Novel Pathogenic Variant in IL2RG Affecting the Signal Peptide Results in mRNA Instability, Decreased IL2RG Expression, and Atypical Late-Onset Immunodeficiency

X-linked severe combined immunodeficiency (SCID-X1) presents as T-B+NK- SCID, due to mutations in the common γ chain (IL2RG/CD132), a shared component of several cytokine receptors. Without definitive therapy, SCID-X1 is fatal within two years due to severe recurrent infections. Atypical SCID-X1 can arise from hypomorphic variants that preserve partial immunity and delay diagnosis, sometimes into adulthood. IL2RG is produced as a precursor with a 22-amino acid cleavable N-terminal signal peptide (SP), recognized by the signal recognition particle (SRP) during translation initiation. SRP engagement is essential for mRNA stability; when the SP fails to bind SRP efficiently, the corresponding mRNA is degraded through the regulation of aberrant protein production (RAPP) pathway. Because the SP is critical for proper protein expression, variants in this region have been linked to human disease. To date, however, none have been reported in association with SCID. We studied a patient with a novel 25 bp deletion in exon 1 of the IL2RG (c.26_50del; p.Ser10Cysfs*6). Although this frameshift would be expected to generate a null allele and typical SCID-X1, he instead presented at age 17 with severe T cell lymphopenia (110 cells/uL), arthritis, disseminated zoster, and at age 22 developed progressive multifocal leukoencephalopathy due to the JC virus. We found that this mutation produces an IL2RG mRNA that enables in-frame translation from an upstream translation initiation site, generating a protein nearly identical to the wild-type except for the N-terminal 17 amino acids of the SP. Patient cells showed markedly reduced and variable expression of functional wild-type IL2RG, and proportionally defective cytokine response. The altered SP exhibited reduced hydrophobicity and an extremely low Bowman index, predicting impaired SP–SRP interaction and suggesting RAPP-mediated mRNA degradation as the cause of diminished and fluctuating protein levels. Assessment of mRNA turnover in patient versus healthy control EBV-transformed cells confirmed preferential degradation of the patient’s IL2RG mRNA. We thus believe inefficient SP-SRP binding triggered IL2RG mRNA degradation, in turn causing low, variable IL2RG expression and atypical XSCID-X1. These findings identify a novel SP-region mutation that disrupts mRNA stability and causes SCID-X1, underscoring the pathogenic impact of SP mutations in immunodeficiencies. Figure 1. Schematic representation of the mechanism of disease pathogenesis in the patient is shown. Normally, the signal recognition particle (SRP) recognizes the signal peptide upon exiting from the ribosome exit tunnel, which halts translation of the protein until the ribosome–nascent chain complex (RNC) is translocated to the ER membrane. At the ER membrane, SRP binds to the SRP-receptor, and the RNC complex is transferred to the translocon, resuming translation. The translated protein is processed (signal peptide cleavage, protein folding, and post-translational modifications), and the protein is transported to the plasma membrane via the Golgi apparatus. In the patient, the mutation in the signal peptide results in inefficient SRP recognition during translation. SRP recognition protects the mRNA, and failure of signal peptide recognition by SRP triggers regulation of aberrant protein production (RAPP)-mediated mRNA degradation, resulting in reduced and variable IL2RG protein expression in the patient.