A point mutation within CD45 exon A is the cause of variant CD45RA splicing in humans

Zilch, Christian F.; Walker, A. M.; Timón, Marcos; Goff, Lindsey K.; Wallace, Diana L.; Beverley, P. C. L.

doi:10.1002/(sici)1521-4141(199801)28:01<22::aid-immu22>3.0.co;2-7

Cited by 38 publications

(24 citation statements)

References 15 publications

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“…CD45 isoforms, in contrast to the normal pattern of low m.w. isoform expression (22). While these individuals are apparently normal, no homozygotes have yet been identified.…”

Section: Discussionmentioning

confidence: 96%

“…The expression of different CD45 isoforms depends on the state of activation and differentiation of hemopoietic cells, and in humans has been used to distinguish naive and memory T lymphocytes (17)(18)(19)(20)(21). Variations in CD45 isoform expression exist as normal variants (22), but can also be associated with some human disorders of immune activation (23)(24)(25). However, the mechanisms linking the expression of different CD45 isoforms to T cell function and the regulation of CD45 activity remain unclear.…”

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confidence: 99%

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

Tchilian

Wallace

Wells

et al. 2001

The Journal of Immunology

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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.

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“…CD45 isoforms, in contrast to the normal pattern of low m.w. isoform expression (22). While these individuals are apparently normal, no homozygotes have yet been identified.…”

Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

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

Tchilian

Wallace

Wells

et al. 2001

The Journal of Immunology

Self Cite

160

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“…The molecular basis for the aberrant expression of CD45RA is a point mutation at position 77 in exon A (77C3 G) (8,9). The mutation does not change the encoded amino acids but disrupts an exon-splicing silencer that normally represses the use of the 5Ј splice site of exon A (10).…”

Section: The 77c3 G Mutation In the Human Cd45 (Ptprc) Gene Leads To mentioning

confidence: 99%

The 77C→G Mutation in the Human CD45 (PTPRC) Gene Leads to Increased Intensity of TCR Signaling in T Cell Lines from Healthy Individuals and Patients with Multiple Sclerosis

Do¹,

Baars²,

Borns³

et al. 2006

The Journal of Immunology

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The 77C→G mutation in exon A of the human CD45 gene occurs with low frequency in healthy individuals. An enhanced frequency of 77C→G individuals has been reported in cohorts of patients suffering from multiple sclerosis, systemic sclerosis, autoimmune hepatitis, and HIV-1. To investigate the mechanisms by which the variant allele may contribute to disease susceptibility, we compared T cell reactivity in heterozygous carriers of the mutation (healthy individuals and multiple sclerosis patients) and wild-type controls. In vitro-generated T cell lines and freshly isolated CD4+CD45R0+ primed/memory T cells from 77C→G individuals aberrantly expressed CD45RA isoforms and showed enhanced proliferation and IL-2 production when stimulated with anti-TCR/CD3 mAb or Ag. Mutant T cell lines contained a more active pool of p56lck tyrosine kinase and responded with increased phosphorylation of Zap70 and TCR-ζ and an enhanced Ca2+ flux to TCR/CD3 stimulation. These data suggest that 77C→G may act as a risk factor for certain diseases by increasing the intensity of TCR signaling.

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“…Subject 1 was unusual, in that he was found to be heterozygous for the CD45 C77G allelic variant known to cause altered splicing of CD45 [16]. This mutation, found in approximately 1:60 of the UK population, results in an inability to generate low molecular weight isoforms of the CD45 molecule encoded by that allele [17].…”

Section: Lymphocyte Phenotypementioning

confidence: 99%

Rapid turnover of T cells in acute infectious mononucleosis

et al. 2003

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During acute infectious mononucleosis (AIM), large clones of Epstein-Barr virus-specific T lymphocytes are produced. To investigate the dynamics of clonal expansion, we measured cell proliferation during AIM using deuterated glucose to label DNA of dividing cells in vivo, analyzing cells according to CD4, CD8 and CD45 phenotype. The proportion of labeled CD8 + CD45R0 + T lymphocytes was dramatically increased in AIM subjects compared to controls (mean 17.5 versus 2.8%/day; p X 0.005), indicating very rapid proliferation. Labeling was also increased in CD4 + CD45R0+ cells (7.1 versus 2.1%/day; p X 0.01), but less so in CD45RA + cells. Mathematical modeling, accounting for death of labeled cells and changing pool sizes, gave estimated proliferation rates in CD8 + CD45R0 + cells of 11-130% of cells proliferating per day (mean 47%/day), equivalent to a doubling time of 1.5 days and an appearance rate in blood of about 5×10 9 cells/day (versus 7×10 7 cells/day in controls). Very rapid death rates were also observed amongst labeled cells (range 28-124, mean 57%/day), indicating very short survival times in the circulation. Thus, we have shown direct evidence for massive proliferation of CD8 + CD45R0 + T lymphocytes in AIM and demonstrated that rapid cell division continues concurrently with greatly accelerated rates of cell disappearance.

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A point mutation within CD45 exon A is the cause of variant CD45RA splicing in humans

Cited by 38 publications

References 15 publications

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

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

The 77C→G Mutation in the Human CD45 (PTPRC) Gene Leads to Increased Intensity of TCR Signaling in T Cell Lines from Healthy Individuals and Patients with Multiple Sclerosis

Rapid turnover of T cells in acute infectious mononucleosis

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