title: A hypermorphic missense mutation in PLCG2, encoding phospholipase Cγ2, causes a dominantly inherited autoinflammatory disease with immunodeficiency.
abstract: Whole-exome sequencing was performed in a family affected by dominantly inherited inflammatory disease characterized by recurrent blistering skin lesions, bronchiolitis, arthralgia, ocular inflammation, enterocolitis, absence of autoantibodies, and mild immunodeficiency. Exome data from three samples, including the affected father and daughter and unaffected mother, were filtered for the exclusion of reported variants, along with benign variants, as determined by PolyPhen-2. A total of eight transcripts were identified as possible candidate genes. We confirmed a variant, c.2120C>A (p.Ser707Tyr), within PLCG2 as the only de novo variant that was present in two affected family members and not present in four unaffected members. PLCG2 encodes phospholipase Cγ2 (PLCγ2), an enzyme with a critical regulatory role in various immune and inflammatory pathways. The p.Ser707Tyr substitution is located in an autoinhibitory SH2 domain that is crucial for PLCγ2 activation. Overexpression of the altered p.Ser707Tyr protein and ex vivo experiments using affected individuals' leukocytes showed clearly enhanced PLCγ2 activity, suggesting increased intracellular signaling in the PLCγ2-mediated pathway. Recently, our laboratory identified in individuals with cold-induced urticaria and immune dysregulation PLCG2 exon-skipping mutations resulting in protein products with constitutive phospholipase activity but with reduced intracellular signaling at physiological temperatures. In contrast, the p.Ser707Tyr substitution in PLCγ2 causes a distinct inflammatory phenotype that is not provoked by cold temperatures and that has different end-organ involvement and increased intracellular signaling at physiological temperatures. Our results highlight the utility of exome-sequencing technology in finding causal mutations in nuclear families with dominantly inherited traits otherwise intractable by linkage analysis.
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD 20892, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.forename: Geun-Shik
authors.initials: GS
authors.lastname: Lee
authors.forename: Jillian
authors.initials: J
authors.lastname: Brady
authors.forename: Shrimati
authors.initials: S
authors.lastname: Datta
authors.forename: Matilda
authors.initials: M
authors.lastname: Katan
authors.forename: Afzal
authors.initials: A
authors.lastname: Sheikh
authors.forename: Marta S
authors.initials: MS
authors.lastname: Martins
authors.forename: Tom D
authors.initials: TD
authors.lastname: Bunney
authors.forename: Brian H
authors.initials: BH
authors.lastname: Santich
authors.forename: Susan
authors.initials: S
authors.lastname: Moir
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Kuhns
authors.forename: Debra A
authors.initials: DA
authors.lastname: Long Priel
authors.forename: Amanda
authors.initials: A
authors.lastname: Ombrello
authors.forename: Deborah
authors.initials: D
authors.lastname: Stone
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ombrello
authors.forename: Javed
authors.initials: J
authors.lastname: Khan
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Milner
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kastner
authors.forename: Ivona
authors.initials: I
authors.lastname: Aksentijevich
mesh_terms: D059472:Exome / Q000235:genetics; D005091:Exons; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D056660:Hereditary Autoinflammatory Diseases / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D020125:Mutation, Missense; D051966:Phospholipase C gamma / Q000235:genetics*; D018909:src Homology Domains / Q000235:genetics
chemical_list: D051966:Phospholipase C gamma