Glomerular Expression of Type IV Collagen Chains in Normal and X-Linked Alport Syndrome Kidneys

Abstract

Alport syndrome is an inherited nephropathy characterized by alterations of the glomerular basement membrane because of mutations in type IV collagen genes. COL4A5 mutations, causing X-linked Alport syndrome, frequently result in the loss of the ␣5 chains of type IV collagen in basement membranes. This is associated with the absence of the ␣3(IV) and ␣4(IV) chains and increased amounts of ␣1(IV) and ␣2(IV) in glomerular basement membranes. The mechanisms resulting in such a configuration are still controversial and are of fundamental importance for understanding the pathology of the disease and for considering gene therapy. In this article we studied, for the first time, type IV collagen expression in kidneys from X-linked Alport syndrome patients, using in situ hybridization and immunohistochemistry. We show that, independent of the type of mutation and of the level of COL4A5 transcription, both COL4A3 and COL4A4 genes are actively transcribed in podocytes. Moreover, using immunofluorescence amplification, we were able to demonstrate that the ␣3 chain of type IV collagen was present in the podocytes of all patients. Finally, the ␣1(IV) chain, which accumulates within glomerular basement membranes, was found to be synthesized by mesangial/endothelial cells. These results strongly suggest that, contrary to what has been found in dogs affected with X-linked Alport syndrome, there is no transcriptional co-regulation of COL4A3, COL4A4, and COL4A5 genes in humans, and that the absence of ␣3(IV) to ␣5(IV) in glomerular basement membranes in the patients results from events downstream of transcription, RNA processing, and protein synthesis.

COL4A2 mutation associated with familial porencephaly and small-vessel disease

“…4 It has been shown that in the kidney expression of COL4A3, COL4A4 and COL4A5 genes can be cell-type specific. 36,37 In summary, we observed that familial COL4A2 mutations could lead to a wide spectrum of cerebrovascular disorders, including porencephaly, white matter lesions and possibly aneurysm and cerebellar hypoplasia, which might go undiagnosed because of reduced penetrance and variable expression. Additional risk factors may influence the course of cerebrovascular diseases in families with COL4A2 mutations.…”

Bone-marrow-derived stem cells repair basement membrane collagen defects and reverse genetic kidney disease

“…ecules comprising ␣3, ␣4, and ␣5 chains. Several studies suggest that ␣3 chain is produced by podocytes and glomerular endothelial cells (10). To further evaluate whether the repair of GBM architecture was caused by de novo synthesis of ␣3 chain by the transplanted podocytes derived from the BM in the COL4A3 Ϫ/Ϫ mice, in situ hybridization for COL4A3 transcript was performed (Fig.…”

Quaternary Organization of the Goodpasture Autoantigen, the α3(IV) Collagen Chain

“…In the X-linked form of the disease, mutations in the COL4A5 gene encoding the ␣5(IV) chain cause the absence of the ␣3, ␣4, and ␣5(IV) chains from the GBM, despite the expression of the ␣3 and ␣4(IV) chains in the podocytes (28,29), and the absence of the ␣5 and ␣6(IV) chains from Bowman's capsule (30 -32). Thus, mutations in the ␣5(IV) chain could either prevent the assembly of ␣3␣4␣5 and (␣5) 2 ␣6 protomers altogether or result in defective protomers that are degraded or cannot self-assemble into networks, causing the loss of the ␣3-␣6(IV) chains.…”