title: Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes.
abstract: TNFRSF13B encodes transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), a B cell- specific tumor necrosis factor (TNF) receptor superfamily member. Both biallelic and monoallelic TNFRSF13B mutations were identified in patients with common variable immunodeficiency disorders. The genetic complexity and variable clinical presentation of TACI deficiency prompted us to evaluate the genetic, immunologic, and clinical condition in 50 individuals with TNFRSF13B alterations, following screening of 564 unrelated patients with hypogammaglobulinemia. We identified 13 new sequence variants. The most frequent TNFRSF13B variants (C104R and A181E; n=39; 6.9%) were also present in a heterozygous state in 2% of 675 controls. All patients with biallelic mutations had hypogammaglobulinemia and nearly all showed impaired binding to a proliferation-inducing ligand (APRIL). However, the majority (n=41; 82%) of the pa-tients carried monoallelic changes in TNFRSF13B. Presence of a heterozygous mutation was associated with antibody deficiency (P< .001, relative risk 3.6). Heterozygosity for the most common mutation, C104R, was associated with disease (P< .001, relative risk 4.2). Furthermore, heterozygosity for C104R was associated with low numbers of IgD(-)CD27(+) B cells (P= .019), benign lymphoproliferation (P< .001), and autoimmune complications (P= .001). These associations indicate that C104R heterozygosity increases the risk for common variable immunodeficiency disorders and influences clinical presentation.
authors.affiliation: Department of Rheumatology and Clinical Immunology, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Salzer
authors.forename: Chiara
authors.initials: C
authors.lastname: Bacchelli
authors.forename: Sylvie
authors.initials: S
authors.lastname: Buckridge
authors.forename: Qiang
authors.initials: Q
authors.lastname: Pan-Hammarström
authors.forename: Stephanie
authors.initials: S
authors.lastname: Jennings
authors.forename: Vassilis
authors.initials: V
authors.lastname: Lougaris
authors.forename: Astrid
authors.initials: A
authors.lastname: Bergbreiter
authors.forename: Tina
authors.initials: T
authors.lastname: Hagena
authors.forename: Jennifer
authors.initials: J
authors.lastname: Birmelin
authors.forename: Alessandro
authors.initials: A
authors.lastname: Plebani
authors.forename: A David B
authors.initials: AD
authors.lastname: Webster
authors.forename: Hans-Hartmut
authors.initials: HH
authors.lastname: Peter
authors.forename: Daniel
authors.initials: D
authors.lastname: Suez
authors.forename: Helen
authors.initials: H
authors.lastname: Chapel
authors.forename: Andrew
authors.initials: A
authors.lastname: McLean-Tooke
authors.forename: Gavin P
authors.initials: GP
authors.lastname: Spickett
authors.forename: Stephanie
authors.initials: S
authors.lastname: Anover-Sombke
authors.forename: Hans D
authors.initials: HD
authors.lastname: Ochs
authors.forename: Simon
authors.initials: S
authors.lastname: Urschel
authors.forename: Bernd H
authors.initials: BH
authors.lastname: Belohradsky
authors.forename: Sanja
authors.initials: S
authors.lastname: Ugrinovic
authors.forename: Dinakantha S
authors.initials: DS
authors.lastname: Kumararatne
authors.forename: Tatiana C
authors.initials: TC
authors.lastname: Lawrence
authors.forename: Are M
authors.initials: AM
authors.lastname: Holm
authors.forename: Jose L
authors.initials: JL
authors.lastname: Franco
authors.forename: Ilka
authors.initials: I
authors.lastname: Schulze
authors.forename: Pascal
authors.initials: P
authors.lastname: Schneider
authors.forename: E Michael
authors.initials: EM
authors.lastname: Gertz
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Schäffer
authors.forename: Lennart
authors.initials: L
authors.lastname: Hammarström
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
authors.forename: H Bobby
authors.initials: HB
authors.lastname: Gaspar
authors.forename: Bodo
authors.initials: B
authors.lastname: Grimbacher
mesh_terms: D000361:Agammaglobulinemia / Q000235:genetics*; D000483:Alleles; D019943:Amino Acid Substitution; D016022:Case-Control Studies; D002478:Cells, Cultured; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D009154:Mutation / Q000502:physiology; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D012307:Risk Factors; D013577:Syndrome; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics*
chemical_list: C108467:TNFRSF13B protein, human; D053303:Transmembrane Activator and CAML Interactor Protein