A Deletion in the Gene Encoding the CD45 Antigen in a Patient with SCID

Abstract

SCID is a heterogeneous group of hereditary diseases. Mutations in the common γ-chain (γc) 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.

Regulation of Src Family Kinases Involved in T Cell Receptor Signaling by Protein-tyrosine Phosphatase CD148

“…Three published cases of CD45-deficient patients revealed an indispensable role of CD45 in the development of mature peripheral T cells also in humans (41)(42)(43). Here we clearly show that although murine thymocytes lose CD148 expression at early stages, human thymocytes gain CD148 positivity at the terminal phase.…”

“…On the other hand, CD148 has been reported to act as a negative regulator of signal transduction in many non-hematopoietic biological systems as well as in TCR signaling in human T cell line Jurkat (29 -31). Moreover, endogenous CD148 is obviously unable to rescue T cell development in CD45-deficient mice and humans (41)(42)(43)(44). To bring more clarity to these somewhat contradictory functions, we carried out a more thorough analysis of CD148 expression during T cell development in mice and humans and also tested the ability of CD148 to positively regulate SFKs involved in TCR signal transduction.…”

The Exon A (C77G) Mutation Is a Common Cause of Abnormal CD45 Splicing in Humans

“…The phosphatase activity of CD45 Ag is crucial for efficient lymphocyte Ag receptor signal transduction as has been shown in CD45-deficient mice (3,4) and in humans lacking CD45 expression (5,6). CD45 knockout mice are severely immunodeficient, with very few T cells but normal B cell numbers, and have a very similar phenotype to the two recently described patients.…”

“…Both patients presented at 2 mo of age and had SCID. The infants showed low T cells numbers, were unresponsive to mitogen stimulation, and although B cell numbers were normal, Ig production was impaired with low concentrations of IgM and IgA (5,6). Three different genetic abnormalities in the gene encoding CD45 were shown to be associated with the lack of CD45 expression in the cells of patients and the immune deficiency, providing the first direct evidence for the crucial role of CD45 in immune function in humans.…”

Unusual case presentations associated with the CD45 C77G polymorphism

“…Furthermore, C77G individuals show lymphocyte functional abnormalities, including increased IL-2 production by memory CD4 T cells and an altered threshold for signalling through the T-cell receptor [21,22]. Another polymorphism of CD45, A138G in exon 6, is also associated with altered disease susceptibility and immune function [23,24], and absence of CD45 is also a cause of severe combined immunodeficiency [25][26][27] There is therefore abundant evidence that altered CD45 expression affects the immune function in man, as in experimental animals [28].…”