Molecular Pathobiology of Alport Syndrome

Hundreds of variants in the COL4A3, COL4A4 and COL4A5 genes cause a broad range of glomerulopathies affecting the function of the glomerular basement membrane (GBM) in patients with Alport syndrome. These genes encode the assembly of collagen IV α345 scaffolds, the major constituent of the GBM. The pathogenic variants lead to a broad array of clinical manifestations, ranging from microscopic hematuria to end stage renal disease. The underlying mechanisms linking these variants with GBM abnormalities and renal failure remain obscure. Current therapy is limited to treatment with ACE inhibitors to slow progression and new therapies are in urgent need. How genetic variants of the α345 scaffold cause Alport syndrome remains unknown. Here, we focus on Z-variant causing Alport syndrome without loss of the α345 scaffold but rather reduction- or loss-of-function effect (hypomorph variant). We use this variant as a vanguard to decipher the pathogenic mechanism of the α345 collagen IV in Alport GBM and develop new forms of therapy. In Aim 1, we will utilize a new Z-variant animal model to understand mechanisms of α345 collagen IV dysfunction. In Aim 2, we will determine exact defects caused by Z-variant and similar pathogenic variants at protein and cellular levels to identify specific targets for small molecule therapies. In Aim 3, we will test protein replacement therapy and screen for pharmacological chaperones correcting assembly and stability of the collagen IV α345 scaffold. The completion of the Aims will advance our knowledge about Alport pathogenesis and lay out foundation for therapy development addressing causative mechanisms in Alport syndrome.