Abnormal RNA Processing and Altered Expression of Serin-Rich Proteins in Minimal-Change Nephrotic Syndrome

Abstract

Mechanisms underlying the pathophysiology of minimalchange nephrotic syndrome (MCNS), the most frequent glomerular disease in children, remain elusive, but recent findings argue for a T cell dysfunction. Starting from a differential cDNA library from T cells of a patient under relapse and remission, we identified 16 transcripts specific for MCNS. All of these transcripts that were selectively up-regulated during the relapse phase of the disease were generated by alternative splicing of known genes. This abnormal RNA expression was associated with a down-regulation of serin-rich protein 75 and serin-rich protein 40, two proteins involved in mRNA splicing. Taken together, these data suggest that T cell dysfunction in MCNS is associated with abnormal mRNA splicing. Our understanding of biologic mechanisms that govern physiologic functions as well as pathologic situations has become more complex with recent insights from genome sequencing projects. In particular, it seems that alternative splicing plays a determinant role in the diversity and the complexity of higher organisms (1).Alternative splicing displays a strong tissue specificity or involvement at a defined developmental stage (2). Recent genome-wide data of human alternative pre-mRNA splicing using exon-junction microarrays indicate that at least 74% of human multi-exon genes are alternatively spliced (3). Moreover, that alternative splicing plays a crucial role in the biologic complexity of vertebrates indicates the possibility of its involvement in a large number of human diseases or pathologic processes. Thus, it has been estimated that 15-20% of diseasecausing mutations in human genes involve misregulation of alternative splicing (4).In this report, we reveal the possible involvement of abnormal RNA processing in the pathogenesis of minimal-change nephrotic syndrome (MCNS). This human glomerular disease is characterized by a heavy proteinuria with a relapsing/ remitting course without histologic evidence of classical immune mechanism-mediated injury (5,6). MCNS is a sporadic disease that occurs in the context of immune activation, and its natural course argues strongly against a fixed genetic defect. It is believed that the mechanism of proteinuria involves the secretion by MCNS immune cells of factors that impair the glomerular filtration barrier (7). How the immune response culminates in MCNS by the production of pathogenic factor remains unresolved.Recently, by analyzing a differential T cell cDNA library of a patient under relapse and remission, we identified 16 clones corresponding to unknown transcripts. The nucleotide sequences of these clones all match within intronic sequences of genes with defined or putative functions. Finally, we showed that this abnormal RNA processing is associated with a downregulation of serin-rich protein 75 (SRp75) and SRp40 proteins that play a crucial role in pre-mRNA processing. METHODS Patients.The cohort of patients analyzed in this study has been described previously (8). In all cases, informed consent was obtain...

Physiopathology of idiopathic nephrotic syndrome: lessons from glucocorticoids and epigenetic perspectives

“…Similarly, Tc-mip is implicated in c-maf activation and highly expressed in MCNS Th2 CD4+ T-cells, while totally absent in non-nephrotic patients [21]. These findings are concordant with the observed abnormal RNA processing and altered expression of serin-rich proteins, involved in mRNA splicing, within MCNS T-cells [23] suggesting that MCNS T-cell dysfunction might be associated with abnormal mRNA splicing/transcription machinery (Table 1).…”

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Blood T-Cell Repertoire in Idiopathic Nephrotic Syndrome Recurrence Following Kidney Transplantation

“…Our results do not exclude a role for T lymphocytes in INS recurrence but discredit an antigen-driven response, and a strong induction of c-maf, which promotes Th2 and attenuates Th1 differentiation (32). Recently, T-cell dysfunction associated with abnormal mRNA splicing was evoked in MCNS patients, highlighting the possibility that independent intrinsic TCR abnormalities could be involved in INS (33). Studies to test these hypotheses are now ongoing in patients with recurrence of INS after kidney transplantation.…”