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*
The Edward Jenner Institute for Vaccine Research, Compton, United Kingdom;
Imperial Cancer Research Fund Cancer and Immunogenetics Laboratory, Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, United Kingdom; and
Medical Research Council Laboratories, Fajara, The Gambia
SCID is a heterogeneous group of hereditary diseases. Mutations in
the common 
-chain (c) of cytokine receptors,
including those for IL-2, IL-4, IL-7, IL-9, and IL-15, are responsible
for an X-linked form of the disease, while mutations of several other
genes, including Janus-associated kinase-3, may cause autosomal
recessive forms of SCID. We investigated the first SCID patient to be
described with minimal cell surface expression of the leukocyte common
(CD45) Ag. CD45 is an abundant transmembrane tyrosine phosphatase,
expressed on all leukocytes, and is required for efficient lymphocyte
signaling. CD45-deficient mice are severely immunodeficient and have
very few peripheral T lymphocytes. We report here that a homozygous
6-bp deletion in the gene encoding CD45 (PTPRC, gene map locus
1q31–32), which results in a loss of glutamic acid 339 and tyrosine
340 in the first fibronectin type III module of the extracellular
domain of CD45, is associated with failure of surface expression of
CD45 and SCID. Molecular modeling suggests that tyrosine 340 is crucial
for the structural integrity of CD45 protein. This is the second
description of a clinically relevant CD45 mutation, provides direct
evidence for the importance of CD45 in immune function in humans, and
suggests that abnormalities in CD45 expression are a possible cause of
SCID in humans.
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