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Please prepare and upload your E-Poster no later than March 14, 2026 11.59PM CET. After this date, you will no longer be able to prepare and upload your E-poster and it will not be displayed and accessible on the congress website.
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Multicentric carpotarsal osteolysis (MCTO) is an ultra-rare osteolysis syndrome frequently complicated by progressive nephropathy. Dominant missense variants clustered in the MAFB transactivation domain are causative, yet renal pathogenesis and targeted therapies remain undefined. MAFB is a bZIP transcription factor that binds Maf recognition elements (MAREs); in podocytes, it maintains homeostasis and directly regulates the slit-diaphragm proteins NPHS1 (nephrin) and NPHS2 (podocin). We investigated how MCTO-associated MAFB (MCTO-MAFB) perturbs podocytes and whether inhibition of the IGF-1/PI3K/AKT axis mitigates injury.
Kidney tissue from a Japanese MCTO patient (MAFB p.Pro63Gln) was evaluated by light microscopy and by immunohistochemistry (IHC) for MAFB and NPHS2. Mouse studies used Mafb^MCTO/MCTO knock-in (patient-region p.Pro59Leu) and Mafb^MCTO/− mice to assess albuminuria, light/electron microscopy, podocyte MAFB IHC, and isolated-glomerular RNA-seq with pathway enrichment. In HEK293T cells, WT or MCTO-MAFB (p.Pro59Leu) was expressed to test protein stability (cycloheximide chase), transcriptional reporter activity, and MAFB abundance by immunoblot. Guided by RNA-seq, -2 kb promoters of PI3K/AKT–related genes upregulated in Mafb^MCTO/MCTO glomeruli (Lpar1, Csf1r, Igf1, Igf2) were screened by luciferase reporter assays; MAREs were mapped by promoter truncation and mutagenesis. AKT pathway phosphorylation arrays compared signaling in WT vs MCTO-MAFB–expressing cells and, in MCTO-MAFB cells, after treatment with imatinib, MK-2206 (AKT inhibitor), or linsitinib (IGF-1R/INSR inhibitor). Mafb^MCTO/MCTO mice were treated with imatinib. Institutional approvals were obtained.
The MCTO patient showed focal segmental glomerulosclerosis (FSGS) with preserved podocyte MAFB and NPHS2. Mafb^MCTO/MCTO mice developed albuminuria, FSGS, and foot-process effacement with increased podocyte MAFB, whereas Mafb^MCTO/− mice were protected, indicating that reducing MAFB dosage mitigates injury. MCTO-MAFB was stabilized in cycloheximide chase assays, accounting for elevated in vivo levels. Glomerular RNA-seq from Mafb^MCTO/MCTO showed enrichment of PI3K/AKT signaling; Mafb transcripts were unchanged, while canonical targets Nphs1 and Nphs2 were increased, consistent with stabilization-driven gain of function. The promoter screen identified Igf1 as MAFB-responsive, with stronger, dose-dependent activation by MCTO-MAFB; two essential MAREs were mapped, and Igf1 mRNA was increased in Mafb^MCTO/MCTO glomeruli. MCTO-MAFB heightened AKT pathway phosphorylation, which was suppressed by imatinib, MK-2206, or linsitinib. Imatinib reduced urinary albumin excretion in vivo.
Collectively, our human mouse, and cell data indicate that stabilized MCTO-MAFB activates the IGF-1/PI3K/AKT pathway in podocytes. We identify Igf1 as a direct MAFB target via two promoter MAREs, linking MAFB gain of function to downstream signaling. Lowering MAFB dosage (Mafb^MCTO/−) is protective, and pathway inhibition—validated in cells (imatinib, MK-2206, linsitinib) and in mice (imatinib)—attenuates disease measures. The MAFB–IGF-1/PI3K/AKT axis therefore represents a tractable therapeutic target in MCTO-associated nephropathy.
