A G to A transition at the last nucleotide of exon 6 of the gamma c gene (868G -> A) may result in either a splice or missense mutation in patients with X-linked severe combined immunodeficiency

We report here that a defect of the interleukin common gamma subunit (gamma c) in X-linked severe combined immunodeficiency (XSCID) previously known a s a missense mutation resulted instead in exon skipping in a Japanese XSCID patient. The phenotype of the patient was consistent with that of typical XSCID, and his Epstein-Barr virus-transformed B cells accordingly entirely lacked surface expression of gamma c. On analysis by the reverse transcript ion-polymerase chain reaction (RT-PCR), a single but small gamma c mRNA spe cies was detected. Exon 6, which encodes the transmembrane domain of gamma c, was skipped in the mRNA. A G to A mutation was found at the last nucleot ide of exon 6 of the gamma c gene (868G-->A). The predicted consequence of the exon skipping is a frameshift resulting in a premature stop codon, and the mutated gamma c presumably loses association with the cell membrane. In XSCID this mutation (868G-->A) is known as a missense mutation that result s in Q285A. Previously reported patients with the same mutation apparently had no aberrant or alternative splicing but did have the Q285A exchange. Si milar mutations at the last nucleotide of an outskipped exon have been repo rted, However, such mutations do not always cause exon skipping. Analyses o f RNA structural changes induced by the mutations supported the variability of consequences of the mutations. Taken together, our findings suggest tha t the 868G-->A mutation of the gamma c' gene may affect gamma c transcripts differently, i.e., generating missense or exon skipping, in XSCID patients with the same mutation. Patient-specific variation in splicing thus appear s to occur.