Ras-MAPK pathway in patients with lupus nephritis
Background Pathogenic mutations in genes encoding components of the Ras/mitogen-activated protein kinase (Ras-MAPK) pathway cause RASopathy. Here, we describe five unrelated patients with SLE carrying mutations associated with RASopathy and investigate the activity of the Ras-MAPK pathway.Methods Pa...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2025-03-01
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| Series: | Lupus Science and Medicine |
| Online Access: | https://lupus.bmj.com/content/12/1/e001345.full |
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| Summary: | Background Pathogenic mutations in genes encoding components of the Ras/mitogen-activated protein kinase (Ras-MAPK) pathway cause RASopathy. Here, we describe five unrelated patients with SLE carrying mutations associated with RASopathy and investigate the activity of the Ras-MAPK pathway.Methods Pathogenic variants were identified by whole-exome/whole-genome sequencing. The activity of the Ras-MAPK pathway in peripheral blood mononuclear cells (PBMC) and kidneys was evaluated using RNA sequencing and datasets from the nephroseq database, respectively.Results Five (likely) pathogenic variants in four Ras-MAPK genes were identified, including NRAS: c.G38A: p.G13D; ARAF: c.C1435T: p.R479C; KRAS: c.T341C: p.V114A; PTPN11: c.G455A: p.R152H and NRAS: c.G34A: p.G12S. Kidney injury is the main feature, presenting with nephrotic syndrome (2/5), proteinuria and haematuria (2/5). Acute kidney injury and rapidly progressive nephritic syndrome were noted in one patient each. Other clinical features included mucocutaneous lesions (5/5), cardiac involvement (4/5) and arthralgia (3/5). Laboratory abnormalities included hypocomplementaemia (5/5), presence of antiphospholipid antibodies (4/5), decreased regulatory T cells (3/3), pancytopenia (3/5) and persistent monocytosis (2/5). Kidney biopsy revealed lupus nephritis. Most patients responded well to standard therapy, with the exception of the patient with the NRAS p.G13D mutation who died. The Ras-MAPK pathway was activated in both PBMC and kidney of patients with LN as indicated by increased expression of NRAS, KRAS, RIT1, MRAS, PPP1CB, SHOC2, SOS2 and MAP2K1, as well as decreased expression of negative regulators of the Ras-MAPK pathway, CBL, LZTR1 and NF1.Conclusion Kidney involvement may be the main feature of the clinical spectrum of RASopathy. Genetic screening should be considered for patients with early onset lupus. |
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| ISSN: | 2053-8790 |