title: Loss-of-function of the protein kinase C δ (PKCδ) causes a B-cell lymphoproliferative syndrome in humans.
abstract: Defective lymphocyte apoptosis results in chronic lymphadenopathy and/or splenomegaly associated with autoimmune phenomena. The prototype for human apoptosis disorders is the autoimmune lymphoproliferative syndrome (ALPS), which is caused by mutations in the FAS apoptotic pathway. Recently, patients with an ALPS-like disease called RAS-associated autoimmune leukoproliferative disorder, in which somatic mutations in NRAS or KRAS are found, also were described. Despite this progress, many patients with ALPS-like disease remain undefined genetically. We identified a homozygous, loss-of-function mutation in PRKCD (PKCδ) in a patient who presented with chronic lymphadenopathy, splenomegaly, autoantibodies, elevated immunoglobulins and natural killer dysfunction associated with chronic, low-grade Epstein-Barr virus infection. This mutation markedly decreased protein expression and resulted in ex vivo B-cell hyperproliferation, a phenotype similar to that of the PKCδ knockout mouse. Lymph nodes showed intense follicular hyperplasia, also mirroring the mouse model. Immunophenotyping of circulating lymphocytes demonstrated expansion of CD5+CD20+ B cells. Knockdown of PKCδ in normal mononuclear cells recapitulated the B-cell hyperproliferative phenotype in vitro. Reconstitution of PKCδ in patient-derived EBV-transformed B-cell lines partially restored phorbol-12-myristate-13-acetate-induced cell death. In summary, homozygous PRKCD mutation results in B-cell hyperproliferation and defective apoptosis with consequent lymphocyte accumulation and autoantibody production in humans, and disrupts natural killer cell function.
authors: Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
authors: Hye Sun
authors: HS
authors: Kuehn
authors: Julie E
authors: JE
authors: Niemela
authors: Andreia
authors: A
authors: Rangel-Santos
authors: Mingchang
authors: M
authors: Zhang
authors: Stefania
authors: S
authors: Pittaluga
authors: Jennifer L
authors: JL
authors: Stoddard
authors: Ashleigh A
authors: AA
authors: Hussey
authors: Moses O
authors: MO
authors: Evbuomwan
authors: Debra A Long
authors: DA
authors: Priel
authors: Douglas B
authors: DB
authors: Kuhns
authors: C Lucy
authors: CL
authors: Park
authors: Thomas A
authors: TA
authors: Fleisher
authors: Gulbu
authors: G
authors: Uzel
authors: João B
authors: JB
authors: Oliveira
mesh_terms: D000818:Animals; D017209:Apoptosis; D056735:Autoimmune Lymphoproliferative Syndrome / Q000150:complications / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D049109:Cell Proliferation; D002648:Child; D016207:Cytokines / Q000276:immunology; D020031:Epstein-Barr Virus Infections / Q000150:complications; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D004854:Herpesvirus 4, Human / Q000302:isolation & purification; D006720:Homozygote; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008206:Lymphatic Diseases / Q000150:complications; D008297:Male; D051379:Mice; D009154:Mutation; D051745:Protein Kinase C-delta / Q000235:genetics* / Q000276:immunology; D013163:Splenomegaly / Q000150:complications
chemical_list: D016207:Cytokines; D051745:Protein Kinase C-delta