immunodeficiency (CVID) is the most common primary immunodeficiency and
antibody deficiency. It is a clinically and genetically heterogeneous group of
disorders caused by a defect in B cell differentiation and impaired
immunoglobulin secretion. CVID is characterized by normal or low circulating B
cell, antibody deficiency, hypogammaglobulinemia and recurrent bacterial
infections (Jolles et al. 2013). Mutations in LRBA are associated with CVID type 8, or LRBA deficiency, an
autosomal recessive condition characterized by respiratory infections and
autoimmune disorders such as idiopathic thrombocytopenic purpura, autoimmune
hemolytic anemia, and inflammatory bowel disease (Alangari et al. 2012;
Lopez-Herrera et al. 2012).
gene encodes the lipopolysaccharide-responsive vesicle trafficking, beach- and
anchor-containing protein, which is found in the cytosol and expressed in many
tissues. This protein is involved in regulating recycling of the cytotoxic T
lymphocyte-associated protein 4 (CTLA4), which is found in intracellular
compartments and regulates autoimmune responses in the body (Lo et al. 2015). Deficient
protein expression has been reported to lead to defects in B and T-cell
activation along with a decreased sensitivity to apoptosis.
Confirmation of diagnosis in a patient with the following:
- Combined immunodeficiency or combined variable immunodeficiency (CVID)
- Early-onset colitis with autoimmunity
- Family member with previously identified LRBA mutation(s)
Testing is performed by Sanger sequencing of the entire coding regions and intron/exon boundaries of the LRBA gene.
The clinical sensitivity of sequencing is
unknown, as only six mutations have been reported in this gene.
The sensitivity of DNA sequencing is over 99% for the
detection of nucleotide base changes, small deletions and insertions in the
Mutations in regulatory regions or other untranslated
regions are not detected by this test. Large deletions involving entire single
exons or multiple exons, large insertions and other complex genetic events have
been reported in many of these genes and will not be identified using this test
methodology. Rare primer site variants may lead to erroneous results.
Alangari, A., A. Alsultan, et
al. (2012) "LPS-Responsive Beige-like Anchor (LRBA) Gene Mutation in a
Family with Inflammatory Bowel Disease and Combined Immunodeficiency." J
Allergy Clin Immunol 130(2): 481–8 e2.
Jolles, S. (2013) "The
Variable in Common Variable Immunodeficiency: A Disease of Complex
Phenotypes." The Journal of Allergy and Clinical Immunology. In Practice
Lo, B., K. Zhang, et al.
(2015) "AUTOIMMUNE DISEASE. Patients with LRBA Deficiency Show CTLA4 Loss
and Immune Dysregulation Responsive to Abatacept Therapy." Science (New
York, N.Y.) 349(6246): 436–40.
Lopez-Herrera, G., G.
Tampella, et al. (2012) "Deleterious Mutations in LRBA Are Associated with
a Syndrome of Immune Deficiency and Autoimmunity." American Journal of
Human Genetics 90(6): 986–1001.
Wang, J.-W., J.J. Gamsby, et al. (2004)
"Deregulated Expression of LRBA Facilitates Cancer Cell Growth."
Oncogene 23(23): 4089–97.