Mutation of Jak3 in a Patient with SCID: Essential Role of Jak3 in Lymphoid Development

TLDR

Males with X‑linked severe combined immunodeficiency have mutations in the common γ‑chain receptor that is essential for IL‑2, IL‑4, IL‑7, IL‑9, and IL‑15 signaling. The authors hypothesized that loss‑of‑function mutations in Jak3, the sole kinase associated with the γ‑chain, could produce an X‑SCID‑like phenotype. They examined a girl with X‑SCID‑like immunologic features and found that her EBV‑transformed lymphocyte line expressed normal γ‑chain but lacked Jak3 protein and mRNA. Sequencing revealed compound heterozygous Jak3 mutations causing premature truncation, and the absence of Jak3 prevented IL‑4‑induced Stat6 activation, demonstrating that Jak3 is essential for γ‑chain‑dependent lymphoid development and signaling.

Abstract

Males with X-linked severe combined immunodeficiency (XSCID) have defects in the common cytokine receptor γ chain (γ c ) gene that encodes a shared, essential component of the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL-15. The Janus family tyrosine kinase Jak3 is the only signaling molecule known to be associated with γ c , so it was hypothesized that defects in Jak3 might cause an XSCID-like phenotype. A girl with immunological features indistinguishable from those of XSCID was therefore selected for analysis. An Epstein-Barr virus (EBV)-transformed cell line derived from her lymphocytes had normal γ c expression but lacked Jak3 protein and had greatly diminished Jak3 messenger RNA. Sequencing revealed a different mutation on each allele: a single nucleotide insertion resulting in a frame shift and premature termination in the Jak3 JH4 domain and a nonsense mutation in the Jak3 JH2 domain. The lack of Jak3 expression correlated with impaired B cell signacrcling, as demonstrated by the inability of IL-4 to activate Stat6 in the EBV-transformed cell line from the patient. These observations indicate that the functions of γ c are dependent on Jak3 and that Jak3 is essential for lymphoid development and signaling.