Protein tyrosine phosphatase receptor-type C exon 4 gene mutation distribution in an Italian multiple sclerosis population

Ballerini, Clara; Rosati, Eleonora; Salvetti, Marco; Ristori, Giovanni; Cannoni, Stefania; Biagioli, Tiziana; Massacesi, Luca; Sorbi, Sandro; Vergelli, Marco

doi:10.1016/s0304-3940(02)00565-7

Cited by 35 publications

(25 citation statements)

References 11 publications

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“…Here we show a frequency of 0.5% individuals with C77G polymorphism among 199 healthy donors from Italy, which is in agreement with another study (16). However another more recent study found frequencies of 2.3 and 1.3% in Northern and Southern Italy respectively (40).…”

Section: Discussionsupporting

confidence: 93%

Abnormal Cell Surface Antigen Expression in Individuals with Variant CD45 Splicing and Histiocytosis

et al. 2004

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Hemophagocytic lymphohistiocytosis (HLH) and Langerhans cell histiocytosis (LCH) are members of a group of rare heterogenous disorders, the histiocytoses, characterized by uncontrolled accumulation of pleomorphic infiltrates of leukocytes. The etiology of these diseases is mainly unknown. CD45 is a hemopoietic cell specific tyrosine phosphatase essential for antigen receptor mediated signaling in lymphocytes and different patterns of CD45 splicing are associated with distinct functions. Recently a polymorphism (C77G) in exon 4 of CD45 causing abnormal CD45 splicing and a point mutation affecting CD45 dimerization were implicated in multiple sclerosis in humans and lymphoproliferation and autoimmunity in mice respectively. Here we show that two patients with HLH exhibited abnormal CD45 splicing caused by the C77G variant allele, while a further 21 HLH patients have normal CD45. We have also examined 62 LCH patients and found three to have the C77G mutation. Peripheral blood thymus-derived (T) CD8ϩ cells from normal individuals carrying the C77G mutation show a significant decrease in the proportion of cells expressing L-selectin and increased frequency of cells with LFA-1 hi expression. It remains to be established whether C77G is a contributing factor in these histiocytic disorders. The leukocyte common antigen CD45 is an abundant tyrosine phosphatase, essential for lymphocyte antigen receptor signal transduction (1). Both CD45 knockout mice (2, 3) and humans lacking CD45 expression (4, 5) are severely immunodeficient with very few peripheral T lymphocytes and impaired T and B cell responses.Multiple CD45 isoforms can be generated by alternative splicing of exons A, B, and C of the extracellular domain (6, 7). In humans naïve T cells express high molecular weight CD45 isoforms, recognized by CD45RA MAb ("CD45RA" cells), but activation of the cells results in a change to expression of low molecular weight isoforms, detected by a CD45R0 MAb ("CD45R0" or memory cells) (8). Paragraph deleted. Several polymorphisms of the gene encoding CD45 (PTPRC at 1q31-32) have been described and several of these cause altered splicing (9 -14).The C77G polymorphism (9 -12) has been linked to the development of multiple sclerosis in German (15)

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Section: Discussionsupporting

confidence: 93%

Abnormal Cell Surface Antigen Expression in Individuals with Variant CD45 Splicing and Histiocytosis

et al. 2004

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“…The most common mutation is the C77G mutation in a splicing silencer element in exon 4 that prevents excision of the exon so that heterozygous carriers express both CD45RA and CD45R0 isoforms. The C77G allele has been associated with susceptibility to autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and HIV/AIDS (30)(31)(32)(33)(34)(35). Other CD45 alleles that have been characterized include an exon 4 allele C59A and an exon 6 allele A138G (36,37).…”

Section: Discussionmentioning

confidence: 99%

Consequences of Increased CD45RA and RC Isoforms for TCR Signaling and Peripheral T Cell Deficiency Resulting from Heterogeneous Nuclear Ribonucleoprotein L-Like Mutation

Yates

Hoyne

et al. 2010

The Journal of Immunology

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“…Because an association with MS has been confirmed in some studies (13,14) but not in others (15,16), the role of 77C3 G in MS is not yet clear. Nevertheless, recent reports on an excess of 77C3 G individuals in cohorts of patients suffering from systemic sclerosis (17), autoimmune hepatitis (18), and HIV-1 infection (19) strongly suggested that the mutation and aberrant CD45 splicing may alter the immune responses of affected individuals.…”

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

confidence: 96%

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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Protein tyrosine phosphatase receptor-type C exon 4 gene mutation distribution in an Italian multiple sclerosis population

Cited by 35 publications

References 11 publications

Abnormal Cell Surface Antigen Expression in Individuals with Variant CD45 Splicing and Histiocytosis

Abnormal Cell Surface Antigen Expression in Individuals with Variant CD45 Splicing and Histiocytosis

Consequences of Increased CD45RA and RC Isoforms for TCR Signaling and Peripheral T Cell Deficiency Resulting from Heterogeneous Nuclear Ribonucleoprotein L-Like Mutation

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

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