Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K.
Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K.
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PIK3R1 的杂合剪接突变会导致人类免疫缺陷，并由于 PI3K 的显性激活而导致淋巴细胞增殖。
DOI：
10.1084/jem.20141759
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发表时间：
2014-12-15
期刊：
影响因子：
--
通讯作者：
Lenardo MJ
中科院分区：
文献类型：
--
作者：
Lucas CL;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 VK;Su HC;Lenardo MJ
Lucas等人鉴定了PIK 3R 1（编码PI 3 K的p85α亚基）中存在功能获得性突变的人类。剪接位点突变导致外显子11的框内跳跃，导致p85α与p110δ的结合改变，从而稳定催化亚基，但不能适当抑制催化活性。患者有免疫缺陷和淋巴细胞增殖，CD 8 + T细胞向端粒缩短的终末分化和衰老效应细胞倾斜。IA类磷脂酰肌醇3-激酶（PI 3 K）产生PIP 3作为细胞生长和增殖的信号，作为催化亚基与调节亚基结合的细胞内复合物存在。我们和其他人以前曾报道过，编码p110δ催化PI 3 K亚基的PIK 3CD中的杂合突变引起一种独特的疾病，称为p110δ激活突变，引起衰老T细胞，淋巴结病和免疫缺陷（PASLI）疾病。我们报告了来自三个家族的四名患有类似疾病的患者，他们最近报告了PIK 3R 1杂合剪接位点突变，PIK 3R 1编码p85α，p55α和p50α调节PI 3 K亚基。这些患者患有复发性鼻窦炎感染和淋巴细胞增殖，表现出过度活跃的PI 3 K信号传导，并且具有显著的扩增和外周血CD 8 + T细胞向具有短端粒的终末分化衰老效应细胞的偏斜。PIK 3R 1剪接位点突变导致外显子跳跃，对应于SH 2间结构域中氨基酸残基434-475的丢失。突变型p85α蛋白在患者细胞中以低水平表达，当在健康受试者的T细胞中过表达时，由于p85α-p110δ复合物的定性和定量结合变化以及C末端区域无法适当抑制p110δ催化活性，激活PI 3 K信号传导。
Lucas et al. identify humans with a gain-of-function mutation in PIK3R1, encoding the p85α subunit of PI3K. The splice site mutation causes in-frame skipping of exon 11, resulting in altered p85α association with p110δ that stabilizes the catalytic subunit but fails to properly inhibit catalytic activity. The patients have immunodeficiency and lymphoproliferation with skewing of CD8+ T cells toward terminally differentiated and senescent effector cells that have shortened telomeres. Class IA phosphatidylinositol 3-kinases (PI3K), which generate PIP3 as a signal for cell growth and proliferation, exist as an intracellular complex of a catalytic subunit bound to a regulatory subunit. We and others have previously reported that heterozygous mutations in PIK3CD encoding the p110δ catalytic PI3K subunit cause a unique disorder termed p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency (PASLI) disease. We report four patients from three families with a similar disease who harbor a recently reported heterozygous splice site mutation in PIK3R1, which encodes the p85α, p55α, and p50α regulatory PI3K subunits. These patients suffer from recurrent sinopulmonary infections and lymphoproliferation, exhibit hyperactive PI3K signaling, and have prominent expansion and skewing of peripheral blood CD8+ T cells toward terminally differentiated senescent effector cells with short telomeres. The PIK3R1 splice site mutation causes skipping of an exon, corresponding to loss of amino acid residues 434–475 in the inter-SH2 domain. The mutant p85α protein is expressed at low levels in patient cells and activates PI3K signaling when overexpressed in T cells from healthy subjects due to qualitative and quantitative binding changes in the p85α–p110δ complex and failure of the C-terminal region to properly inhibit p110δ catalytic activity.
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影响因子：
30.8
作者：
Lindhurst, Marjorie J.;Parker, Victoria E. R.;Payne, Felicity;Sapp, Julie C.;Rudge, Simon;Harris, Julie;Witkowski, Alison M.;Zhang, Qifeng;Groeneveld, Matthijs P.;Scott, Carol E.;Daly, Allan;Huson, Susan M.;Tosi, Laura L.;Cunningham, Michael L.;Darling, Thomas N.;Geer, Joseph;Gucev, Zoran;Sutton, V. Reid;Tziotzios, Christos;Dixon, Adrian K.;Helliwell, Timothy;O'Rahilly, Stephen;Savage, David B.;Wakelam, Michael J. O.;Barroso, Ines;Biesecker, Leslie G.;Semple, Robert K.
通讯作者：
Semple, Robert K.
DOI：
10.1126/science.1243292
发表时间：
2013-11-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Angulo I;Vadas O;Garçon F;Banham-Hall E;Plagnol V;Leahy TR;Baxendale H;Coulter T;Curtis J;Wu C;Blake-Palmer K;Perisic O;Smyth D;Maes M;Fiddler C;Juss J;Cilliers D;Markelj G;Chandra A;Farmer G;Kielkowska A;Clark J;Kracker S;Debré M;Picard C;Pellier I;Jabado N;Morris JA;Barcenas-Morales G;Fischer A;Stephens L;Hawkins P;Barrett JC;Abinun M;Clatworthy M;Durandy A;Doffinger R;Chilvers ER;Cant AJ;Kumararatne D;Okkenhaug K;Williams RL;Condliffe A;Nejentsev S
通讯作者：
Nejentsev S
影响因子：
2
作者：
Keppler-Noreuil, Kim M.;Sapp, Julie C.;Lindhurst, Marjorie J.;Parker, Victoria E. R.;Blumhorst, Cathy;Darling, Thomas;Tosi, Laura L.;Huson, Susan M.;Whitehouse, Richard W.;Jakkula, Eveliina;Grant, Ian;Balasubramanian, Meena;Chandler, Kate E.;Fraser, Jamie L.;Gucev, Zoran;Crow, Yanick J.;Brennan, Leslie Manace;Clark, Robin;Sellars, Elizabeth A.;Pena, Loren D. M.;Krishnamurty, Vidya;Shuen, Andrew;Braverman, Nancy;Cunningham, Michael L.;Sutton, V. Reid;Tasic, Velibor;Graham, John M., Jr.;Geer, Joseph, Jr.;Henderson, Alex;Semple, Robert K.;Biesecker, Leslie G.
通讯作者：
Biesecker, Leslie G.
影响因子：
15.9
作者：
Mauvais-Jarvis, F;Ueki, K;Kahn, CR
通讯作者：
Kahn, CR
影响因子：
9.8
作者：
Dyment, David A.;Smith, Amanda C.;Innes, A. Micheil
通讯作者：
Innes, A. Micheil