Abstract:Purpose of reviewIn Alport syndrome, over 1,700 genetic variants in the COL4A3, COL4A4, and COL4A5 genes cause the absence or malfunctioning of the collagen IVα345 scaffold – an essential component of the glomerular basement membrane (GBM). Therapies are limited to treatment with Angiotensin-Converting enzyme (ACE) inhibitors to slow progression of the disease. Here, we review recent progress in therapy development to replace the scaffold or restore its function.Recent findingsMultiple approaches emerged recen… Show more
“…Although it is only one-seventh part of the whole collagen IV molecule, the NC1 domain bears information for homing it to the BM. It provides an initial clue of using NC1-containing fragments of collagen IV for developing protein replacement therapy in humans ( 89 ). Figure 12 Collagen IV scaffold assembly in Drosophila .…”
“…Although it is only one-seventh part of the whole collagen IV molecule, the NC1 domain bears information for homing it to the BM. It provides an initial clue of using NC1-containing fragments of collagen IV for developing protein replacement therapy in humans ( 89 ). Figure 12 Collagen IV scaffold assembly in Drosophila .…”
“…Importantly, recent clinical trials support the use of ACE inhibitors at very early stages of the disease, even when presenting with only low-grade of proteinuria (urine albumin <300 mg/g creatinine or isolated hematuria), for which genetic documentation of an AS diagnosis is needed [ 23 , 69 ]. Other treatments are also under scrutiny, while new ones are being explored [ 70 , 71 ]. SGLT2-mediated correction of the hemodynamic overload of the glomerular filtration barrier appears to be a very promising therapeutic approach [ 72 ].…”
Alport syndrome (AS) is the most frequent monogenic inherited glomerulopathy and is also genetically and clinically heterogeneous. It is caused by semi-dominant pathogenic variants in the X-linked COL4A5 (NM_000495.5) gene or recessive variants in the COL4A3/COL4A4 (NM_000091.4/NM_000092.4) genes. The disease manifests in early childhood with persistent microhematuria and can progress to proteinuria and kidney failure in adolescence or early adulthood if left untreated. On biopsy, pathognomonic features include alternate thinning, thickening and lamellation of the glomerular basement membrane (GBM), in the presence of podocyte foot process effacement. Although previous studies indicate a prevalence of AS of about 1/50,000, a recent publication reported a predicted rate of pathogenic COL4A5 variants of 1/2320. We herewith present 98 patients (40 M/58 F) from 26 Greek families. We are selectively presenting the families segregating the X-linked form of AS with pathogenic variants in the COL4A5 gene. We found 21 different pathogenic variants, 12 novel: eight glycine and one proline substitutions in the collagenous domain, one cysteine substitution in the NC1 domain, two premature termination of translation codons, three splicing variants, one 5-bp insertion/frameshift variant, one indel-frameshift variant and four gross deletions. Notably, patients in six families we describe here and three families we reported previously, carried the COL4A5-p.G624D substitution, a founder defect encountered all over Europe which is hypomorphic with mostly milder symptomatology. Importantly, on several occasions, the correct genetic diagnosis reclassified patients as patients with AS, leading to termination of previous immunosuppressive/cyclosporine A therapy and a switch to angiotensin converting enzyme inhibitors (ACEi). With the understanding that all 98 patients span a wide range of ages from infancy to late adulthood, 15 patients (11 M/4 F) reached kidney failure and 11 (10 M/1 F) received a transplant. The prospects of avoiding lengthy diagnostic investigations and erroneous medications, and the advantage of delaying kidney failure with very early administration of renin-angiotensin-aldosterone system (RAAS) blockade, highlights the importance of timely documentation of AS by genetic diagnosis.
“…Alport syndrome (AS), the progressive hereditary kidney disease that is estimated to impact approximately 1 in 50,000 newborns, is associated with aberrant glomerular basement membrane (GBM) type IV collagen composition, and it remains a clinical challenge that ultimately requires renal transplant. GBM defects in AS arise from mutations in either of the three genes ( Col4a3 , Col4a4 , or Col4a5 genes) that encode for three chains of type IV collagen, respectively ( Hudson et al, 2003 ; Cosgrove et al, 2007 ; LeBleu et al, 2010 ; Cosgrove & Liu, 2017 ; Boudko et al, 2022 ). Patho-mechanistic studies suggest that loss of one chain type can lead to loss of the other two chain types due to the obligate requirement for integration of the three α-chain types into the triple helical type IV collagen molecule (α3α4α5 triple helical protomers).…”
Glomerular filtration relies on the type IV collagen (ColIV) network of the glomerular basement membrane, namely, in the triple helical molecules containing the α3, α4, and α5 chains of ColIV. Loss of function mutations in the genes encoding these chains (Col4a3,Col4a4, andCol4a5) is associated with the loss of renal function observed in Alport syndrome (AS). Precise understanding of the cellular basis for the patho-mechanism remains unknown and a specific therapy for this disease does not currently exist. Here, we generated a novel allele for the conditional deletion ofCol4a3in different glomerular cell types in mice. We found that podocytes specifically generate α3 chains in the developing glomerular basement membrane, and that its absence is sufficient to impair glomerular filtration as seen in AS. Next, we show that horizontal gene transfer, enhanced by TGFβ1 and using allogenic bone marrow–derived mesenchymal stem cells and induced pluripotent stem cells, rescuesCol4a3expression and revive kidney function in Col4a3-deficient AS mice. Our proof-of-concept study supports that horizontal gene transfer such as cell fusion enables cell-based therapy in Alport syndrome.
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