A human immunodeficiency caused by mutations in the PIK3R1 gene

被引:199
作者
Deau, Marie-Celine [1 ,2 ]
Heurtier, Lucie [1 ,2 ]
Frange, Pierre [3 ]
Suarez, Felipe [2 ,4 ]
Bole-Feysot, Christine [2 ]
Nitschke, Patrick [2 ]
Cavazzana, Marina [1 ,2 ]
Picard, Capucine [2 ,3 ,5 ]
Durandy, Anne [1 ,2 ]
Fischer, Alain [1 ,2 ,3 ,6 ]
Kracker, Sven [1 ,2 ]
机构
[1] INSERM, UMR 1163, Human Lymphohematopoiesis Lab, Paris, France
[2] Univ Paris 05, Sorbonne Paris Cite, Imagine Inst, Paris, France
[3] Hop Necker Enfants Malad, AP HP, Unite Immunol & Hematol Pediat, Paris, France
[4] Hop Necker Enfants Malad, AP HP, Serv Hematol Adultes, Paris, France
[5] Hop Necker Enfants Malad, AP HP, Ctr Primary Immunodeficiencies, Paris, France
[6] Coll France, F-75231 Paris, France
基金
欧洲研究理事会;
关键词
PHOSPHOINOSITIDE; 3-KINASE; PHOSPHATIDYLINOSITOL; ACTIVATION; P85-ALPHA; PI3K; DIFFERENTIATION; SUBUNIT; CELLS; PTEN;
D O I
10.1172/JCI75746
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Recently, patient mutations that activate PI3K signaling have beer linked to a primary antibody deficiency. Here, we used whole-exome sequencing and characterized the molecular defects in 4 patients from 3 unrelated families diagnosed with hypogarnmaglobulinemia and recurrent infections. We identified 2 different heterozygous splice site mutations that affect the same splice site in PIK3R1, which encodes the p85 alpha subunit of PI3K. The resulting deletion of exon 10 produced a shortened p85 alpha protein that lacks part of the PI3K110-binding domain. The hypothetical loss of p85 alpha-mediated inhibition of p110 activity was supported by elevated phosphorylation of the known downstream signaling kinase AKT in patient T cell blasts. Analysis of patient blood revealed that naive T and memory B cell counts were low, and T cell blasts displayed enhanced activation-induced cell death, which was corrected by addition of the PI3K delta inhibitor IC87114. Furthermore, B lymphocytes proliferated weakly in response to activation via the B cell receptor and TLR9, indicating a B cell defect. The phenotype exhibited by patients carrying the PIK3R1 splice site mutation is similar to that of patients carrying gain-of-function mutations in PIK3CD. Our results suggest that PI3K activity is tightly regulated in T and B lymphocytes and that various defects in the PI3K-triggered pathway can cause primary immunodeficiencies.
引用
收藏
页码:3923 / 3928
页数:6
相关论文
共 13 条
[1]   Phosphoinositide 3-Kinase δ Gene Mutation Predisposes to Respiratory Infection and Airway Damage [J].
Angulo, Ivan ;
Vadas, Oscar ;
Garcon, Fabien ;
Banham-Hall, Edward ;
Plagnol, Vincent ;
Leahy, Timothy R. ;
Baxendale, Helen ;
Coulter, Tanya ;
Curtis, James ;
Wu, Changxin ;
Blake-Palmer, Katherine ;
Perisic, Olga ;
Smyth, Deborah ;
Maes, Mailis ;
Fiddler, Christine ;
Juss, Jatinder ;
Cilliers, Deirdre ;
Markelj, Gasper ;
Chandra, Anita ;
Farmer, George ;
Kielkowska, Anna ;
Clark, Jonathan ;
Kracker, Sven ;
Debre, Marianne ;
Picard, Capucine ;
Pellier, Isabelle ;
Jabado, Nada ;
Morris, James A. ;
Barcenas-Morales, Gabriela ;
Fischer, Alain ;
Stephens, Len ;
Hawkins, Phillip ;
Barrett, Jeffrey C. ;
Abinun, Mario ;
Clatworthy, Menna ;
Durandy, Anne ;
Doffinger, Rainer ;
Chilvers, Edwin R. ;
Cant, Andrew J. ;
Kumararatne, Dinakantha ;
Okkenhaug, Klaus ;
Williams, Roger L. ;
Condliffe, Alison ;
Nejentsev, Sergey .
SCIENCE, 2013, 342 (6160) :866-871
[2]   New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase AKT pathway [J].
Cantley, LC ;
Neel, BG .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (08) :4240-4245
[3]   Direct positive regulation of PTEN by the p85 subunit of phosphatidylinositol 3-kinase [J].
Chagpar, Ryaz B. ;
Links, Philip H. ;
Pastor, M. Chris ;
Furber, Levi A. ;
Hawrysh, Andrea D. ;
Chamberlain, M. Dean ;
Anderson, Deborah H. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (12) :5471-5476
[4]   Functional differences between memory and naive CD8 T cells [J].
Cho, BK ;
Wang, CY ;
Sugawa, S ;
Eisen, HN ;
Chen, JZ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (06) :2976-2981
[5]   Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K [J].
Conley, Mary Ellen ;
Dobbs, A. Kerry ;
Quintana, Anita M. ;
Bosompem, Amma ;
Wang, Yong-Dong ;
Coustan-Smith, Elaine ;
Smith, Amber M. ;
Perez, Elena E. ;
Murray, Peter J. .
JOURNAL OF EXPERIMENTAL MEDICINE, 2012, 209 (03) :463-470
[6]   Phosphoinositide 3-kinase: Diverse roles in immune cell activation [J].
Deane, JA ;
Fruman, DA .
ANNUAL REVIEW OF IMMUNOLOGY, 2004, 22 :563-598
[7]   Somatic Mutations in p85α Promote Tumorigenesis through Class IA PI3K Activation [J].
Jaiswal, Bijay S. ;
Janakiraman, Vasantharajan ;
Kljavin, Noelyn M. ;
Chaudhuri, Subhra ;
Stern, Howard M. ;
Wang, Weiru ;
Kan, Zhengyan ;
Dbouk, Hashem A. ;
Peters, Brock A. ;
Waring, Paul ;
Dela Vega, Trisha ;
Kenski, Denise M. ;
Bowman, Krista K. ;
Lorenzo, Maria ;
Li, Hong ;
Wu, Jiansheng ;
Modrusan, Zora ;
Stinson, Jeremy ;
Eby, Michael ;
Yue, Peng ;
Kaminker, Josh S. ;
de Sauvage, Frederic J. ;
Backer, Jonathan M. ;
Seshagiri, Somasekar .
CANCER CELL, 2009, 16 (06) :463-474
[8]   Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency [J].
Lucas, Carrie L. ;
Kuehn, Hye Sun ;
Zhao, Fang ;
Niemel, Julie E. ;
Deenick, Elissa K. ;
Palendira, Umaimainthan ;
Avery, Danielle T. ;
Moens, Leen ;
Cannons, Jennifer L. ;
Lanai, Matthew Bianca ;
Stoddard, Jennifer ;
Ouyane, Weiming ;
Frucht, David M. ;
Rao, V. Koneti ;
Atkinson, T. Prescott ;
Agharahimi, Anahita ;
Hussey, Ashleigh A. ;
Folioll, Les R. ;
Olivier, Kenneth N. ;
Fleisher, Thomas A. ;
Pittaluga, Stefania ;
Holland, Steven M. ;
Cohen, Jeffrey I. ;
Oliveira, Joao B. ;
Tangye, Stuart G. ;
Schwartzberg, Pamela L. ;
Lenardol, Michael J. ;
Uzel, Gulbu .
NATURE IMMUNOLOGY, 2014, 15 (01) :88-97
[9]   A frequent kinase domain mutation that changes the interaction between PI3Kα and the membrane [J].
Mandelker, Diana ;
Gabelli, Sandra B. ;
Schmidt-Kittler, Oleg ;
Zhu, Jiuxiang ;
Cheong, Ian ;
Huang, Chuan-Hsiang ;
Kinzler, Kenneth W. ;
Vogelstein, Bert ;
Amzel, L. Mario .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (40) :16996-17001
[10]   PI3K in lymphocyte development, differentiation and activation [J].
Okkenhaug, K ;
Vanhaesebroeck, B .
NATURE REVIEWS IMMUNOLOGY, 2003, 3 (04) :317-330