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

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 au...

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Bibliographic Details
Published in:The Journal of clinical investigation 2011-02, Vol.121 (2), p.695
Main Authors: Morgan, Neil V, Goddard, Sarah, Cardno, Tony S, McDonald, David, Rahman, Fatimah, Barge, Dawn, Ciupek, Andrew, Straatman-Iwanowska, Anna, Pasha, Shanaz, Guckian, Mary, Anderson, Graham, Huissoon, Aarnoud, Cant, Andrew, Tate, Warren P, Hambleton, Sophie, Maher, Eamonn R
Format: Article
Language:English
Subjects:
Autoimmunity
Disease susceptibility
Genetic aspects
Properties
Risk factors
T cells
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Summary: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 themRNA, 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.sup.+] T cells in the affected individuals was associated with immune dysregulation and autoimmunity, they had a surprising level of protection against infection.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI41931