LAMA5 pathogenic variant uncovers a novel autoantigen in membranous nephropathy.
Xiao Han H, Yin Hui H, Shi Yulu Y, Zhou Xindi X et al.
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.