Novel mutations in TACI (TNFRSF13B) causing common variable immunodeficiency.
BACKGROUND
Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by impaired immunoglobulin production. The disorder is also characterized by co-occurrence of autoimmune, lymphoproliferative, and granulomatous diseases. Mutations in the gene encoding TACI (Transmembrane Activator and CAML Interactor, TNFRSF13B) were previously found to be associated with CVID.


METHODS
We therefore sequenced TNFRSF13B gene in a cohort of 48 Iranian CVID patients. Expression of TACI and binding of A proliferation-inducing ligand (APRIL) were tested by FACS.


RESULTS
We identified one patient with a homozygous G to T substitution in the TNFRSF13B gene at the splice site of intron 1 (c.61+1G>T), which abolished expression of the TACI molecule and binding capacity of APRIL. This represents the second CVID patient in the world with a complete absence of TACI expression. B cell lines from family members carrying the same mutation in a heterozygous form showed a reduced level of TACI expression and APRIL-binding capacity, suggesting a gene dosage effect. In addition, we found the previously recognized C104R and C172Y mutations in a heterozygous form in two patients with CVID and one, novel, heterozygous P42T mutation.


CONCLUSIONS
TACI mutations were observed in Iran CVID patients in a similar frequency as in other Caucasian populations. The novel mutations identified in this study support the notion of a crucial role for TACI in B cell differentiation.
Mohammadi
Javad
J
Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.
Liu
Chonghai
C
Aghamohammadi
Asghar
A
Bergbreiter
Astrid
A
Du
Likun
L
Lu
Jiayi
J
Rezaei
Nima
N
Amirzargar
Ali Akbar
AA
Moin
Mostafa
M
Salzer
Ulrich
U
Pan-Hammarström
Qiang
Q
Hammarström
Lennart
L
D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation; D015331:Cohort Studies; D017074:Common Variable Immunodeficiency / Q000209:etiology / Q000235:genetics*; D005192:Family Health; D005260:Female; D018628:Gene Dosage; D006720:Homozygote; D006801:Humans; D007492:Iran / Q000453:epidemiology; D008297:Male; D009154:Mutation; D010375:Pedigree; D011485:Protein Binding; D053303:Transmembrane Activator and CAML Interactor Protein / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000378:metabolism
C108467:TNFRSF13B protein, human; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13