Efficient detection of thirty-seven new IL2RG mutations in human X-linked severe combined immunodeficiency

X-linked severe combined immunodeficiency (XSCID) is a rare and potentially fatal disease caused by mutations of IL2RG, the gene encoding the interleu kin-2 receptor gamma chain, a component of multiple cytokine receptors that are essential for lymphocyte development and function. To date, over 100 d ifferent mutations of IL2RG resulting in XSCID have been published. Using n onradioactive, direct DNA sequencing of a single PCR amplicon containing th e whole IL2RG gene, we found IL2RG mutations in 78 previously unpublished u nrelated cases of XSCID, We report 37 newly identified mutations of IL2RG, including 23 point mutations, 10 small deletions, 3 instances of the same s ingle nucleotide insertion, 1 large deletion, and 2 complex mutations. More than half of the mutations (22 of 37) were predicted to result in unstable IL2RG mRNA. The remaining 14 mutations disrupted conserved functional moti fs common to all cytokine receptor family members; changed protein conforma tion, charge, or hydrophobicity; or altered the intracellular portion of th e protein, which is critical for proper interaction with signal-transducing molecules including Janus family tyrosine kinase 3.