Unexpected and variable phenotypes in a family with JAK3 deficiency

Details

Serval ID
serval:BIB_33661FADA28D
Type
Article: article from journal or magazin.
Collection
Publications
Title
Unexpected and variable phenotypes in a family with JAK3 deficiency
Journal
Genes Immun
Author(s)
Frucht D. M., Gadina M., Jagadeesh G. J., Aksentijevich I., Takada K., Bleesing J. J., Nelson J., Muul L. M., Perham G., Morgan G., Gerritsen E. J., Schumacher R. F., Mella P., Veys P. A., Fleisher T. A., Kaminski E. R., Notarangelo L. D., O'Shea J. J., Candotti F.
ISSN
1466-4879 (Print)
ISSN-L
1466-4879
Publication state
Published
Issued date
12/2001
Volume
2
Number
8
Pages
422-32
Language
english
Notes
Frucht, D M
Gadina, M
Jagadeesh, G J
Aksentijevich, I
Takada, K
Bleesing, J J
Nelson, J
Muul, L M
Perham, G
Morgan, G
Gerritsen, E J
Schumacher, R F
Mella, P
Veys, P A
Fleisher, T A
Kaminski, E R
Notarangelo, L D
O'Shea, J J
Candotti, F
eng
England
Genes Immun. 2001 Dec;2(8):422-32.
Abstract
Mutations of the Janus kinase 3 (JAK3) have been previously described to cause an autosomal recessive variant of severe combined immunodeficiency (SCID) usually characterized by the near absence of T and NK cells, but preserved numbers of B lymphocytes (T-B+SCID). We now report a family whose JAK3 mutations are associated with the persistence of circulating T cells, resulting in previously undescribed clinical presentations, ranging from a nearly unaffected 18-year-old subject to an 8-year-old sibling with a severe lymphoproliferative disorder. Both siblings were found to be compound heterozygotes for the same deleterious JAK3 mutations: an A96G initiation start site mutation, resulting in a dysfunctional, truncated protein product and a G2775(+3)C mutation in the splice donor site sequence of intron 18, resulting in a splicing defect and a predicted premature stop. These mutations were compatible with minimal amounts of functional JAK3 expression, leading to defective cytokine-dependent signaling. Activated T cells in these patients failed to express Fas ligand (FasL) in response to IL-2, which may explain the accumulation of T cells with an activated phenotype and a skewed T cell receptor (TcR) Vbeta family distribution. We speculate that residual JAK3 activity accounted for the maturation of thymocytes, but was insufficient to sustain IL-2-mediated homeostasis of peripheral T cells via Fas/FasL interactions. These data demonstrate that the clinical spectrum of JAK3 deficiency is quite broad and includes immunodeficient patients with accumulation of activated T cells, and indicate an essential role for JAK3 in the homeostasis of peripheral T cells in humans.
Keywords
Adolescent, Amino Acid Sequence, B-Lymphocytes/metabolism, Cell Line, Transformed, Child, DNA, Complementary, Fas Ligand Protein, Female, Gene Expression, Humans, Immunophenotyping, Interleukin-2/metabolism, Janus Kinase 3, Male, Membrane Glycoproteins/metabolism, Molecular Sequence Data, Mutation, Pedigree, Protein-Tyrosine Kinases/*deficiency/genetics, Receptors, Antigen, T-Cell, alpha-beta/metabolism, Receptors, Interleukin-2/metabolism, Sequence Analysis, DNA, Severe Combined Immunodeficiency/genetics/immunology/pathology, Signal Transduction, T-Lymphocytes, Up-Regulation
Pubmed
Open Access
Yes
Create date
01/11/2017 10:29
Last modification date
20/08/2019 13:19
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