title: Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K.
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.
authors.affiliation: Molecular Development of the Immune System Section, Laboratory of Immunology; NIAID Clinical Genomics Program; Human Immunological Diseases Unit, Laboratory of Host Defenses; and Intramural Clinical Management and Operations Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 Molecular Development of the Immune System Section, Laboratory of Immunology; NIAID Clinical Genomics Program; Human Immunological Diseases Unit, Laboratory of Host Defenses; and Intramural Clinical Management and Operations Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Lucas
authors.affiliation: Molecular Development of the Immune System Section, Laboratory of Immunology; NIAID Clinical Genomics Program; Human Immunological Diseases Unit, Laboratory of Host Defenses; and Intramural Clinical Management and Operations Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 Molecular Development of the Immune System Section, Laboratory of Immunology; NIAID Clinical Genomics Program; Human Immunological Diseases Unit, Laboratory of Host Defenses; and Intramural Clinical Management and Operations Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Molecular Development of the Immune System Section, Laboratory of Immunology; NIAID Clinical Genomics Program; Human Immunological Diseases Unit, Laboratory of Host Defenses; and Intramural Clinical Management and Operations Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 Molecular Development of the Immune System Section, Laboratory of Immunology; NIAID Clinical Genomics Program; Human Immunological Diseases Unit, Laboratory of Host Defenses; and Intramural Clinical Management and Operations Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Anthony
authors.initials: A
authors.lastname: Venida
authors.affiliation: Department of Clinical Immunology, Children's Hospital of Fudan University, Shanghai 200433, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Merck Research Laboratories, Merck & Co, Boston, MA 02115.
authors.forename: Jason
authors.initials: J
authors.lastname: Hughes
authors.affiliation: Merck Research Laboratories, Merck & Co, Boston, MA 02115.
authors.forename: Joshua
authors.initials: J
authors.lastname: McElwee
authors.affiliation: Molecular Development of the Immune System Section, Laboratory of Immunology; NIAID Clinical Genomics Program; Human Immunological Diseases Unit, Laboratory of Host Defenses; and Intramural Clinical Management and Operations Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 Molecular Development of the Immune System Section, Laboratory of Immunology; NIAID Clinical Genomics Program; Human Immunological Diseases Unit, Laboratory of Host Defenses; and Intramural Clinical Management and Operations Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Morgan
authors.initials: M
authors.lastname: Butrick
authors.affiliation: Molecular Development of the Immune System Section, Laboratory of Immunology; NIAID Clinical Genomics Program; Human Immunological Diseases Unit, Laboratory of Host Defenses; and Intramural Clinical Management and Operations Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 Molecular Development of the Immune System Section, Laboratory of Immunology; NIAID Clinical Genomics Program; Human Immunological Diseases Unit, Laboratory of Host Defenses; and Intramural Clinical Management and Operations Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Helen
authors.initials: H
authors.lastname: Matthews
authors.affiliation: Molecular Development of the Immune System Section, Laboratory of Immunology; NIAID Clinical Genomics Program; Human Immunological Diseases Unit, Laboratory of Host Defenses; and Intramural Clinical Management and Operations Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 Molecular Development of the Immune System Section, Laboratory of Immunology; NIAID Clinical Genomics Program; Human Immunological Diseases Unit, Laboratory of Host Defenses; and Intramural Clinical Management and Operations Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Susan
authors.initials: S
authors.lastname: Price
authors.affiliation: Molecular Development of the Immune System Section, Laboratory of Immunology; NIAID Clinical Genomics Program; Human Immunological Diseases Unit, Laboratory of Host Defenses; and Intramural Clinical Management and Operations Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 Molecular Development of the Immune System Section, Laboratory of Immunology; NIAID Clinical Genomics Program; Human Immunological Diseases Unit, Laboratory of Host Defenses; and Intramural Clinical Management and Operations Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Matthew
authors.initials: M
authors.lastname: Biancalana
authors.affiliation: Department of Clinical Immunology, Children's Hospital of Fudan University, Shanghai 200433, China.
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Hematology/Oncology Clinic and Infectious Diseases and Immunology, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN 55404.
authors.forename: Michael
authors.initials: M
authors.lastname: Richards
authors.affiliation: Hematology/Oncology Clinic and Infectious Diseases and Immunology, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN 55404.
authors.forename: Tamara
authors.initials: T
authors.lastname: Pozos
authors.affiliation: Pediatric Allergy and Immunology, Marmara University, Istanbul 34660, Turkey.
authors.forename: Isil
authors.initials: I
authors.lastname: Barlan
authors.affiliation: Pediatric Allergy and Immunology, Marmara University, Istanbul 34660, Turkey.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Ozen
authors.affiliation: Molecular Development of the Immune System Section, Laboratory of Immunology; NIAID Clinical Genomics Program; Human Immunological Diseases Unit, Laboratory of Host Defenses; and Intramural Clinical Management and Operations Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 Molecular Development of the Immune System Section, Laboratory of Immunology; NIAID Clinical Genomics Program; Human Immunological Diseases Unit, Laboratory of Host Defenses; and Intramural Clinical Management and Operations Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: V Koneti
authors.initials: VK
authors.lastname: Rao
authors.affiliation: Molecular Development of the Immune System Section, Laboratory of Immunology; NIAID Clinical Genomics Program; Human Immunological Diseases Unit, Laboratory of Host Defenses; and Intramural Clinical Management and Operations Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 Molecular Development of the Immune System Section, Laboratory of Immunology; NIAID Clinical Genomics Program; Human Immunological Diseases Unit, Laboratory of Host Defenses; and Intramural Clinical Management and Operations Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Helen C
authors.initials: HC
authors.lastname: Su
authors.affiliation: Molecular Development of the Immune System Section, Laboratory of Immunology; NIAID Clinical Genomics Program; Human Immunological Diseases Unit, Laboratory of Host Defenses; and Intramural Clinical Management and Operations Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 Molecular Development of the Immune System Section, Laboratory of Immunology; NIAID Clinical Genomics Program; Human Immunological Diseases Unit, Laboratory of Host Defenses; and Intramural Clinical Management and Operations Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 lenardo@nih.gov.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lenardo
mesh_terms: D000293:Adolescent; D000328:Adult; D017398:Alternative Splicing / Q000235:genetics*; D000917:Antibody Formation; D001483:Base Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D020134:Catalytic Domain; D002454:Cell Differentiation; D002675:Child, Preschool; D058543:Class Ia Phosphatidylinositol 3-Kinase; D004789:Enzyme Activation; D005091:Exons / Q000235:genetics; D005260:Female; D005799:Genes, Dominant; D006579:Heterozygote; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000201:enzymology* / Q000235:genetics* / Q000276:immunology; D008232:Lymphoproliferative Disorders / Q000201:enzymology / Q000235:genetics* / Q000276:immunology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000235:genetics*; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016615:Telomere / Q000378:metabolism
chemical_list: D058543:Class Ia Phosphatidylinositol 3-Kinase; D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; C588001:PIK3R1 protein, human