Publication Date:
1995-11-03
Description:
Males with X-linked severe combined immunodeficiency (XSCID) have defects in the common cytokine receptor gamma chain (gamma c) gene that encodes a shared, essential component of the receptors of 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 gamma 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 gamma 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 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 gamma c are dependent on Jak3 and that Jak3 is essential for lymphoid development and signaling.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- M01-RR30/RR/NCRR NIH HHS/ -- R37AI18613-13/AI/NIAID NIH HHS/ -- T32 CA09058/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 1995 Nov 3;270(5237):797-800.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/7481768" target="_blank"〉PubMed〈/a〉
Keywords:
Amino Acid Sequence
;
Animals
;
B-Lymphocytes/*immunology
;
Base Sequence
;
Cell Line, Transformed
;
Female
;
Frameshift Mutation
;
Genetic Linkage
;
Humans
;
Infant
;
Interleukin-4/pharmacology
;
Janus Kinase 3
;
Molecular Sequence Data
;
Phenotype
;
Point Mutation
;
Protein-Tyrosine Kinases/deficiency/genetics/*physiology
;
RNA, Messenger/genetics/metabolism
;
Receptors, Interleukin/physiology
;
STAT6 Transcription Factor
;
Severe Combined Immunodeficiency/*enzymology/genetics/immunology
;
Signal Transduction
;
T-Lymphocytes/*immunology
;
Trans-Activators/metabolism
;
X Chromosome
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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