Mice harboring an MCTO mutation exhibit renal failure resembling nephropathy in human patients

Area of Science:

• Genetics and Molecular Biology
• Nephrology
• Skeletal Biology

Background:

• Multicentric carpotarsal osteolysis (MCTO) is a rare genetic disorder characterized by progressive bone loss in the wrists and ankles.
• MCTO is frequently associated with kidney disease, termed MCTO nephropathy, leading to glomerular sclerosis and renal failure.
• A specific autosomal dominant mutation in the MAFB gene has been identified as the cause of MCTO.

Purpose of the Study:

• To establish a viable mouse model for studying the in vivo pathogenesis of MCTO nephropathy.
• To provide a preclinical tool for the development of novel therapeutic strategies for MCTO nephropathy.
• To investigate the effects of the Mafb mutation on kidney development and function.

Main Methods:

• Utilized the CRISPR/Cas9 gene-editing system to introduce a specific Mafb mutation into the mouse genome.
• Phenotypically characterized the generated Mafb mutant mice (Mafb^MCTO/MCTO) from birth.
• Assessed kidney function through urine albumin-to-creatinine ratio measurements and performed histological analysis of kidney tissues.

Main Results:

• Mafb^MCTO/MCTO mice displayed reduced body weight from birth, persisting throughout aging.
• Elevated urine albumin-to-creatinine levels were observed in young mutant mice, indicating significant nephropathy.
• Histological examination revealed focal segmental glomerulosclerosis (FSGS), podocyte foot process effacement, and microvillus transformation, mirroring human MCTO nephropathy.

Conclusions:

• The generated Mafb^MCTO/MCTO mouse model accurately recapitulates the key features of human MCTO nephropathy.
• This mouse model serves as a crucial platform for understanding MCTO pathogenesis and for testing potential treatments.
• The study facilitates the advancement of therapeutic interventions for patients suffering from this debilitating condition.