title: Protein kinase cδ deficiency causes mendelian systemic lupus erythematosus with B cell-defective apoptosis and hyperproliferation.
abstract: OBJECTIVE
  Systemic lupus erythematosus (SLE) is a prototype autoimmune disease that is assumed to occur via a complex interplay of environmental and genetic factors. Rare causes of monogenic SLE have been described, providing unique insights into fundamental mechanisms of immune tolerance. The aim of this study was to identify the cause of an autosomal-recessive form of SLE.
  
  
  METHODS
  We studied 3 siblings with juvenile-onset SLE from 1 consanguineous kindred and used next-generation sequencing to identify mutations in the disease-associated gene. We performed extensive biochemical, immunologic, and functional assays to assess the impact of the identified mutations on B cell biology.
  
  
  RESULTS
  We identified a homozygous missense mutation in PRKCD, encoding protein kinase δ (PKCδ), in all 3 affected siblings. Mutation of PRKCD resulted in reduced expression and activity of the encoded protein PKCδ (involved in the deletion of autoreactive B cells), leading to resistance to B cell receptor- and calcium-dependent apoptosis and increased B cell proliferation. Thus, as for mice deficient in PKCδ, which exhibit an SLE phenotype and B cell expansion, we observed an increased number of immature B cells in the affected family members and a developmental shift toward naive B cells with an immature phenotype.
  
  
  CONCLUSIONS
  Our findings indicate that PKCδ is crucial in regulating B cell tolerance and preventing self-reactivity in humans, and that PKCδ deficiency represents a novel genetic defect of apoptosis leading to SLE.
authors.affiliation: Centre de Référence des Maladies Rénales Rares, Hospices Civils de Lyon, INSERM U1111, UMS3444/US8, Université Claude Bernard Lyon 1, and Université de Lyon, Lyon, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Belot
authors.forename: Paul R
authors.initials: PR
authors.lastname: Kasher
authors.forename: Eleanor W
authors.initials: EW
authors.lastname: Trotter
authors.forename: Anne-Perrine
authors.initials: AP
authors.lastname: Foray
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Debaud
authors.forename: Gillian I
authors.initials: GI
authors.lastname: Rice
authors.forename: Marcin
authors.initials: M
authors.lastname: Szynkiewicz
authors.forename: Marie-Therese
authors.initials: MT
authors.lastname: Zabot
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rouvet
authors.forename: Sanjeev S
authors.initials: SS
authors.lastname: Bhaskar
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Daly
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Dickerson
authors.forename: Josephine
authors.initials: J
authors.lastname: Mayer
authors.forename: James
authors.initials: J
authors.lastname: O'Sullivan
authors.forename: Laurent
authors.initials: L
authors.lastname: Juillard
authors.forename: Jill E
authors.initials: JE
authors.lastname: Urquhart
authors.forename: Shameem
authors.initials: S
authors.lastname: Fawdar
authors.forename: Anna A
authors.initials: AA
authors.lastname: Marusiak
authors.forename: Natalie
authors.initials: N
authors.lastname: Stephenson
authors.forename: Bohdan
authors.initials: B
authors.lastname: Waszkowycz
authors.forename: Michael
authors.initials: M
authors.lastname: W Beresford
authors.forename: Leslie G
authors.initials: LG
authors.lastname: Biesecker
authors.forename: Graeme
authors.initials: G
authors.lastname: C M Black
authors.forename: Céline
authors.initials: C
authors.lastname: René
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Eliaou
authors.forename: Nicole
authors.initials: N
authors.lastname: Fabien
authors.forename: Bruno
authors.initials: B
authors.lastname: Ranchin
authors.forename: Pierre
authors.initials: P
authors.lastname: Cochat
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Gaffney
authors.forename: Flore
authors.initials: F
authors.lastname: Rozenberg
authors.forename: Pierre
authors.initials: P
authors.lastname: Lebon
authors.forename: Christophe
authors.initials: C
authors.lastname: Malcus
authors.forename: Yanick J
authors.initials: YJ
authors.lastname: Crow
authors.forename: John
authors.initials: J
authors.lastname: Brognard
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bonnefoy
mesh_terms: D000293:Adolescent; D000328:Adult; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D002648:Child; D005260:Female; D014644:Genetic Variation; D006720:Homozygote; D006801:Humans; D006965:Hyperplasia; D007108:Immune Tolerance; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D008297:Male; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D051745:Protein Kinase C-delta / Q000172:deficiency* / Q000235:genetics* / Q000276:immunology; D055815:Young Adult
chemical_list: D051745:Protein Kinase C-delta