|
|
 Previous Article | Table of Contents | Next Article 
Structural and Functional Basis for JAK3-Deficient Severe Combined Immunodeficiency
Fabio Candotti,
Scott A. Oakes,
James A. Johnston,
Silvia Giliani,
Richard F. Schumacher,
Patrizia Mella,
Maurilia Fiorini,
Alberto G. Ugazio,
Raffaele Badolato,
Luigi D. Notarangelo,
Fabio Bozzi,
Paolo Macchi,
Dario Strina,
Paolo Vezzoni,
R. Michael Blaese,
John J. O'Shea, and
Anna Villa
From the Clinical Gene Therapy Branch, National Center for Human Genome Research; the Leukocyte Cell Biology Section, National Institute of Arthritis and Musculoskeletal and Skin Disease, National Institutes of Health, Bethesda, MD; the Department of Pediatrics, University of Brescia, Brescia, Italy; and the Istituto di Tecnologie Biomediche Avanzate, CNR, Milan, Italy.
Mutations of the Janus family kinase JAK3 have been found to be responsible for autosomal recessive severe combined immunodeficiency (SCID) in humans. We report here the analysis of four new unrelated patients affected by JAK3-deficient SCID. The genetic defects were heterogeneous and included a large intragenic deletion as well as different point mutations, leading to missense substitutions, early stop codons, or splicing defects. We performed a series of studies of the biochemical events induced by cytokines on lymphoblastoid B-cell lines obtained from these patients. Abnormalities in tyrosine phosphorylation of JAK3 in response to interleukin-2 (IL-2) and IL-4 were present in all patients. Accordingly, IL-2-mediated phosphorylation of STAT5 was also absent or barely detectable. On the contrary, in all cases, we could show reduced but clear phosphorylation of STAT6 upon IL-4 stimulation. In one patient carrying a single amino acid change (Glu481Gly) in the JH3 domain of JAK3, we observed partially conserved IL-2 responses resulting in reduced but detectable levels of JAK3 and STAT5 phosphorylation. Interestingly, the patient bearing this mutation developed a substantial number of circulating CD4+/CD45RO+ activated T lymphocytes that were functionally impaired. In two cases, patients' cells expressed JAK3 proteins with mutations in the JH2 pseudo-kinase domain. A single cysteine to arginine substitution (Cys759Arg) in this region resulted in high basal levels of constitutive JAK3 tyrosine phosphorylation unresponsive to either downregulation by serum starvation or cytokine-mediated upregulation. The characterization of the genetic defects and biochemical abnormalities in these JAK3-deficient patients will help define the role of JAK3 in the ontogeny of a competent immune system and may lead to a better understanding of the JAK3 functional domains.
Blood, Vol. 90 No. 10 (November 15), 1997:
pp. 3996-4003
© 1997 by The American Society of Hematology.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
J J O'Shea
Targeting the Jak/STAT pathway for immunosuppression
Ann Rheum Dis,
November 1, 2004;
63(suppl_2):
ii67 - ii71.
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Behrmann, T. Smyczek, P. C. Heinrich, H. Schmitz-Van de Leur, W. Komyod, B. Giese, G. Muller-Newen, S. Haan, and C. Haan
Janus Kinase (Jak) Subcellular Localization Revisited: THE EXCLUSIVE MEMBRANE LOCALIZATION OF ENDOGENOUS JANUS KINASE 1 BY CYTOKINE RECEPTOR INTERACTION UNCOVERS THE Jak{middle dot}RECEPTOR COMPLEX TO BE EQUIVALENT TO A RECEPTOR TYROSINE KINASE
J. Biol. Chem.,
August 20, 2004;
279(34):
35486 - 35493.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Wagner, A. Ansorge, U. Wirkner, V. Eckstein, C. Schwager, J. Blake, K. Miesala, J. Selig, R. Saffrich, W. Ansorge, et al.
Molecular evidence for stem cell function of the slow-dividing fraction among human hematopoietic progenitor cells by genome-wide analysis
Blood,
August 1, 2004;
104(3):
675 - 686.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. R. Hofmann, A. Q. Lam, S. Frank, Y.-J. Zhou, H. L. Ramos, Y. Kanno, D. Agnello, R. J. Youle, and J. J. O'Shea
Jak3-Independent Trafficking of the Common {gamma} Chain Receptor Subunit: Chaperone Function of Jaks Revisited
Mol. Cell. Biol.,
June 1, 2004;
24(11):
5039 - 5049.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. K. Mangan, S. G. Rane, A. D. Kang, A. Amanullah, B. C. Wong, and E. P. Reddy
Mechanisms associated with IL-6-induced up-regulation of Jak3 and its role in monocytic differentiation
Blood,
June 1, 2004;
103(11):
4093 - 4101.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. S. Lim and K. S.J. Elenitoba-Johnson
The Molecular Pathology of Primary Immunodeficiencies
J. Mol. Diagn.,
May 1, 2004;
6(2):
59 - 83.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. L. Roberts, A. Lengi, S. M. Brown, M. Chen, Y.-J. Zhou, J. J. O'Shea, and R. H. Buckley
Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation
Blood,
March 15, 2004;
103(6):
2009 - 2018.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Saharinen, M. Vihinen, and O. Silvennoinen
Autoinhibition of Jak2 Tyrosine Kinase Is Dependent on Specific Regions in Its Pseudokinase Domain
Mol. Biol. Cell,
April 1, 2003;
14(4):
1448 - 1459.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Saharinen and O. Silvennoinen
The Pseudokinase Domain Is Required for Suppression of Basal Activity of Jak2 and Jak3 Tyrosine Kinases and for Cytokine-inducible Activation of Signal Transduction
J. Biol. Chem.,
November 27, 2002;
277(49):
47954 - 47963.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H B Gaspar, K C Gilmour, and A M Jones
Current topic: Severe combined immunodeficiency{---}molecular pathogenesis and diagnosis
Arch. Dis. Child.,
February 1, 2001;
84(2):
169 - 173.
[Full Text]
|
|
|
|
|
|
|
U. Mei{beta}ner, H. Blum, M. Schnare, M. Rollinghoff, and A. Gessner
A soluble form of the murine common {gamma} chain is present at high concentrations in vivo and suppresses cytokine signaling
Blood,
January 1, 2001;
97(1):
183 - 191.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. J O'Shea, R. Visconti, T. P Cheng, and M. Gadina
Jaks and Stats as therapeutic targets
Ann Rheum Dis,
November 1, 2000;
59(90001):
i115 - 118.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. C. Yeh, E. Dondi, G. Uzé, and S. Pellegrini
A dual role for the kinase-like domain of the tyrosine kinase Tyk2 in interferon-alpha signaling
PNAS,
July 19, 2000;
(2000)
160130297.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
P. Saharinen, K. Takaluoma, and O. Silvennoinen
Regulation of the Jak2 Tyrosine Kinase by Its Pseudokinase Domain
Mol. Cell. Biol.,
May 15, 2000;
20(10):
3387 - 3395.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
M. Chen, A. Cheng, F. Candotti, Y.-J. Zhou, A. Hymel, A. Fasth, L. D. Notarangelo, and J. J. O'Shea
Complex Effects of Naturally Occurring Mutations in the JAK3 Pseudokinase Domain: Evidence for Interactions between the Kinase and Pseudokinase Domains
Mol. Cell. Biol.,
February 1, 2000;
20(3):
947 - 956.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
Y. Y. Wu and R. A. Bradshaw
Activation of the Stat3 Signaling Pathway Is Required for Differentiation by Interleukin-6 in PC12-E2 Cells
J. Biol. Chem.,
January 21, 2000;
275(3):
2147 - 2156.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. D. Bunting, K. J. Flynn, J. M. Riberdy, P. C. Doherty, and B. P. Sorrentino
Virus-specific immunity after gene therapy in a murine model of severe combined immunodeficiency
PNAS,
January 5, 1999;
96(1):
232 - 237.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Brugnoni, L. D. Notarangelo, A. Sottini, P. Airo, M. Pennacchio, E. Mazzolari, S. Signorini, F. Candotti, A. Villa, P. Mella, et al.
Development of Autologous, Oligoclonal, Poorly Functioning T Lymphocytes in a Patient With Autosomal Recessive Severe Combined Immunodeficiency Caused by Defects of the Jak3 Tyrosine Kinase
Blood,
February 1, 1998;
91(3):
949 - 955.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. C. Yeh, E. Dondi, G. Uze, and S. Pellegrini
A dual role for the kinase-like domain of the tyrosine kinase Tyk2 in interferon-alpha signaling
PNAS,
August 1, 2000;
97(16):
8991 - 8996.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
