Phosphoinositide 3-Kinase δ Gene Mutation Predisposes to Respiratory Infection and Airway Damage

Ângulo, Ivan L.; Vadas, Oscar; Garçon, Fabien; Banham-Hall, Edward; Plagnol, Vincent; Leahy, Timothy Ronan; Baxendale, Helen; Coulter, Tanya; Curtis, James; Wu, Changxin; Blake-Palmer, Katherine G.; Perišić, Olga; Smyth, Deborah J.; Maes, Mailis; Fiddler, Christine; Juss, Jatinder K.; Cilliers, Deirdre; Markelj, Gašper; Chandra, Anita; Farmer, George; Kielkowska, Anna; Clark, Jonathan; Kracker, Sven; Debré, Marianne; Pïcard, Capucine; Pellier, Isabelle; Jabado, Nada; Morris, James A.; Barcenas-Morales, Gabriela; Fischer, Alain; Stephens, Len R.; Hawkins, Phillip T.; Barrett, Jeffrey C.; Abinun, Mario; Clatworthy, Menna R.; Durandy, Anne; Döffinger, Rainer; Chilvers, Edwin R.; Cant, Andrew J.; Kumararatne, Dinakantha; Okkenhaug, Klaus; Williams, Roger L.; Condliffe, Alison M.; Nejentsev, Sergey

doi:10.1126/science.1243292

Cited by 527 publications

(657 citation statements)

References 36 publications

(24 reference statements)

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“…Immunological findings described previously in APDS include B cell lymphopenia with relatively increased transitional B cell numbers and reduced immunoglobulin (Ig)G, but elevated IgM levels in serum [6,7], features that are shared partially with CVID [10]. The differential diagnosis of APDS also extends to combined immunodeficiency (CID) or 'atypical' severe combined immunodeficiency (SCID) (defined as immunodeficiency due to mutations in SCID-causing genes in patients with a presentation different from typical SCID and Omenn syndrome and T cell levels above 500 cells/ll [11,12]).…”

Section: Introductionmentioning

confidence: 99%

“…In APDS, increased Akt/mTOR signalling leads to an immune dysregulation and an immunodeficiency, characterized by respiratory infections, bronchiectasis and autoimmune cytopenias [6,7]. Loss of function mutations in phosphatidylinositol 3-kinase regulatory (PIK3R1) encoding the p85a regulatory subunit also result in hyperactivation of PI3K signalling with the same phenotype resulting from PIK3CD gain of function mutations, namely immunodeficiency, lymphoproliferation, poor antibody responses and expansion of senescent CD8…”

Section: Introductionmentioning

confidence: 99%

“…Four gain-of-function mutations in PIK3CD encoding the catalytic p110d subunit were targeted for screening, namely: C!A at cDNA position c.1002 resulting in the amino acid substitution N334K in the C2 domain; G!A at position c.1573 with consequent E525K substitution in the helical domain; G!A at position c.3061 resulting in an E1021K substitution in the C-lobe of the kinase domain [ [6],7]; and T!C at position c.1246, resulting in the amino acid substitution C416R in the C2 domain [19]. The study population was screened further for a splice site mutation in PIK3R1 corresponding to c.1425 1 1 that results in skipping of exon 11 of the gene with in-frame deletion of the nucleotides encoding the amino acid residues 434-475 of p85a, which constitute part of the inter-SH2 domain common to PIK3R1 isoforms [8,9].…”

Section: Target Mutationsmentioning

confidence: 99%

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Activating PI3Kδ mutations in a cohort of 669 patients with primary immunodeficiency

Elgizouli

Lowe

Speckmann

et al. 2015

Clinical and Experimental Immunology

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SummaryThe gene PIK3CD codes for the catalytic subunit of phosphoinositide 3-kinase d (PI3Kd), and is expressed solely in leucocytes. Activating mutations of PIK3CD have been described to cause an autosomal dominant immunodeficiency that shares clinical features with common variable immunodeficiency (CVID). We screened a cohort of 669 molecularly undefined primary immunodeficiency patients for five reported mutations (four gain-of-function mutations in PIK3CD and a loss of function mutation in PIK3R1) using pyrosequencing. PIK3CD mutations were identified in three siblings diagnosed with CVID and two sporadic cases with a combined immunodeficiency (CID). The PIK3R1 mutation was not identified in the cohort. Our patients with activated PI3Kd syndrome (APDS) showed a range of clinical and immunological findings, even within a single family, but shared a reduction in naive T cells. PIK3CD gain of function mutations are more likely to occur in patients with defective B and T cell responses and should be screened for in CVID and CID, but are less likely in patients with a pure B cell/hypogammaglobulinaemia phenotype.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Target Mutationsmentioning

confidence: 99%

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Activating PI3Kδ mutations in a cohort of 669 patients with primary immunodeficiency

Elgizouli

Lowe

Speckmann

et al. 2015

Clinical and Experimental Immunology

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“…It highlights that mutations occurring in different parts of the gene can lead to the very same consequences, and should thus be screened in patients with a phenotype resembling APDS. Jean-Marc Plaza, 4 Mélanie Parisot, 5 Benoit Dumont, 6 Delphine Turpin, 7 Etienne Merlin, 8 Despina Moshous, 1,2,9 Nathalie Aladjidi, 10 Bénédicte Neven, 1,2,9 Capucine Picard, 1,2,3 Marina Cavazzana, 1,2,11 Alain Fischer, 1,2,9,12 Anne Durandy, 1,2 Jean-Louis Stephan 6 and Sven Kracker …”

Section: 13mentioning

confidence: 99%

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

et al. 2017

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“…Furthermore, certain T-cell signaling defects that may cause SCID or CID, such as ORAI-1, STIM-1, MAGT1, STK4, or LCK deficiencies as well as activating mutations of PI3KD, predispose to autoimmunity including cytopenias. 3,[28][29][30][31][32] Recently, loss of function of tripeptidyl peptidase 2 was demonstrated to cause ). In WAS, however, the basis of thrombocytopenia and microplatelets is the underlying cytoskeletal dysfunction.…”

Section: Autoimmune-mediated Cytopenia In Pidmentioning

confidence: 99%

Autoimmune and other cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment

Seidel

2014

Blood

124

137

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Autoimmunity and immune dysregulation may lead to cytopenia and represent key features of many primary immunodeficiencies (PIDs). Especially when cytopenia is the initial symptom of a PID, the order and depth of diagnostic steps have to be performed in accordance with both an immunologic and a hematologic approach and will help exclude disorders such as systemic lupus erythematosus, common variable immunodeficiency, and autoimmune lymphoproliferative syndromes, hemophagocytic disorders, lymphoproliferative diseases, and novel differential diagnoses such as MonoMac syndrome (GATA2 deficiency), CD27 deficiency, lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency, activated PI3KD syndrome (APDS), X-linked immunodeficiency with magnesium defect (MAGT1 deficiency), and others. Immunosuppressive treatment often needs to be initiated urgently, which impedes further relevant immunologic laboratory analyses aimed at defining the underlying PID. Awareness of potentially involved disease spectra ranging from hematologic to rheumatologic and immunologic disorders is crucial for identifying a certain proportion of PID phenotypes and genotypes among descriptive diagnoses such as autoimmune hemolytic anemia, chronic immune thrombocytopenia, Evans syndrome, severe aplastic anemia/refractory cytopenia, and others. A synopsis of pathomechanisms, novel differential diagnoses, and advances in treatment options for cytopenias in PID is provided to facilitate multidisciplinary management and to bridge different approaches.

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Phosphoinositide 3-Kinase δ Gene Mutation Predisposes to Respiratory Infection and Airway Damage

Cited by 527 publications

References 36 publications

Activating PI3Kδ mutations in a cohort of 669 patients with primary immunodeficiency

Activating PI3Kδ mutations in a cohort of 669 patients with primary immunodeficiency

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

Autoimmune and other cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment

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