Mutation of Jak3 in a Patient with SCID: Essential Role of Jak3 in Lymphoid Development (original) (raw)

Published November 3, 1995 | Version v1

Journal article Open

Creators

• Russell, S. M.
• Tayebi, N.
• Nakajima, H.
• Riedy, M. C.
• Roberts, J. L.
• Aman, M. J.
• Migone, T.-S.
• Noguchi, M.
• Markert, M. L.
• Buckley, R. H.
• O'Shea, J. J.
• Leonard, W. J.

Description

Males with X-linked severe combined immunodeficiency (XSCID) have defects in the common cytokine receptor γ chain (γc) 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 γc, 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 γc 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 signaling, 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 γc are dependent on Jak3 and that Jak3 is essential for lymphoid development and signaling.

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