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
Institution
Title
Unexpected and variable phenotypes in a family with JAK3 deficiency
Journal
Genes Immun
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.
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 11:29
Last modification date
20/08/2019 14:19