A G to A transition at the last nucleotide of exon 6 of the γc 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 (γc) in X-linked severe combined immunodeficiency (XSCID) previously known as 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 γc. On analysis by the reverse transcription-polymerase chain reaction (RT-PCR), a single but small γc mRNA species was detected. Exon 6, which encodes the transmembrane domain of γc, was skipped in the mRNA. A G to A mutation was found at the last nucleotide of exon 6 of the γc gene (868G→A). The predicted consequence of the exon skipping is a frameshift resulting in a premature stop codon, and the mutated γc presumably loses association with the cell membrane. In XSCID, this mutation (868G→A) is known as a missense mutation that results in Q285A. Previously reported patients with the same mutation apparently had no aberrant or alternative splicing but did have the Q285A exchange. Similar mutations at the last nucleotide of an outskipped exon have been reported. However, such mutations do not always cause exon skipping. Analyses of RNA structural changes induced by the mutations supported the variability of consequences of the mutations. Taken together, our findings suggest that the 868G→A mutation of the γc gene may affect γc transcripts differently, i.e., generating missense or exon skipping, in XSCID patients with the same mutation. Patient-specific variation in splicing thus appears to occur. [ABSTRACT FROM AUTHOR]