 )].…”

Section: Introductionmentioning

confidence: 99%

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Respiratory Manifestations of the Activated Phosphoinositide 3-Kinase Delta Syndrome

Condliffe

Chandra

2018

Front. Immunol.

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The activated phosphoinositide 3-kinase δ syndrome (APDS), also known as p110δ-activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency (PASLI), is a combined immunodeficiency syndrome caused by gain-of-function mutations in the phosphoinositide 3-kinase (PI3K) genes PIK3CD (encoding p110δ: APDS1 or PASLI-CD) and PIK3R1 (encoding p85α: APDS2 or PASLI-R1). While the disease is clinically heterogeneous, respiratory symptoms and complications are near universal and often severe. Infections of the ears, sinuses, and upper and lower respiratory tracts are the earliest and most frequent manifestation of APDS, secondary to both respiratory viruses and to bacterial pathogens typical of defective B cell function. End organ damage in the form of small airways disease and bronchiectasis frequently complicates APDS, but despite documented T cell defects, opportunistic infections have rarely been observed. Antimicrobial (principally antibiotic) prophylaxis and/or immunoglobulin replacement have been widely used to reduce the frequency and severity of respiratory infection in APDS, but outcome data to confirm the efficacy of these interventions are limited. Despite these measures, APDS patients are often afflicted by benign lymphoproliferative disease, which may present in the respiratory system as tonsillar/adenoidal enlargement, mediastinal lymphadenopathy, or mucosal nodular lymphoid hyperplasia, potentially causing airways obstruction and compounding the infection phenotype. Treatment with rapamycin and PI3Kδ inhibitors has been reported to be of benefit in benign lymphoproliferation, but hematopoietic stem cell transplantation (ideally undertaken before permanent airway damage is established) remains the only curative treatment for APDS.

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“…Clinically, these mutations can lead to varied phenotypes, and original PIK3CD cohorts were identified by screening patients with recurrent chest infections ( 114 ) and herpesviral infections ( 65 ), respectively. Patients with activating mutations in PIK3R1 leading to an increased PI3Kδ activity also have primary immunodeficiency ( 67 , 69 , 116 – 123 ), and many studies, including large cohort studies, have defined new mutations in PIK3CD leading to activated PI3K delta syndrome (APDS) and expanded the phenotype of disease ( 64 , 66 , 67 , 124 – 131 ). While the clinical features of patients with mutations in PIK3CD and PIK3R1 can be similar, there is evidence that PIK3R1 mutations can also have extra-immune phenotypes ( 118 ).…”

Section: Introductionmentioning

confidence: 99%

Phosphoinositide-3-Kinase Signaling in Human Natural Killer Cells: New Insights from Primary Immunodeficiency

Mace

2018

Front. Immunol.

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Human natural killer (NK) cells play a critical role in the control of viral infections and malignancy. Their importance in human health and disease is illustrated by severe viral infections in patients with primary immunodeficiencies that affect NK cell function and/or development. The recent identification of patients with phosphoinositide-3-kinase (PI3K)-signaling pathway mutations that can cause primary immunodeficiency provides valuable insight into the role that PI3K signaling plays in human NK cell maturation and lytic function. There is a rich literature that demonstrates a requirement for PI3K in multiple key aspects of NK cell biology, including development/maturation, homing, priming, and function. Here, I briefly review these previous studies and place them in context with recent findings from the study of primary immunodeficiency patients, particularly those with hyperactivating mutations in PI3Kδ signaling.

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Gain-of-function mutation in PIK3R1 in a patient with a narrow clinical phenotype of respiratory infections

Cited by 17 publications

References 12 publications

PI3K pathway defects leading to immunodeficiency and immune dysregulation

PI3K pathway defects leading to immunodeficiency and immune dysregulation

Respiratory Manifestations of the Activated Phosphoinositide 3-Kinase Delta Syndrome

Phosphoinositide-3-Kinase Signaling in Human Natural Killer Cells: New Insights from Primary Immunodeficiency

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