77 C/G mutation in the tyrosine phosphatase CD45 gene and autoimmune hepatitis: evidence for a genetic link

Vogel, Arndt; Strassburg, CP; Manns, Michael P.

doi:10.1038/sj.gene.6363918

Cited by 73 publications

(52 citation statements)

References 23 publications

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“…Therefore, the shift to smaller CD45 isoforms upon activation of T cells reduces CD45 phosphatase activity and is thought to contribute to the attenuation of T cell signaling (8,12). Such a model for the importance of CD45 alternative splicing in maintaining T cell homeostasis is supported by studies that have correlated defects in CD45 splicing regulation with susceptibility to various autoimmune diseases, including multiple sclerosis, systemic sclerosis, and autoimmune hepatitis (13)(14)(15).…”

mentioning

confidence: 59%

“…At least two polymorphisms in CD45 exon 4 and one in CD45 exon 6 have already been described in the human population to alter CD45 isoform expression and have been potentially linked to autoimmune disease susceptibility (13)(14)(15)(22)(23)(24). These three polymorphisms all fall within or near the regulatory sequences described here or in our previous study (18).…”

Section: Discussionmentioning

confidence: 90%

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Differential Expression of CD45 Isoforms Is Controlled by the Combined Activity of Basal and Inducible Splicing-regulatory Elements in Each of the Variable Exons

Tong

Nguyen

Lynch

2005

Journal of Biological Chemistry

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The human CD45 gene encodes five isoforms of a transmembrane tyrosine phosphatase that differ in their extracellular domains as a result of alternative splicing of exons 4 -6. Expression of the CD45 isoforms is tightly regulated in peripheral T cells such that resting cells predominantly express the larger CD45 isoforms, encoded by mRNAs containing two or three variable exons. In contrast, activated T cells express CD45 isoforms encoded by mRNAs lacking most or all of the variable exons. We have previously identified the sequences within CD45 variable exon 4 that control its level of inclusion into spliced mRNAs. Here we map the splicingregulatory sequences within CD45 variable exons 5 and 6. We show that, like exon 4, exons 5 and 6 each contain an exonic splicing silencer (ESS) and an exonic splicing enhancer (ESE), which together determine the level of exon inclusion in naïve cells. We further demonstrate that the primary activation-responsive silencing motif in exons 5 and 6 is homologous to that in exon 4 and, as in exon 4, binds specifically to the protein heterogeneous nuclear ribonucleoprotein L. Together these studies reveal common themes in the regulation of the CD45 variable exons and provide a mechanistic explanation for the observed physiological expression of CD45 isoforms.In order to attain proteomic and functional complexity, higher eukaryotes have developed numerous mechanisms to amplify the informational content of their relatively limited genomes. One such mechanism, alternative splicing, allows for the production of multiple unique mRNAs from a single gene through the differential inclusion of exons. Since the variant mRNAs produced by alternative splicing can each potentially encode for a functionally distinct protein, alternative splicing is recognized to be a ubiquitous and critical mechanism for regulating cellular function (1, 2).The importance of regulated alternative splicing in humans is exemplified by the CD45 gene, which encodes a transmembrane proteintyrosine phosphatase (3). CD45 phosphatase activity is critical for intracellular signaling in T cells in response to antigen stimulation, as indicated by the severe immunodeficiency observed in CD45-deficient mice and humans (4 -7). Five isoforms of the CD45 protein are expressed in humans as a result of alternative inclusion of exons 4 -6 (see Fig. 1A). In human T cells, the expression of the CD45 isoforms is tightly regulated throughout development and upon activation (3). In particular, naive peripheral T cells express significant amounts of the larger isoforms of CD45, which have high phosphatase activity and maintain the T cell receptor in a state primed for antigen recognition (8). Subsequent to antigen stimulation, however, there is a marked shift in the processing of CD45 pre-mRNA, such that the variable exons are predominantly excluded from the final message, resulting in expression of the smaller CD45 isoforms (9, 10). The smaller isoforms of CD45 are more prone to homodimerization than the larger isoforms (8, 11). Importantl...

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confidence: 59%

Section: Discussionmentioning

confidence: 90%

Differential Expression of CD45 Isoforms Is Controlled by the Combined Activity of Basal and Inducible Splicing-regulatory Elements in Each of the Variable Exons

Tong

Nguyen

Lynch

2005

Journal of Biological Chemistry

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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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“…An increased frequency of C77G has been found in HIV [14], Langerhans cell histiocytosis [15], systemic sclerosis [16], hepatitis C [17] and autoimmune hepatitis [18], but no association with common variable immunodeficiency (CVID), Graves' disease or diabetes [10,19,20]. 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].…”

Section: Introductionmentioning

confidence: 99%

Unusual case presentations associated with the CD45 C77G polymorphism

Tchilian

Gil

Navarro

et al. 2006

Clinical and Experimental Immunology

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SummaryCD45, the leucocyte common antigen, is a haematopoietic cell specific tyrosine phosphatase. Human polymorphic CD45 variants are associated with autoimmune and infectious diseases and alter the phenotype and function of lymphocytes, establishing CD45 as an important regulator of immune function. Here we report four patients with diverse diseases with unusual clinical features. All four have the C77G polymorphism of CD45 exon 4, which alters the splicing and CD45RA/CD45R0 phenotype of lymphocytes. We suggest that C77G may be a contributing factor in these unusual cases.

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77 C/G mutation in the tyrosine phosphatase CD45 gene and autoimmune hepatitis: evidence for a genetic link

Cited by 73 publications

References 23 publications

Differential Expression of CD45 Isoforms Is Controlled by the Combined Activity of Basal and Inducible Splicing-regulatory Elements in Each of the Variable Exons

Differential Expression of CD45 Isoforms Is Controlled by the Combined Activity of Basal and Inducible Splicing-regulatory Elements in Each of the Variable Exons

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

Unusual case presentations associated with the CD45 C77G polymorphism

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