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Monocyte function in a severe combined immunodeficient patient with a donor
splice site mutation in the Jak3 gene
A Villa, M Sironi, P Macchi, C Matteucci, LD Notarangelo, P Vezzoni and A Mantovani
Istituto di Tecnologie Biomediche Avanzate, Consiglio Nazionale delle
Ricerche, Milano, Italy.
Janus kinase-3 (Jak3) is a nonreceptor tyrosine kinase functionally coupled
to cytokine receptors which share a "common" gamma chain (gamma c).
Mutations in gamma c and Jak3 genes have been identified in X- linked and
autosomal severe combined immuno deficiency (SCID), respectively. Jak3 is
expressed and activated in myelomonocytic cells. The present study was
designed to define the structural alteration responsible for lack of Jak3
in a patient with autosomal SCID and to characterize monocyte function in
the absence of this signal transduction element, as well as to establish
the whole exon-intron structure. Polymerase chain reaction analysis,
performed with primers designed on exon sequences, identified 20 exons
spanning approximately 15 kb. These primers, or others designed on the
flanking sequences provided in the present report, can be used to amplify
the whole gene, allowing the definition of the molecular defects in all
cases, including prenatal diagnosis, in which transcript analysis is not
possible. On this basis, the deletion transcript found at the homozygous
state in patient CM, with both his consanguineous parents being
heterozygous for the deletion, was associated with mutation (T to C) of a
splice donor site of intron 16 that was also detected in his mother's DNA.
Monocytes from Jak3-SCID showed normal cytokine production in response to
interleukin-4 (IL-4) (release of IL-1 receptor antagonist) and IL-2
(release of tumor necrosis factor-alpha and IL-8).
Lipopolysaccharide-induced cytokine production was also normal and was
blocked by IL-4 in Jak3- SCID monocytes. Interferon- gamma induced
augmented expression of major histocompatibility class II in Jak3-SCID
monocytes. These data indicate that Jak3, expressed and activated in
myelomonocytic cells, is dispensable for monocyte differentiation and
responsiveness to cytokines that interact with gamma c receptors as well as
to other regulatory signals.
Volume 88,
Issue 3,
pp. 817-823,
08/01/1996
Copyright © 1996 by The American Society of Hematology
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