Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes.

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Serval ID
serval:BIB_22BCF4E648BF
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes.
Journal
Blood
Author(s)
Salzer U., Bacchelli C., Buckridge S., Pan-Hammarström Q., Jennings S., Lougaris V., Bergbreiter A., Hagena T., Birmelin J., Plebani A., Webster A.D., Peter H.H., Suez D., Chapel H., McLean-Tooke A., Spickett G.P., Anover-Sombke S., Ochs H.D., Urschel S., Belohradsky B.H., Ugrinovic S., Kumararatne D.S., Lawrence T.C., Holm A.M., Franco J.L., Schulze I., Schneider P., Gertz E.M., Schäffer A.A., Hammarström L., Thrasher A.J., Gaspar H.B., Grimbacher B.
ISSN
1528-0020 (Electronic)
ISSN-L
0006-4971
Publication state
Published
Issued date
2009
Peer-reviewed
Oui
Volume
113
Number
9
Pages
1967-1976
Language
english
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.
Keywords
Agammaglobulinemia/genetics, Alleles, Amino Acid Substitution, Case-Control Studies, Cells, Cultured, Cohort Studies, DNA Mutational Analysis, Gene Frequency, Genetic Predisposition to Disease/genetics, Heterozygote, Homozygote, Humans, Mutation/physiology, Pedigree, Polymorphism, Single Nucleotide/physiology, Risk Factors, Syndrome, Transmembrane Activator and CAML Interactor Protein/genetics
Pubmed
Web of science
Open Access
Yes
Create date
13/02/2009 20:14
Last modification date
20/08/2019 13:00
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