Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K

Journal of Experimental Medicine

Volumn 211, Issue 13, 2014, Pages 2537-2547

  Lucas, Carrie L ^a,b   Zhang, Yu ^a,b   Venida, Anthony ^a,b   Wang, Ying ^c   Hughes, Jason ^d   McElwee, Joshua ^d   Butrick, Morgan ^b   Matthews, Helen ^a,b   Price, Susan ^a,b   Biancalana, Matthew ^a,b   Wang, Xiaochuan ^c   Richards, Michael ^e   Pozos, Tamara ^e   Barlan, Isil ^f   Ozen, Ahmet ^f   Rao, V Koneti ^a,b   Su, Helen C ^a,b   Lenardo, Michael J ^a,b  

^a NATIONAL INSTITUTES OF HEALTH   (United States)

^b NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES   (United States)

^c CHILDREN S HOSPITAL OF FUDAN UNIVERSITY   (China)

^d MERCK RESEARCH LABORATORIES   (United States)

^e CHILDREN S HOSPITALS AND CLINICS OF MINNESOTA   (United States)

^f MARMARA UNIVERSITY   (Turkey)

Author keywords

[No Author keywords available]

Indexed keywords

AMINO ACID; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN P110; PROTEIN P110DELTA; PROTEIN P50; PROTEIN P50ALPHA; PROTEIN P55; PROTEIN P55ALPHA; PROTEIN P85; PROTEIN P85ALPHA; UNCLASSIFIED DRUG; PIK3R1 PROTEIN, HUMAN; TARGET OF RAPAMYCIN KINASE;

ADOLESCENT; ADULT; ANTIBODY PRODUCTION; ARTICLE; BLOOD; CASE REPORT; CATALYSIS; CD8+ T LYMPHOCYTE; CELL DIFFERENTIATION; CELL EXPANSION; CHILD; CONTROLLED STUDY; EFFECTOR CELL; ENZYME ACTIVATION; ENZYME ACTIVE SITE; EXON; FEMALE; GENE MUTATION; GENE OVEREXPRESSION; HETEROZYGOTE; HUMAN; HUMAN CELL; IMMUNE DEFICIENCY; INFLAMMATORY DISEASE; LUNG INFECTION; LYMPHOCYTE PROLIFERATION; MALE; MUTANT; PERIPHERAL BLOOD MONONUCLEAR CELL; PRESCHOOL CHILD; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN EXPRESSION; QUALITATIVE ANALYSIS; QUANTITATIVE ANALYSIS; RECURRENT INFECTION; SIGNAL TRANSDUCTION; TELOMERE; ALTERNATIVE RNA SPLICING; ANTAGONISTS AND INHIBITORS; CHEMISTRY; DOMINANT GENE; ENZYMOLOGY; GENE DELETION; GENETICS; IMMUNOLOGY; LYMPHOPROLIFERATIVE DISEASE; METABOLISM; MOLECULAR GENETICS; MUTATION; NUCLEOTIDE SEQUENCE; PEDIGREE; PROTEIN TERTIARY STRUCTURE;

ADOLESCENT; ADULT; ALTERNATIVE SPLICING; ANTIBODY FORMATION; BASE SEQUENCE; CATALYTIC DOMAIN; CD8-POSITIVE T-LYMPHOCYTES; CELL DIFFERENTIATION; CHILD, PRESCHOOL; ENZYME ACTIVATION; EXONS; FEMALE; GENES, DOMINANT; HETEROZYGOTE; HUMANS; IMMUNOLOGIC DEFICIENCY SYNDROMES; LYMPHOPROLIFERATIVE DISORDERS; MALE; MOLECULAR SEQUENCE DATA; MUTATION; PEDIGREE; PHOSPHATIDYLINOSITOL 3-KINASES; PROTEIN STRUCTURE, TERTIARY; SEQUENCE DELETION; SIGNAL TRANSDUCTION; TELOMERE; TOR SERINE-THREONINE KINASES;

EID: 84921847830     PISSN: 00221007     EISSN: 15409538     Source Type: Journal    
DOI: 10.1084/jem.20141759     Document Type: Article

References (37)

1. Angulo, I., O. Vadas, F. Garçon, E. Banham-Hall, V. Plagnol, T.R. Leahy, H. Baxendale, T. Coulter, J. Curtis, C. Wu, et al. 2013. Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage. Science. 342:866-871. http://dx.doi.org/10.1126/science.1243292
2. Bárcena, C., V. Quesada, A. De Sandre-Giovannoli, D.A. Puente, J. Fernández-Toral, S. Sigaudy, A. Baban, N. Lévy, G. Velasco, and C. López-Otín. 2014. Exome sequencing identifies a novel mutation in PIK3R1 as the cause of SHORT syndrome. BMC Med. Genet. 15:51. http://dx.doi.org/10.1186/1471-2350-15-51
3. Brachmann, S.M., K. Ueki, J.A. Engelman, R.C. Kahn, and L.C. Cantley. 2005. Phosphoinositide 3-kinase catalytic subunit deletion and regulatory subunit deletion have opposite effects on insulin sensitivity in mice. Mol. Cell. Biol. 25:1596-1607. http://dx.doi.org/10.1128/MCB.25.5.1596-1607.2005
4. Brown, J.R., J.C. Byrd, S.E. Coutre, D.M. Benson, I.W. Flinn, N.D. Wagner-Johnston, S.E. Spurgeon, B.S. Kahl, C. Bello, H.K. Webb, et al. 2014. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia. Blood. 123:3390-3397. http://dx.doi.org/10.1182/blood-2013-11-535047
5. Burke, J.E., O. Vadas, A. Berndt, T. Finegan, O. Perisic, and R.L. Williams. 2011. Dynamics of the phosphoinositide 3-kinase p110δ interaction with p85α and membranes reveals aspects of regulation distinct from p110α. Structure. 19:1127-1137. http://dx.doi.org/10.1016/j.str.2011.06.003
6. Cancer Genome Atlas Research Network. 2008. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 455:1061-1068. http://dx.doi.org/10.1038/nature07385
7. Chudasama, K.K., J. Winnay, S. Johansson, T. Claudi, R. König, I. Haldorsen, B. Johansson, J.R. Woo, D. Aarskog, J.V. Sagen, et al. 2013. SHORT syndrome with partial lipodystrophy due to impaired phosphatidylinositol 3 kinase signaling. Am. J. Hum. Genet. 93:150-157. http://dx.doi.org/10.1016/j.ajhg.2013.05.023
8. Conley, M.E., A.K. Dobbs, A.M. Quintana, A. Bosompem, Y.D. Wang, E. Coustan-Smith, A.M. Smith, E.E. Perez, and P.J. Murray. 2012. Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K. J. Exp. Med. 209:463-470.
9. Crank, M.C., J.K. Grossman, S. Moir, S. Pittaluga, C.M. Buckner, L. Kardava, A. Agharahimi, H. Meuwissen, J. Stoddard, J. Niemela, et al. 2014. Mutations in PIK3CD can cause hyper IgM syndrome (HIGM) associated with increased cancer susceptibility. J. Clin. Immunol. 34:272-276. http://dx.doi.org/10.1007/s10875-014-0012-9
10. Deau, M.C., L. Heurtier, P. Frange, F. Suarez, C. Bole-Feysot, P. Nitschke, M. Cavazzana, C. Picard, A. Durandy, A. Fischer, and S. Kracker. 2014. A human immunodeficiency caused by mutations in the PIK3R1 gene. J. Clin. Invest. 124:3923-3928. http://dx.doi.org/10.1172/JCI75746
11. Dhand, R., K. Hara, I. Hiles, B. Bax, I. Gout, G. Panayotou, M.J. Fry, K. Yonezawa, M. Kasuga, and M.D. Waterfield. 1994. PI 3-kinase: structural and functional analysis of intersubunit interactions. EMBO J. 13:511-521.
12. Dyment, D.A., A.C. Smith, D. Alcantara, J.A. Schwartzentruber, L. Basel- Vanagaite, C.J. Curry, I.K. Temple, W. Reardon, S. Mansour, M.R. Haq, et al. FORGE Canada Consortium. 2013. Mutations in PIK3R1 cause SHORT syndrome. Am. J. Hum. Genet. 93:158-166. http://dx.doi.org/10.1016/j.ajhg.2013.06.005
13. Flinn, I.W., B.S. Kahl, J.P. Leonard, R.R. Furman, J.R. Brown, J.C. Byrd, N.D. Wagner-Johnston, S.E. Coutre, D.M. Benson, S. Peterman, et al. 2014. Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-δ, as therapy for previously treated indolent non-Hodgkin lymphoma. Blood. 123:3406-3413. http://dx.doi.org/10.1182/blood-2013-11-538546
14. Fruman, D.A., F. Mauvais-Jarvis, D.A. Pollard, C.M. Yballe, D. Brazil, R.T. Bronson, C.R. Kahn, and L.C. Cantley. 2000. Hypoglycaemia, liver necrosis and perinatal death in mice lacking all isoforms of phosphoinositide 3-kinase p85α. Nat. Genet. 26:379-382. http://dx.doi.org/10.1038/81715
15. Geering, B., P.R. Cutillas, G. Nock, S.I. Gharbi, and B. Vanhaesebroeck. 2007a. Class IA phosphoinositide 3-kinases are obligate p85-p110 heterodimers. Proc. Natl. Acad. Sci. USA. 104:7809-7814. http://dx.doi.org/10.1073/pnas.0700373104
16. Geering, B., P.R. Cutillas, and B. Vanhaesebroeck. 2007b. Regulation of class IA PI3Ks: is there a role for monomeric PI3K subunits? Biochem. Soc. Trans. 35:199-203. http://dx.doi.org/10.1042/BST0350199
17. Gilbert, J.A. 2014. Idelalisib: targeting PI3Kδ in B-cell malignancies. Lancet Oncol. 15:e108. http://dx.doi.org/10.1016/S1470-2045(14)70052-X
18. Jaiswal, B.S., V. Janakiraman, N.M. Kljavin, S. Chaudhuri, H.M. Stern, W. Wang, Z. Kan, H.A. Dbouk, B.A. Peters, P. Waring, et al. 2009. Somatic mutations in p85α promote tumorigenesis through class IA PI3K activation. Cancer Cell. 16:463-474. http://dx.doi.org/10.1016/j.ccr.2009.10.016
19. Kahl, B.S., S.E. Spurgeon, R.R. Furman, I.W. Flinn, S.E. Coutre, J.R. Brown, D.M. Benson, J.C. Byrd, S. Peterman, Y. Cho, et al. 2014. A phase 1 study of the PI3Kδ inhibitor idelalisib in patients with relapsed/refractory mantle cell lymphoma (MCL). Blood. 123:3398-3405. http://dx.doi.org/10.1182/blood-2013-11-537555
20. Keppler-Noreuil, K.M., J.C. Sapp, M.J. Lindhurst, V.E. Parker, C. Blumhorst, T. Darling, L.L. Tosi, S.M. Huson, R.W. Whitehouse, E. Jakkula, et al. 2014. Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum. Am. J. Med. Genet. A. 164:1713-1733. http://dx.doi.org/10.1002/ajmg.a.36552
21. Kracker, S., J. Curtis, M.A. Ibrahim, A. Sediva, J. Salisbury, V. Campr, M. Debré, J.D. Edgar, K. Imai, C. Picard, et al. 2014. Occurrence of B-cell lymphomas in patients with activated phosphoinositide 3-kinase δ syndrome. J. Allergy Clin. Immunol. 134:233-236: 236.e3. http://dx.doi.org/10.1016/j.jaci.2014.02.020
22. Lannutti, B.J., S.A. Meadows, S.E. Herman, A. Kashishian, B. Steiner, A.J. Johnson, J.C. Byrd, J.W. Tyner, M.M. Loriaux, M. Deininger, et al. 2011. CAL-101, a p110δ selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood. 117:591-594. http://dx.doi.org/10.1182/blood- 2010-03-275305
23. Lee, J.H., M. Huynh, J.L. Silhavy, S. Kim, T. Dixon-Salazar, A. Heiberg, E. Scott, V. Bafna, K.J. Hill, A. Collazo, et al. 2012. De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nat. Genet. 44:941-945. http://dx.doi.org/10.1038/ng.2329
24. Lindhurst, M.J., V.E. Parker, F. Payne, J.C. Sapp, S. Rudge, J. Harris, A.M. Witkowski, Q. Zhang, M.P. Groeneveld, C.E. Scott, et al. 2012. Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. Nat. Genet. 44:928-933. http://dx.doi.org/10.1038/ng.2332
25. Lucas, C.L., H.S. Kuehn, F. Zhao, J.E. Niemela, E.K. Deenick, U. Palendira, D.T. Avery, L. Moens, J.L. Cannons, M. Biancalana, et al. 2014. 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. 15:88-97. http://dx.doi.org/10.1038/ni.2771
26. Mauvais-Jarvis, F., K. Ueki, D.A. Fruman, M.F. Hirshman, K. Sakamoto, L.J. Goodyear, M. Iannacone, D. Accili, L.C. Cantley, and C.R. Kahn. 2002. Reduced expression of the murine p85α subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes. J. Clin. Invest. 109:141-149. http://dx.doi.org/10.1172/JCI0213305
27. Parsons, D.W., S. Jones, X. Zhang, J.C. Lin, R.J. Leary, P. Angenendt, P. Mankoo, H. Carter, I.M. Siu, G.L. Gallia, et al. 2008. An integrated genomic analysis of human glioblastoma multiforme. Science. 321:1807-1812. http://dx.doi.org/10.1126/science.1164382
28. Rivière, J.B., G.M. Mirzaa, B.J. O'Roak, M. Beddaoui, D. Alcantara, R.L. Conway, J. St-Onge, J.A. Schwartzentruber, K.W. Gripp, S.M. Nikkel, et al. Finding of Rare Disease Genes (FORGE) Canada Consortium. 2012. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat. Genet. 44:934-940. http://dx.doi.org/10.1038/ng.2331
29. Sun, M., P. Hillmann, B.T. Hofmann, J.R. Hart, and P.K. Vogt. 2010. Cancerderived mutations in the regulatory subunit p85α of phosphoinositide 3-kinase function through the catalytic subunit p110α. Proc. Natl. Acad. Sci. USA. 107:15547-15552. http://dx.doi.org/10.1073/pnas.1009652107
30. Thauvin-Robinet, C., M. Auclair, L. Duplomb, M. Caron-Debarle, M. Avila, J. St-Onge, M. Le Merrer, B. Le Luyer, D. Héron, M. Mathieu- Dramard, et al. 2013. PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy. Am. J. Hum. Genet. 93:141-149. http://dx.doi.org/10.1016/j.ajhg.2013.05.019
31. Ueki, K., D.A. Fruman, S.M. Brachmann, Y.H. Tseng, L.C. Cantley, and C.R. Kahn. 2002. Molecular balance between the regulatory and catalytic subunits of phosphoinositide 3-kinase regulates cell signaling and survival. Mol. Cell. Biol. 22:965-977. http://dx.doi.org/10.1128/MCB.22.3.965-977.2002
32. Ueki, K., D.A. Fruman, C.M. Yballe, M. Fasshauer, J. Klein, T. Asano, L.C. Cantley, and C.R. Kahn. 2003. Positive and negative roles of p85α and p85β regulatory subunits of phosphoinositide 3-kinase in insulin signaling. J. Biol. Chem. 278:48453-48466. http://dx.doi.org/10.1074/jbc. M305602200
33. Urick, M.E., M.L. Rudd, A.K. Godwin, D. Sgroi, M. Merino, and D.W. Bell. 2011. PIK3R1 (p85α) is somatically mutated at high frequency in primary endometrial cancer. Cancer Res. 71:4061-4067. http://dx.doi.org/10.1158/0008-5472.CAN-11-0549
34. Vanhaesebroeck, B., K. Ali, A. Bilancio, B. Geering, and L.C. Foukas. 2005. Signalling by PI3K isoforms: insights from gene-targeted mice. Trends Biochem. Sci. 30:194-204. http://dx.doi.org/10.1016/j.tibs.2005.02.008
35. Wong, K.K., J.A. Engelman, and L.C. Cantley. 2010. Targeting the PI3K signaling pathway in cancer. Curr. Opin. Genet. Dev. 20:87-90. http://dx.doi.org/10.1016/j.gde.2009.11.002
36. Yu, J., Y. Zhang, J. McIlroy, T. Rordorf-Nikolic, G.A. Orr, and J.M. Backer. 1998. Regulation of the p85/p110 phosphatidylinositol 3'-kinase: stabilization and inhibition of the p110α catalytic subunit by the p85 regulatory subunit. Mol. Cell. Biol. 18:1379-1387.
37. Zhao, J.J., H. Cheng, S. Jia, L. Wang, O.V. Gjoerup, A. Mikami, and T.M. Roberts. 2006. The p110α isoform of PI3K is essential for proper growth factor signaling and oncogenic transformation. Proc. Natl. Acad. Sci. USA. 103:16296-16300. http://dx.doi.org/10.1073/pnas.0607899103