Autoimmune Lymphoproliferative Syndrome, Type V
CTLA4 gene encodes the cytotoxic T
lymphocyte antigen-4 (CTLA-4) protein, an inhibitory receptor which is
constitutively expressed by regulatory T-cells and activated T-cells. The
CTLA-4 protein functions as a critical checkpoint in suppressing excessive T-cell
proliferation. Kuehn et al. (2014) described a syndrome of immune dysregulation
caused by loss of CTLA-4 expression. This is characterized by autoimmune
cytopenias, hypogammaglobulinemia, CD4 T-cell lymphopenia, and lymphocytic
infiltrations of non-lymphoid organs in patients with heterozygous CTLA4 mutations (Kuehn et al. 2014).
Schubert et al. (2014) identified CTLA4
mutations in six additional families with hypogammaglobulinemia, recurrent
infections, and autoimmune features. The inheritance pattern of immune
dysregulation caused by CTLA4
mutations is autosomal dominant and penetrance may be incomplete (Kuehn et al.
Confirmation of diagnosis in a patient with the following:
autoimmune cytopenias, hypogammaglobulinemia, and B-cell abnormalities (with
accumulation of CD21 B-cells), with or without recurrent infections
member with a previously identified CTLA4
Testing is performed by Sanger sequencing of the entire coding regions and intron/exon boundaries of the CTLA4 gene.
In a cohort of 23 patients with autoimmune
hypogammaglobulinemia, CD4 T cell
lymphopenia, and lymphocytic infiltration of nonlymphoid organs, Kuehn et al. (2014)
identified a CTLA4 mutation in four
patients, providing a clinical sensitivity of approximately 17%.
The sensitivity of DNA sequencing is over 99%
for the detection of nucleotide base changes, small deletions and insertions in
the regions analyzed.
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
S.R. Brant, et al. (2010) "CTLA4 -1661A/G and 3’UTR Long Repeat
Polymorphisms Are Associated with Ulcerative Colitis and Influence CTLA4 mRNA
and Protein Expression." Genes and Immunity 11(7): 573–83.
W. Ouyang, et al. (2014) "Immune Dysregulation in Human Subjects with
Heterozygous Germline Mutations in CTLA4." Science (New York, N.Y.)
L. Karabon, et al. (2010) "Influence of CTLA-4/CD28/ICOS Gene
Polymorphisms on the Susceptibility to Cervical Squamous Cell Carcinoma and
Stage of Differentiation in the Polish Population." Human Immunology
D., C. Bode, et al. (2014) "Autosomal Dominant Immune Dysregulation
Syndrome in Humans with CTLA4 Mutations." Nature Medicine 20(12): 1410–6.
T., Y. Hidaka, et al. (1995) "CTLA-4 Gene Polymorphism Associated with
Graves’ Disease in a Caucasian Population." The Journal of Clinical
Endocrinology and Metabolism 80(1): 41–5.
Zhernakova, A., P. Eerligh, et al. (2005)
"CTLA4 Is Differentially Associated with Autoimmune Diseases in the Dutch
Population." Human Genetics 118(1): 58-66.