IL2RG hypomorphic mutation: identification of a novel pathogenic mutation in exon 8 and a review of the literature

Abstract

Background: Atypical X-linked severe combined immunodeficiency (X-SCID) is a variant of cellular immunodeficiency due to hypomorphic mutations in the interleukin 2 receptor gamma (IL2RG) gene. Due to a leaky clinical phenotype, diagnosis and appropriate treatment are challenging in these patients.

Case presentation: We report a 16-year-old patient with a T^low B⁺ NK⁺ cellular immunodeficiency due to a novel nonsense mutation in exon 8 (p.R328X) of the IL2RG gene. Functional impairment of the IL2RG was confirmed by IL2-Janus kinase 3-signal transducer and activator of transcription signaling pathway investigation. In addition, the characteristics of the mutations previously described in 39 patients with an atypical phenotype were reviewed and analyzed from the literature.

Conclusion: This is the first report of an atypical X-SCID phenotype due to an exon 8 mutation in the IL2RG gene. The variability in the phenotypic spectrum of classic X-SCID associated gene highlights the necessity of multi-disciplinary cooperation vigilance for a more accurate diagnostic workup.

Keywords: Atypical severe combined immunodeficiency; Hypomorphic mutations; Interleukin 2 receptor gamma.

Fig. 1

a Family pedigree of the patient(s). b Sanger sequencing

Fig. 2

Schematic representation of the IL-2 receptor with a 42 amino-acids deletion of the intracellular domain of the γC shown in red

Fig. 3

JAK3-STAT5 signaling pathway in patients with atypical X-SCID. Expression of activated JAK3 and STAT5, as well as total JAK3, JAK3* (reprobe with anti-JAK3 antibody binding to the kinase domain), STAT5, IL2R and GAPDH in unstimulated or IL2 stimulated cells, were evaluated by Western blot

Fig. 4

IL2RG gene location of pathogenic hypomorphic mutations [27, 28] in 39 reported atypical X-SCID patients [, , , , , , , , , –36] (S: Signaling sequence; C: Conserved cysteine residues, W: WSXWS box; B: box1/box2 domain)