PIK3R1 Mutation Associated with Hyper IgM (APDS2 Syndrome): A Case Report and Review of the Literature

Author(s): Reza Yazdani, Zahra Hamidi, Fateme Babaha, Gholamreza Azizi, Saba Fekrvand, Hassan Abolhassani, Asghar Aghamohammadi*.

Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets
(Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders)

Volume 19 , Issue 7 , 2019

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Abstract:

Background and Objective: APDS [Activated phosphoinositide 3-kinase (PI3K) δ Syndrome] is a newly found special form of primary immunodeficiency caused by mutations in genes encoding PI3Kδ subunits and over-activation of the PI3K signaling pathway. Gain-of-function and loss-of-function mutations in PIK3CD (encoding P110δ) and PIK3R1 (encoding p85α, p55α and p50α) lead to APDS1 and APDS2, respectively. The subsequent irregular PI3K downstream signaling cascade is associated with abnormalities in B cells and T cells and the consequent heterogeneous clinical manifestations including respiratory tract infections, autoimmunity, lymphoproliferation and not to mention primary antibody deficiency. In this study, we report a 12-year-old girl with a mutation in the PIK3R1 gene who manifested immunological phenotypes resembling hyper IgM syndrome along with a review of the literature of the previously reported patients.

Methods: Whole exome sequencing was performed to detect the underlying genetic mutation in this patient.

Results: A de novo heterozygous splice site mutation in the hot spot of the PIK3R1 gene within the intron 10 was found (c.1425+1G>A).

Conclusion: Further investigations are required for evaluation of the underlying genetic defects and the possible associations between genetic underpinning and heterogeneous severity and features of the disease.

Keywords: Primary immunodeficiency, Activated phosphoinositide 3-kinase Delta Syndrome (APDS), APDS2, PASLI-R1, Hyper IgM syndrome, PIK3R1, p85α.

[1]
Deau, M.C.; Heurtier, L.; Frange, P.; Suarez, F.; Bole-Feysot, C.; Nitschke, P.; Cavazzana, M.; Picard, C.; Durandy, A.; Fischer, A.; Kracker, S. A human immunodeficiency caused by mutations in the PIK3R1 gene. J. Clin. Invest., 2014, 124(9), 3923-3928.
[http://dx.doi.org/10.1172/JCI75746] [PMID: 25133428]
[2]
Lucas, C.L.; Zhang, Y.; Venida, A.; Wang, Y.; Hughes, J.; McElwee, J.; Butrick, M.; Matthews, H.; Price, S.; Biancalana, M.; Wang, X.; Richards, M.; Pozos, T.; Barlan, I.; Ozen, A.; Rao, V.K.; Su, H.C.; Lenardo, M.J. Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K. J. Exp. Med., 2014, 211(13), 2537-2547.
[http://dx.doi.org/10.1084/jem.20141759] [PMID: 25488983]
[3]
Burke, J.E.; Williams, R.L. Synergy in activating class I PI3Ks. Trends Biochem. Sci., 2015, 40(2), 88-100.
[http://dx.doi.org/10.1016/j.tibs.2014.12.003] [PMID: 25573003]
[4]
Lucas, C.L.; Kuehn, H.S.; Zhao, F.; Niemela, J.E.; Deenick, E.K.; Palendira, U.; Avery, D.T.; Moens, L.; Cannons, J.L.; Biancalana, M.; Stoddard, J.; Ouyang, W.; Frucht, D.M.; Rao, V.K.; Atkinson, T.P.; Agharahimi, A.; Hussey, A.A.; Folio, L.R.; Olivier, K.N.; Fleisher, T.A.; Pittaluga, S.; Holland, S.M.; Cohen, J.I.; Oliveira, J.B.; Tangye, S.G.; Schwartzberg, P.L.; Lenardo, M.J.; Uzel, G. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency. Nat. Immunol., 2014, 15(1), 88-97.
[http://dx.doi.org/10.1038/ni.2771] [PMID: 24165795]
[5]
Conley, M.E.; Dobbs, A.K.; Quintana, A.M.; Bosompem, A.; Wang, Y.D.; Coustan-Smith, E.; Smith, A.M.; Perez, E.E.; Murray, P.J. Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K. J. Exp. Med., 2012, 209(3), 463-470.
[http://dx.doi.org/10.1084/jem.20112533] [PMID: 22351933]
[6]
Tang, P.; Upton, J.E.M.; Barton-Forbes, M.A.; Salvadori, M.I.; Clynick, M.P.; Price, A.K.; Goobie, S.L. Autosomal Recessive Agammaglobulinemia Due to a Homozygous Mutation in PIK3R1. J. Clin. Immunol., 2018, 38(1), 88-95.
[http://dx.doi.org/10.1007/s10875-017-0462-y] [PMID: 29178053]
[7]
Zhang, K.; Husami, A.; Marsh, R.; Jordan, M.B. Identification of a phosphoinositide 3-kinase (PI-3K) p110δ (PIK3CD) deficient individual. J. Clin. Immunol., 2013, 33(3), 673-674.
[PMID: 23184091]
[8]
Walsh, C.M.; Fruman, D.A. Too much of a good thing: immunodeficiency due to hyperactive PI3K signaling. J. Clin. Invest., 2014, 124(9), 3688-3690.
[http://dx.doi.org/10.1172/JCI77198] [PMID: 25133419]
[9]
Asano, T.; Okada, S.; Tsumura, M.; Yeh, T-W.; Mitsui-Sekinaka, K.; Tsujita, Y.; Ichinose, Y.; Shimada, A.; Hashimoto, K.; Wada, T.; Imai, K.; Ohara, O.; Morio, T.; Nonoyama, S.; Kobayashi, M. Enhanced AKT Phosphorylation of Circulating B Cells in Patients With Activated PI3Kδ Syndrome. Front. Immunol., 2018, 9, 568.
[http://dx.doi.org/10.3389/fimmu.2018.00568] [PMID: 29675019]
[10]
Maccari, M.E.; Abolhassani, H.; Aghamohammadi, A.; Aiuti, A.; Aleinikova, O.; Bangs, C.; Baris, S.; Barzaghi, F.; Baxendale, H.; Buckland, M.; Burns, S.O.; Cancrini, C.; Cant, A.; Cathébras, P.; Cavazzana, M.; Chandra, A.; Conti, F.; Coulter, T.; Devlin, L.A.; Edgar, J.D.M.; Faust, S.; Fischer, A.; Garcia-Prat, M.; Hammarström, L.; Heeg, M.; Jolles, S.; Karakoc-Aydiner, E.; Kindle, G.; Kiykim, A.; Kumararatne, D.; Grimbacher, B.; Longhurst, H.; Mahlaoui, N.; Milota, T.; Moreira, F.; Moshous, D.; Mukhina, A.; Neth, O.; Neven, B.; Nieters, A.; Olbrich, P.; Ozen, A.; Pachlopnik Schmid, J.; Picard, C.; Prader, S.; Rae, W.; Reichenbach, J.; Rusch, S.; Savic, S.; Scarselli, A.; Scheible, R.; Sediva, A.; Sharapova, S.O.; Shcherbina, A.; Slatter, M.; Soler-Palacin, P.; Stanislas, A.; Suarez, F.; Tucci, F.; Uhlmann, A.; van Montfrans, J.; Warnatz, K.; Williams, A.P.; Wood, P.; Kracker, S.; Condliffe, A.M.; Ehl, S. Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry. Front. Immunol., 2018, 9, 543.
[http://dx.doi.org/10.3389/fimmu.2018.00543] [PMID: 29599784]
[11]
Elkaim, E.; Neven, B.; Bruneau, J.; Mitsui-Sekinaka, K.; Stanislas, A.; Heurtier, L.; Lucas, C.L.; Matthews, H.; Deau, M.C.; Sharapova, S.; Curtis, J.; Reichenbach, J.; Glastre, C.; Parry, D.A.; Arumugakani, G.; McDermott, E.; Kilic, S.S.; Yamashita, M.; Moshous, D.; Lamrini, H.; Otremba, B.; Gennery, A.; Coulter, T.; Quinti, I.; Stephan, J.L.; Lougaris, V.; Brodszki, N.; Barlogis, V.; Asano, T.; Galicier, L.; Boutboul, D.; Nonoyama, S.; Cant, A.; Imai, K.; Picard, C.; Nejentsev, S.; Molina, T.J.; Lenardo, M.; Savic, S.; Cavazzana, M.; Fischer, A.; Durandy, A.; Kracker, S. Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase δ syndrome 2: A cohort study. J. Allergy Clin. Immunol., 2016, 138(1), 210-218.e9.
[http://dx.doi.org/10.1016/j.jaci.2016.03.022] [PMID: 27221134]
[12]
Salek Farrokhi, A.; Aghamohammadi, A.; Pourhamdi, S.; Mohammadinejad, P.; Abolhassani, H.; Moazzeni, S.M. Evaluation of class switch recombination in B lymphocytes of patients with common variable immunodeficiency. J. Immunol. Methods, 2013, 394(1-2), 94-99.
[http://dx.doi.org/10.1016/j.jim.2013.05.008] [PMID: 23714403]
[13]
Yazdani, R.; Seify, R.; Ganjalikhani-Hakemi, M.; Abolhassani, H.; Eskandari, N.; Golsaz-Shirazi, F.; Ansaripour, B.; Salehi, E.; Azizi, G.; Rezaei, N.; Aghamohammadi, A. Comparison of various classifications for patients with common variable immunodeficiency (CVID) using measurement of B-cell subsets. Allergol. Immunopathol. (Madr.), 2017, 45(2), 183-192.
[http://dx.doi.org/10.1016/j.aller.2016.07.001] [PMID: 27717724]
[14]
Arandi, N.; Mirshafiey, A.; Jeddi-Tehrani, M.; Abolhassani, H.; Sadeghi, B.; Mirminachi, B.; Shaghaghi, M.; Aghamohammadi, A. Evaluation of CD4+CD25+FOXP3+ regulatory T cells function in patients with common variable immunodeficiency. Cell. Immunol., 2013, 281(2), 129-133.
[http://dx.doi.org/10.1016/j.cellimm.2013.03.003] [PMID: 23623844]
[15]
Abolhassani, H.; Aghamohammadi, A.; Fang, M.; Rezaei, N.; Jiang, C.; Liu, X.; Pan-Hammarström, Q.; Hammarström, L. Clinical implications of systematic phenotyping and exome sequencing in patients with primary antibody deficiency. Genet. Med., 2019, 21(1), 243-251.
[http://dx.doi.org/10.1038/s41436-018-0012-x] [PMID: 29921932]
[16]
Aghamohammadi, A.; Mohammadinejad, P.; Abolhassani, H.; Mirminachi, B.; Movahedi, M.; Gharagozlou, M.; Parvaneh, N.; Zeiaee, V.; Mirsaeed-Ghazi, B.; Chavoushzadeh, Z.; Mahdaviani, A.; Mansouri, M.; Yousefzadegan, S.; Sharifi, B.; Zandieh, F.; Hedayat, E.; Nadjafi, A.; Sherkat, R.; Shakerian, B.; Sadeghi-Shabestari, M.; Hosseini, R.F.; Jabbari-Azad, F.; Ahanchian, H.; Behmanesh, F.; Zandkarimi, M.; Shirkani, A.; Cheraghi, T.; Fayezi, A.; Mohammadzadeh, I.; Amin, R.; Aleyasin, S.; Moghtaderi, M.; Ghaffari, J.; Arshi, S.; Javahertrash, N.; Nabavi, M.; Bemanian, M.H.; Shafiei, A.; Kalantari, N.; Ahmadiafshar, A.; Khazaei, H.A.; Atarod, L.; Rezaei, N. Primary immunodeficiency disorders in Iran: update and new insights from the third report of the national registry. J. Clin. Immunol., 2014, 34(4), 478-490.
[http://dx.doi.org/10.1007/s10875-014-0001-z] [PMID: 24659230]
[17]
Omori, S.A.; Cato, M.H.; Anzelon-Mills, A.; Puri, K.D.; Shapiro-Shelef, M.; Calame, K.; Rickert, R.C. Regulation of class-switch recombination and plasma cell differentiation by phosphatidylinositol 3-kinase signaling. Immunity, 2006, 25(4), 545-557.
[http://dx.doi.org/10.1016/j.immuni.2006.08.015] [PMID: 17000121]
[18]
Petrovski, S.; Parrott, R.E.; Roberts, J.L.; Huang, H.; Yang, J.; Gorentla, B.; Mousallem, T.; Wang, E.; Armstrong, M.; McHale, D.; MacIver, N.J.; Goldstein, D.B.; Zhong, X.P.; Buckley, R.H. Dominant Splice Site Mutations in PIK3R1 Cause Hyper IgM Syndrome, Lymphadenopathy and Short Stature. J. Clin. Immunol., 2016, 36(5), 462-471.
[http://dx.doi.org/10.1007/s10875-016-0281-6] [PMID: 27076228]
[19]
Lougaris, V.; Faletra, F.; Lanzi, G.; Vozzi, D.; Marcuzzi, A.; Valencic, E.; Piscianz, E.; Bianco, A.; Girardelli, M.; Baronio, M.; Loganes, C.; Fasth, A.; Salvini, F.; Trizzino, A.; Moratto, D.; Facchetti, F.; Giliani, S.; Plebani, A.; Tommasini, A. Altered germinal center reaction and abnormal B cell peripheral maturation in PI3KR1-mutated patients presenting with HIGM-like phenotype. Clin. Immunol., 2015, 159(1), 33-36.
[http://dx.doi.org/10.1016/j.clim.2015.04.014] [PMID: 25939554]
[20]
Martínez-Saavedra, M.T.; García-Gomez, S.; Domínguez Acosta, A.; Mendoza Quintana, J.J.; Páez, J.P.; García-Reino, E.J.; Camps, G.; Martinez-Barricarte, R.; Itan, Y.; Boisson, B.; Sánchez-Ramón, S.; Regueiro, J.R.; Casanova, J.L.; Rodríguez-Gallego, C.; Pérez de Diego, R. Gain-of-function mutation in PIK3R1 in a patient with a narrow clinical phenotype of respiratory infections. Clin. Immunol., 2016, 173, 117-120.
[http://dx.doi.org/10.1016/j.clim.2016.09.011] [PMID: 27693481]
[21]
Olbrich, P.; Lorenz, M. Cura, Daball, P.; Lucena, J.M.; Rensing-Ehl, A.; Sanchez, B.; Fuhrer, M.; Camacho-Lovillo, M.; Melon, M.; Schwarz, K.; Neth, O.; Speckmann, C. Activated PI3Kdelta syndrome type 2: Two patients, a novel mutation, and review of the literature. Pediatr. Allergy Immunol., 2016, 27(6), 640-644.
[http://dx.doi.org/10.1111/pai.12585] [PMID: 27116393]
[22]
Bravo, G-M.M.; Garcia-Minaur, S. Molina, Garicano, J.; Santos, Simarro, F.; Del, Pino, Molina, L.; Lopez-Granados, E.; Ferreira, Cerdan, A.; Rodriguez, Pena, R. Mutations in PIK3R1 can lead to APDS2, SHORT syndrome or a combination of the two. Clin. Immunol., 2017, 179, 77-80.
[23]
Deau, M-C.; Heurtier, L.; Frange, P.; Suarez, F.; Bole-Feysot, C.; Nitschke, P.; Cavazzana, M.; Picard, C.; Durandy, A.; Fischer, A.; Kracker, S. A human immunodeficiency caused by mutations in the PIK3R1 gene. J. Clin. Invest., 2015, 125(4), 1764-1765.
[http://dx.doi.org/10.1172/JCI81746] [PMID: 25831445]
[24]
Kuhlen, M.; Hönscheid, A.; Loizou, L.; Nabhani, S.; Fischer, U.; Stepensky, P.; Schaper, J.; Klapper, W.; Siepermann, M.; Schuster, F.; Meisel, R.; Borkhardt, A. De novo PIK3R1 gain-of-function with recurrent sinopulmonary infections, long-lasting chronic CMV-lymphadenitis and microcephaly. Clin. Immunol., 2016, 162, 27-30.
[http://dx.doi.org/10.1016/j.clim.2015.10.008] [PMID: 26529633]
[25]
Wentink, M.; Dalm, V.; Lankester, A.C.; van Schouwenburg, P.A.; Schölvinck, L.; Kalina, T.; Zachova, R.; Sediva, A.; Lambeck, A.; Pico-Knijnenburg, I.; van Dongen, J.J.; Pac, M.; Bernatowska, E.; van Hagen, M.; Driessen, G.; van der Burg, M. Genetic defects in PI3Kδ affect B-cell differentiation and maturation leading to hypogammaglobulineamia and recurrent infections. Clin. Immunol., 2017, 176, 77-86.
[http://dx.doi.org/10.1016/j.clim.2017.01.004] [PMID: 28104464]
[26]
Condliffe, A.M.; Chandra, A. Respiratory Manifestations of the Activated Phosphoinositide 3-Kinase Delta Syndrome. Front. Immunol., 2018, 9, 338.
[http://dx.doi.org/10.3389/fimmu.2018.00338] [PMID: 29556229]
[27]
Lucas, C.L.; Kuehn, H.S.; Zhao, F.; Niemela, J.E.; Deenick, E.K.; Palendira, U.; Avery, D.T.; Moens, L.; Cannons, J.L.; Biancalana, M.; Stoddard, J.; Ouyang, W.; Frucht, D.M.; Rao, V.K.; Atkinson, T.P.; Agharahimi, A.; Hussey, A.A.; Folio, L.R.; Olivier, K.N.; Fleisher, T.A.; Pittaluga, S.; Holland, S.M.; Cohen, J.I.; Oliveira, J.B.; Tangye, S.G.; Schwartzberg, P.L.; Lenardo, M.J.; Uzel, G. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency. Nat. Immunol., 2014, 15(1), 88-97.
[http://dx.doi.org/10.1038/ni.2771] [PMID: 24165795]
[28]
Dornan, G.L.; Siempelkamp, B.D.; Jenkins, M.L.; Vadas, O.; Lucas, C.L.; Burke, J.E. Conformational disruption of PI3Kδ regulation by immunodeficiency mutations in PIK3CD and PIK3R1. Proc. Natl. Acad. Sci. USA, 2017, 114(8), 1982-1987.
[http://dx.doi.org/10.1073/pnas.1617244114] [PMID: 28167755]


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VOLUME: 19
ISSUE: 7
Year: 2019
Page: [941 - 958]
Pages: 18
DOI: 10.2174/1871530319666190225114739
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