| Title | Genetic Variants of the COL4A3, COL4A4, and COL4A5 Genes Contribute to Thinned Glomerular Basement Membrane Lesions in Sporadic IgA Nephropathy Patients |
| Authors | Yuan, Xiaohan Su, Qing Wang, Hui Shi, Sufang Liu, Lijun Lv, Jicheng Wang, Suxia Zhu, Li Zhang, Hong |
| Affiliation | Peking Univ First Hosp, Dept Med, Renal Div, Beijing, Peoples R China Peking Univ, Key Lab Renal Dis, Natl Hlth Commiss, Beijing, Peoples R China Minist Educ, Key Lab Chron Kidney Dis Prevent & Treatment, Beijing, Peoples R China Chinese Acad Med Sci, Res Units Diag & Treatment Immunomediated Kidney D, Beijing, Peoples R China Peking Univ First Hosp, Ultrastruct Pathol Ctr, Lab Electron Microscopy, Beijing, Peoples R China Peking Univ, Peking Univ First Hosp, Dept Med, Renal Div,Inst Nephrol, Beijing 100034, Peoples R China |
| Keywords | ASSOCIATION DISEASE SUSCEPTIBILITY GLYCOSYLATION THICKNESS MUTATIONS INJURY |
| Issue Date | Jan-2023 |
| Publisher | JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY |
| Abstract | Background Thinned glomerular basement membrane (tGBM) lesions are not uncommon in IgA nephropathy (IgAN). Type IV collagen & mdash;built of a3, a4, and a5 chains, encoded by COL4A3/COL4A4/COL4A5 genes & mdash;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 wholeexome 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. |
| URI | http://hdl.handle.net/20.500.11897/670147 |
| ISSN | 1046-6673 |
| DOI | 10.1681/ASN.2021111447 |
| Indexed | SCI(E) |
| Appears in Collections: | 第一医院 |
