Mutation in the TCRα subunit constant gene (TRAC) leads to a human immunodeficiency disorder characterized by a lack of TCRαβ+ T cells
Neil V. Morgan, … , Sophie Hambleton, Eamonn R. Maher
Neil V. Morgan, … , Sophie Hambleton, Eamonn R. Maher
Published January 4, 2011
Citation Information: J Clin Invest. 2011;121(2):695-702. https://doi.org/10.1172/JCI41931.
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Research Article Immunology

Mutation in the TCRα subunit constant gene (TRAC) leads to a human immunodeficiency disorder characterized by a lack of TCRαβ+ T cells

Abstract

Inherited immunodeficiency disorders can be caused by mutations in any one of a large number of genes involved in the function of immune cells. Here, we describe two families with an autosomal recessive inherited immunodeficiency disorder characterized by increased susceptibility to infection and autoimmunity. Genetic linkage studies mapped the disorder to chromosomal region 14q11.2, and a homozygous guanine-to-adenine substitution was identified at the last base of exon 3 immediately following the translational termination codon in the TCRα subunit constant gene (TRAC). RT-PCR analysis in the two affected individuals revealed impaired splicing of the mRNA, as exon 3 was lost from the TRAC transcript. The mutant TCRα chain protein was predicted to lack part of the connecting peptide domain and all of the transmembrane and cytoplasmic domains, which have a critical role in the regulation of the assembly and/or intracellular transport of TCR complexes. We found that T cells from affected individuals were profoundly impaired for surface expression of the TCRαβ complex. We believe this to be the first report of a disease-causing human TRAC mutation. Although the absence of TCRαβ+ T cells in the affected individuals was associated with immune dysregulation and autoimmunity, they had a surprising level of protection against infection.

Authors

Neil V. Morgan, Sarah Goddard, Tony S. Cardno, David McDonald, Fatimah Rahman, Dawn Barge, Andrew Ciupek, Anna Straatman-Iwanowska, Shanaz Pasha, Mary Guckian, Graham Anderson, Aarnoud Huissoon, Andrew Cant, Warren P. Tate, Sophie Hambleton, Eamonn R. Maher

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Figure 2

Candidate region of linkage at chromosome 14q11.2.

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Candidate region of linkage at chromosome 14q11.2. (A) Affymetrix 250K S...
(A) Affymetrix 250K SNP arrays in affected individuals with the immunodeficiency disorder (F1;II:3, F2;II:2) identified a common region of autozygosity (between SNPs rs7159964 [21,443,181 bp] and rs3759611 [22,906,052 bp]). Homozygous AA and BB SNPs are shown in dark blue and light blue, respectively; heterozygous AB SNPs are shown in white; and homozygous regions are boxed. (B) Family pedigrees and haplotypes for microsatellite markers from chromosome 14q in two families. Boxed regions indicate homozygous disease alleles. The minimal candidate interval that encompasses the disease locus is the region between markers D14S742 and D14S1280.