Genetic Variants of the COL4A3, COL4A4, and COL4A5 Genes Contribute to Thinned Glomerular Basement Membrane Lesions in Sporadic IgA Nephropathy Patients

Significance Statement Thinned glomerular basement membrane (tGBM) lesions, usually associated with COL4A3 / COL4A4 / COL4A5 gene variants, are not uncommon in sporadic IgA nephropathy (IgAN), but the underlying mechanism is unclear. Exome sequence analysis of 122 patients with sporadic IgAN with tGBM lesions (IgAN-tGBM) identified diagnostic COL4A3 / COL4A4 / COL4A5 gene variants in 38 patients (31.1%), with 37 different variants. Patients with IgAN-tGBM who did not have diagnostic variants showed more characteristics of IgAN, whereas those who did have diagnostic variants had higher proportions of GBM thickness <250 nm and milder glomerular injury. These findings suggest different mechanisms in patients with IgAN-tGBM with and without diagnostic variants in these collagen genes. The research indicated the importance of COL4A3 / COL4A4 / COL4A5 variant detection in patients with IgAN-tGBM. Background Thinned glomerular basement membrane (tGBM) lesions are not uncommon in IgA nephropathy (IgAN). Type IV collagen—built of α 3, α 4, and α 5 chains, encoded by COL4A3 / COL4A4 / COL4A5 genes—is the major component of glomerular basement membrane (GBM). In recent years, mutations in type IV collagen–encoding genes were also reported in patients with a histologic diagnosis of FSGS. Pathogenic COL4A3 / COL4A4 / COL4A5 variants were recently identified in familial cases of IgAN, but the contribution of these variants to sporadic IgAN is still unclear. Methods We compared 161 patients with sporadic IgAN with tGBM lesions (IgAN-tGBM) to matched patients with IgAN without tGBM lesions and matched patients with thin basement membrane nephropathy (TBMN). Variants of COL4A3 / COL4A4 / COL4A5 genes were screened and evaluated after whole-exome sequencing. GBM thickness was measured, and levels of circulating galactose-deficient IgA1 (Gd-IgA1) were assessed by ELISA. Results The patients with IgAN-tGBM manifested milder disease than did patients with IgAN without tGBM but had more severe features than the patients with TBMN. Exome sequence analysis of the 122 patients with IgAN-tGBM identified 37 diagnostic variants of the COL4A3 / COL4A4 / COL4A5 genes among 38 patients (31.1%). Furthermore, patients with IgAN-tGBM who had diagnostic variants had higher proportions of GBM thickness <250 nm and milder glomerular injury, whereas patients with IgAN-tGBM who did not have diagnostic variants showed more characteristic features of IgAN, including higher intensity of glomerular IgA deposits and elevated Gd-IgA1 levels. These findings suggest different mechanisms in patients with versus without diagnostic variants of these collagen genes. Conclusions COL4A3 / COL4A4 / COL4A5 variant detection is essential in evaluating patients with sporadic IgAN with tGBM lesions.