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Background and Aims Transcription factor MafB in podocytes is essential for podocyte differentiation and maintenance. Previous works identified a missense mutation in the transactivation domain of MAFB as the cause of multicentric carpotarsal osteolysis (MCTO). MCTO is a condition involving progressive osteolysis of the carpal and tarsal bones. MCTO patients also develop with focal segmental glomerulosclerosis (FSGS) and renal failure (MCTO nephropathy). However, the pathogenesis of MCTO in vivo is unclear. Method In order to address this question, we generated an MCTO mouse model using the CRISPR/Cas9-mediated genome editing. This mouse has a human MCTO mutation c.176C>T, (p.Pro59Leu). Mafb MCTO/ MCTO mice were obtained by crossing Mafb MCTO/WT mice. Control animals were Mafb WT/WT mice. Sequencing analysis was performed to confirm the integration of the MCTO mutation on F2 generations. We checked urine of these mice every 4 weeks, and biochemical and histological analysis were performed at 26 weeks-ages. RNA-seq analysis of the isolated glomeruli of these mice was performed at 10 weeks-ages. Results Interestingly, MafbMCTO/MCTO newborn mice exhibited a 10% lower body weight than control mice. The differences were still observed at 2 weeks, with Mafb MCTO/MCTO mice presenting a 23% lower body weight than control animals. The length of femoral bones in Mafb MCTO/MCTO mice was shorter than that of control. MCTO model mice exhibit growth deficiency. In addition, Mafb MCTO/ MCTO mice resulted in albuminuria at 4 weeks-ages from postnatal periods and became persistent. Renal histological analysis in adult stage revealed FSGS-like glomerular lesions in Mafb MCTO/ MCTO mice. In electron microscope analysis, microvillous transformation of the foot processes of podocytes in Bowman’s space and foot processes effacements were seen in Mafb MCTO/ MCTO mice. These phenotypes are similar to that seen in MCTO nephropathy patients. Subsequently, we performed RNA-seq analysis of isolated glomeruli to gain insight into the molecular mechanism of the MCTO mutation. We found Cldn1, gene expression in mature podocytes caused profound proteinuria, was significantly increased in Mafb MCTO/ MCTO glomeruli. Conclusion This study is significant for revealing the mechanism of MCTO and contributes to the development of an alternative treatment against MCTO nephropathy by providing model mice for use.