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Lookup NU author(s): Professor Andrew Cant, Professor Sophie HambletonORCiD
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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 TCR alpha 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 TCR alpha 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 TCR alpha beta complex. We believe this to be the first report of a disease-causing human TRAC mutation. Although the absence of TCR alpha beta(+) T cells in the affected individuals was associated with immune dysregulation and autoimmunity, they had a surprising level of protection against infection.
Author(s): Morgan NV, Goddard S, Cardno TS, McDonald D, Rahman F, Barge D, Ciupek A, Straatman-Iwanowska A, Pasha S, Guckian M, Anderson G, Huissoon A, Cant A, Tate WP, Hambleton S, Maher ER
Publication type: Article
Publication status: Published
Journal: Journal of Clinical Investigation
Year: 2011
Volume: 121
Issue: 2
Pages: 695-702
Print publication date: 01/02/2011
ISSN (print): 0021-9738
ISSN (electronic): 1558-8238
Publisher: American Society for Clinical Investigation
URL: http://dx.doi.org/10.1172/JCI41931
DOI: 10.1172/JCI41931
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