Defective activation of the MAPK/ERK pathway, leading to PARP1 and DNMT1 dysregulation, is a common defect in IgA nephropathy and Henoch-Schönlein purpura

Annamaria Milillo, Clelia Molinario, Stefano Costanzi, Gisella Vischini, Francesca La Carpia, Francesco La Greca, Donato Rigante, Giovanni Gambaro, Fiorella Gurrieri, Eugenio Sangiorgi

Research output: Contribution to journalArticle

Abstract

Studies on IgA nephropathy (IgAN) have identified, through GWAS, linkage analysis, and pathway scanning, molecular defects in familial and sporadic IgAN patients. In our previous study, we identified a novel variant in the SPRY2 gene that segregates with the disease in one large family. The functional characterization of this variant led us to discover that the MAPK/ERK pathway was defective not only in this family, but also in two sporadic IgAN patients wild type for SPRY2. In the present study, we have deepened the molecular analysis of the MAPK/ERK pathway and extended our evaluation to a larger cohort of sporadic patients and to one additional family. We found that the ERK pathway is defective in IgAN patients and in patients affected by another IgA-mediated disorder, Henoch-Schönlein purpura (HSP). Furthermore, we found that two other proteins, PARP1 and DNMT1, respectively involved in DNA repair and in antibody class switching and methylation maintenance duties, were critically downregulated in IgAN and HSP patients. This study opens up the possibility that defective ERK activation, in some patients, leads to PARP1 and DNMT1 downregulation suggesting that IgAN could be the consequence of a dysregulated epigenetic maintenance leading to the upregulation of several genes. In particular, PARP1 could be used as a potential biomarker for the disease.

Original languageEnglish
Pages (from-to)731-741
Number of pages11
JournalJournal of Nephrology
Volume31
Issue number5
DOIs
Publication statusPublished - Oct 1 2018

Keywords

  • Henoch-Schönlein
  • IgA nephropathy
  • PARP1

ASJC Scopus subject areas

  • Nephrology

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    Milillo, A., Molinario, C., Costanzi, S., Vischini, G., La Carpia, F., La Greca, F., Rigante, D., Gambaro, G., Gurrieri, F., & Sangiorgi, E. (2018). Defective activation of the MAPK/ERK pathway, leading to PARP1 and DNMT1 dysregulation, is a common defect in IgA nephropathy and Henoch-Schönlein purpura. Journal of Nephrology, 31(5), 731-741. https://doi.org/10.1007/s40620-018-0482-6