LAMA5 pathogenic variant uncovers a novel autoantigen in membranous nephropathy

Membranous nephropathy is a leading cause of nephrotic syndrome, driven by autoantibodies targeting podocyte antigens. Although antibodies against PLA₂R and THSD7A account for the majority of cases, a substantial fraction of patients remain seronegative, implying the existence of additional, unidentified autoantigens. Here, we report the identification of two novel compound heterozygous mutations in LAMA5 encoding Laminin α5, in a pediatric patient with severe nephrotic syndrome. Whole-exome sequencing revealed c.1355A>T (p.N452I) and c.9770A>G (p.N3257S) variants, with structural modeling indicating that p.N452I induces a conformational change in Laminin α5. This altered conformation enhanced its binding to Collagen IV networks, resulting in thickening of the glomerular basement membrane and the creation of a neo-epitope recognized by conformation-specific IgG1/IgG3 autoantibodies. These autoantibodies activated the classical complement pathway, triggering podocyte injury. A knock-in mouse model harboring the Lama5 ^N457I mutation recapitulated the human phenotype, exhibiting proteinuria, glomerular basement membrane thickening, and glomerular IgG deposits. Notably, rituximab treatment in the patient led to the disappearance of anti-Laminin α5 autoantibodies and sustained clinical remission. Our findings establish Laminin α5 as a novel genetic autoantigen in membranous nephropathy and suggest that screening for anti-Laminin α5 antibodies may help identify patients who could benefit from B-cell-targeted therapies.