Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes.
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.
Salzer
Ulrich
U
Department of Rheumatology and Clinical Immunology, University Hospital Freiburg, Freiburg, Germany.
Bacchelli
Chiara
C
Buckridge
Sylvie
S
Pan-Hammarström
Qiang
Q
Jennings
Stephanie
S
Lougaris
Vassilis
V
Bergbreiter
Astrid
A
Hagena
Tina
T
Birmelin
Jennifer
J
Plebani
Alessandro
A
Webster
A David B
AD
Peter
Hans-Hartmut
HH
Suez
Daniel
D
Chapel
Helen
H
McLean-Tooke
Andrew
A
Spickett
Gavin P
GP
Anover-Sombke
Stephanie
S
Ochs
Hans D
HD
Urschel
Simon
S
Belohradsky
Bernd H
BH
Ugrinovic
Sanja
S
Kumararatne
Dinakantha S
DS
Lawrence
Tatiana C
TC
Holm
Are M
AM
Franco
Jose L
JL
Schulze
Ilka
I
Schneider
Pascal
P
Gertz
E Michael
EM
Schäffer
Alejandro A
AA
Hammarström
Lennart
L
Thrasher
Adrian J
AJ
Gaspar
H Bobby
HB
Grimbacher
Bodo
B
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*
C108467:TNFRSF13B protein, human; D053303:Transmembrane Activator and CAML Interactor Protein