A novel splice-site mutation in the common gamma chain (gammac) gene IL2RG results in X-linked severe combined immunodeficiency with an atypical NK+ phenotype.

Mutations in the gene encoding the common gamma chain (gammac) of interleukin receptors 2, 4, 7, 9, 15 and 21 result in X-linked severe combined immunodeficiency (SCID-X1). Classically, this disease is characterised by an absence of T and NK cells, and near normal numbers of functionally deficient B cells (B(+), T(-), NK(-) phenotype). Atypical phenotypes have also been described, but relatively little is known about the mechanisms by which the underlying mutations impair gammac-dependent interleukin receptor signalling to produce these disease variants. Here we describe a novel splice-site mutation resulting in the presence of near normal numbers of functionally deficient NK cells (B(+), T(-), NK(+) phenotype), in a SCID-X1 infant who was subsequently treated by gene therapy. The mutation, c.468+3A>C affecting the third base of intron 3 in the IL2RG gene, was shown to result in the production of two aberrantly spliced gammac mRNA species and reduction of correctly spliced message to trace levels, consistent with failure to detect gammac on the surface of B and NK cells by FACS analysis. The infant's genotype-phenotype correlation supports the hypothesis that interleukin 15 receptor-mediated signalling is preferentially retained as the amount of cell surface gammac becomes limiting. The possible implications for immunological reconstitution following gene therapy are also discussed. Copyright 2004 Wiley-Liss, Inc.