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. 2021 Mar 26;296:100590. doi: 10.1016/j.jbc.2021.100590

Figure 2.

Figure 2

A genetic variant of α3(IV) collagen (Zurich variant) associated with familial Goodpasture’s disease and Alport syndrome is distinct among the 1700 known Alport variants.A, Zurich variant is associated with both familial Goodpasture’s disease (GP) and Alport syndrome. This variant was a risk factor in developing familial Goodpasture’s disease in two Zurich patients (red pie chart wedge and red circle, n = 2). In several cohorts of GP patients from different countries, the presence of Zurich variant was not detected either by Sanger sequencing of exons 48 to 52 (Switzerland, n = 11; Sweden, n = 15; China, n = 171; and UK, n = 29) or whole exome/genome sequencing (USA, n = 36) as shown in the gray pie chart. However, the Zurich variant was detected in patients diagnosed with familial hematuria or suspected Alport syndrome (tan circle, n = 6) and in the general population with unknown phenotype (dark blue circle, n = 48). The extrapolation of the data set to the world population resulted in estimated one million people carrying the Zurich variant, and thus classified as Alport Syndrome. Therefore, the Zurich variant places them at risk of progressing to renal failure and developing Goodpasture’s disease (light blue circle). B, the number and location of 1700+ genetic Alport-associated variants (indicated by yellow dots, zoom in to see individual dots) in the α3, α4, and α5 chains of collagen IV (left). Pathogenic variants cause either loss of α345 protomers from the GBM or assembly of defective α345 protomers that can incorporate into the GBM, causing a broad spectrum of GBM phenotypes. Significant numbers of Alport-associated variants occur within α3, α4, and α5 NC1 domains (right). Zurich variant α3NC1 monomer with an 8-amino acid Z-appendage is shown at top right. Analogous to Zurich variant, a novel variant α5NC1 monomer with a C-terminal 74-amino acid appendage (59) is shown at bottom right. Because these two variants resulted in a C-terminal extension of the protein polypeptide chain, they stood out among over 1700 known variants in the COL4A3, COL4A4, and COL4A5 genes associated with Alport syndrome. The Z-appendage incorporated into the collagen IV scaffold of the GBM and served as a pathogenic reporter group that identified a new therapeutic target (vide infra).