Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K
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 c...
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| Published in | The Journal of experimental medicine Vol. 211; no. 13; pp. 2537 - 2547 |
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| Main Authors | , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
The Rockefeller University Press
15.12.2014
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| Subjects | |
| Online Access | Get full text |
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| Abstract | 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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| AbstractList | Lucas et al. identify humans with a gain-of-function mutation in PIK3R1, encoding the p85 alpha subunit of PI3K. The splice site mutation causes in-frame skipping of exon 11, resulting in altered p85 alpha association with p110 delta 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 p110 delta catalytic PI3K subunit cause a unique disorder termed p110 delta -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 p85 alpha , p55 alpha , and p50 alpha 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 p85 alpha 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 p85 alpha -p110 delta complex and failure of the C-terminal region to properly inhibit p110 delta catalytic activity. 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.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. 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 PIP 3 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. 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. |
| Author | Lucas, Carrie L. Pozos, Tamara Matthews, Helen Barlan, Isil Zhang, Yu Wang, Ying Richards, Michael Ozen, Ahmet Su, Helen C. Wang, Xiaochuan Venida, Anthony Butrick, Morgan Hughes, Jason McElwee, Joshua Lenardo, Michael J. Rao, V. Koneti Price, Susan Biancalana, Matthew |
| AuthorAffiliation | 9 Pediatric Allergy and Immunology, Marmara University, Istanbul 34660, Turkey 5 Department of Clinical Immunology, Children’s Hospital of Fudan University, Shanghai 200433, China 6 Merck Research Laboratories, Merck & Co, Boston, MA 02115 1 Molecular Development of the Immune System Section, Laboratory of Immunology ; 2 NIAID Clinical Genomics Program ; 3 Human Immunological Diseases Unit, Laboratory of Host Defenses ; and 4 Intramural Clinical Management and Operations Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 7 Hematology/Oncology Clinic and 8 Infectious Diseases and Immunology, Children’s Hospitals and Clinics of Minnesota, Minneapolis, MN 55404 |
| AuthorAffiliation_xml | – name: 6 Merck Research Laboratories, Merck & Co, Boston, MA 02115 – name: 7 Hematology/Oncology Clinic and 8 Infectious Diseases and Immunology, Children’s Hospitals and Clinics of Minnesota, Minneapolis, MN 55404 – name: 9 Pediatric Allergy and Immunology, Marmara University, Istanbul 34660, Turkey – name: 1 Molecular Development of the Immune System Section, Laboratory of Immunology ; 2 NIAID Clinical Genomics Program ; 3 Human Immunological Diseases Unit, Laboratory of Host Defenses ; and 4 Intramural Clinical Management and Operations Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 – name: 5 Department of Clinical Immunology, Children’s Hospital of Fudan University, Shanghai 200433, China |
| Author_xml | – sequence: 1 givenname: Carrie L. surname: Lucas fullname: Lucas, Carrie L. – sequence: 2 givenname: Yu surname: Zhang fullname: Zhang, Yu – sequence: 3 givenname: Anthony surname: Venida fullname: Venida, Anthony – sequence: 4 givenname: Ying surname: Wang fullname: Wang, Ying – sequence: 5 givenname: Jason surname: Hughes fullname: Hughes, Jason – sequence: 6 givenname: Joshua surname: McElwee fullname: McElwee, Joshua – sequence: 7 givenname: Morgan surname: Butrick fullname: Butrick, Morgan – sequence: 8 givenname: Helen surname: Matthews fullname: Matthews, Helen – sequence: 9 givenname: Susan surname: Price fullname: Price, Susan – sequence: 10 givenname: Matthew surname: Biancalana fullname: Biancalana, Matthew – sequence: 11 givenname: Xiaochuan surname: Wang fullname: Wang, Xiaochuan – sequence: 12 givenname: Michael surname: Richards fullname: Richards, Michael – sequence: 13 givenname: Tamara surname: Pozos fullname: Pozos, Tamara – sequence: 14 givenname: Isil surname: Barlan fullname: Barlan, Isil – sequence: 15 givenname: Ahmet surname: Ozen fullname: Ozen, Ahmet – sequence: 16 givenname: V. Koneti surname: Rao fullname: Rao, V. Koneti – sequence: 17 givenname: Helen C. surname: Su fullname: Su, Helen C. – sequence: 18 givenname: Michael J. surname: Lenardo fullname: Lenardo, Michael J. |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/25488983$$D View this record in MEDLINE/PubMed |
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| Snippet | Class IA phosphatidylinositol 3-kinases (PI3K), which generate PIP3 as a signal for cell growth and proliferation, exist as an intracellular complex of a... Lucas et al. identify humans with a gain-of-function mutation in PIK3R1, encoding the p85 alpha subunit of PI3K. The splice site mutation causes in-frame... 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... |
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| SubjectTerms | Adolescent Adult Alternative Splicing - genetics Antibody Formation Base Sequence Catalytic Domain CD8-Positive T-Lymphocytes - immunology Cell Differentiation Child, Preschool Enzyme Activation Exons - genetics Female Genes, Dominant Heterozygote Humans Immunologic Deficiency Syndromes - enzymology Immunologic Deficiency Syndromes - genetics Immunologic Deficiency Syndromes - immunology Lymphoproliferative Disorders - enzymology Lymphoproliferative Disorders - genetics Lymphoproliferative Disorders - immunology Male Molecular Sequence Data Mutation - genetics Pedigree Phosphatidylinositol 3-Kinases - chemistry Phosphatidylinositol 3-Kinases - genetics Protein Structure, Tertiary Sequence Deletion Signal Transduction Telomere - metabolism TOR Serine-Threonine Kinases - antagonists & inhibitors TOR Serine-Threonine Kinases - metabolism |
| Title | Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K |
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