Blog entry by Meguid El Nahas

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A window for novel collagen IV nephropathy therapeutics?

Myrtani Pieri, Charalambos Stefanou and Constantinos Deltas
Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics, University of Cyprus, Nicosia, Cyprus
December 2013

Alport Syndrome (AS) is inherited as an X-linked (COL4A5) or autosomal recessive disorder (COL4A3/A4) while thin basement membrane nephropathy (TBMN) follows autosomal dominant inheritance (COL4A3/A4). They are collectively known as collagen IV nephropathies and are characterized by phenotypic heterogeneity. AS is a rare disorder with an incidence of about 1/5000 live births, although it varies among ethnic populations. Most patients reach ESRF before the age of 30 years. TBMN is a much more frequent cause for developing ESRF compared to AS, although at later ages, owing to its much higher frequency in the general population (reported as high as 1%) [1, 2].

Hundreds of different mutations have been identified in the implicated genes that partly explain inheritance patterns and phenotypic heterogeneity [3-5]. Nonetheless, we still have a long way to go before determining the molecular mechanisms by which these mutations exert their deleterious effects on the glomerulus.

It has been shown that most mutation carriers have limited or no expression of the collagen IV chains in the glomerular basement membrane (GBM) and Bowman’s capsule. Interestingly, a recent publication revealed that X-linked AS patients that actually do express the a5(IV) chain in the GBM, exhibit milder clinical manifestations compared to those lacking  GBM expression [6]. Therefore, presence of collagen IV chains in the GBM appears to exert a protective effect on disease course. But does more chains out, also means less chains in the cell? And could increased amount of misfolded protein inside the podocyte be toxic and add to disease progression? As our recent publication in JASN revealed, it does [7].

The focus of our study was the mutational effect on the cell responsible for collagen IV chain expression in the adult glomerulus, the podocyte [7]. For the first time we provided evidence linking collagen chain mislocalization with triggering of the Unfolded Protein Response (UPR), an important cellular pathway [8]. This link, we believe, is a window for testing novel treatments for AS and TBMN.

The glycine missense mutation, COL4A3-G1334E, endemic in the Cypriot population, was expressed in human cell lines and its defective trafficking caused a strong intracellular effect on the podocyte. Interestingly, both overexpression and downregulation of the COL4A3 chain was associated with activation of UPR. This result demonstrates that  collagen IV misfolding does not only result in reduction of all chains in the GBM, but also triggers a cellular pathway that has the potential to drive the cell towards apoptosis should the stress be long lasting [9]. This link was also verified in an in vivo model, the first knock-in mouse model carrying a missense glycine mutation which produced a phenotype consistent with AS. It was also further verified in biopsy specimens from patients with TBMN carrying a heterozygous COL4A3-G1334E mutation [7]. The variable contribution of this intracellular vs. the extracellular pathological effect for these particular syndromes is something that is yet to be determined.

Interestingly, this link between a collagen IV mutation and the UPR pathway is a very important one, as this particular pathway can be manipulated pharmacologically. Next up, would be to try to treat cells and mutant mice with pharmacological chaperones which can facilitate protein folding and trafficking to examine whether this will increase secretion of the mutant COL4A3 and hopefully decrease hematuria and proteinuria in mutant mice. A similar approach was recently shown for a mutation in the laminin β2 gene (LAMB2) that causes Pierson syndrome, a severe congenital nephrotic syndrome with ocular and neurologic defects [10].

UPR activation has been observed in many diseases, including cancer, autoimmune conditions, diabetes, liver disorders, obesity and neurodegenerative disorders [9]. UPR in renal pathophysiology is a relatively new area of research [11-14]. Therefore, recognizing its contributory role to the deleterious consequences of collagen IV-trafficking defects would greatly improve AS/TBMN patient prognosis and would pave ways for development of novel, true therapeutics to improve or ameliorate disease.


1.              Savige, J., et al., Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy. J Am Soc Nephrol, 2013. 24(3): p. 364-75.

2.              Deltas, C., A. Pierides, and K. Voskarides, Molecular genetics of familial hematuric diseases. Nephrol Dial Transplant, 2013.

3.              Jais, J.P., et al., X-linked Alport syndrome: natural history and genotype-phenotype correlations in girls and women belonging to 195 families: a "European Community Alport Syndrome Concerted Action" study. J Am Soc Nephrol, 2003. 14(10): p. 2603-10.

4.              Jais, J.P., et al., X-linked Alport syndrome: natural history in 195 families and genotype- phenotype correlations in males. J Am Soc Nephrol, 2000. 11(4): p. 649-57.

5.              Gross, O., et al., Meta-analysis of genotype-phenotype correlation in X-linked Alport syndrome: impact on clinical counselling. Nephrol Dial Transplant, 2002. 17(7): p. 1218-27.

6.              Hashimura, Y., et al., Milder clinical aspects of X-linked Alport syndrome in men positive for the collagen IV alpha5 chain. Kidney Int, 2013.

7.              Pieri, M., et al., Evidence for Activation of the Unfolded Protein Response in Collagen IV Nephropathies. J Am Soc Nephrol, 2013.

8.              Boot-Handford, R.P. and M.D. Briggs, The unfolded protein response and its relevance to connective tissue diseases. Cell Tissue Res, 2010. 339(1): p. 197-211.

9.              Rajpar, M.H., et al., Targeted induction of endoplasmic reticulum stress induces cartilage pathology. PLoS Genet, 2009. 5(10): p. e1000691.

10.           Chen, Y.M., et al., Laminin beta2 gene missense mutation produces endoplasmic reticulum stress in podocytes. J Am Soc Nephrol, 2013. 24(8): p. 1223-33.

11.           Kitamura, M., Endoplasmic reticulum stress in the kidney. Clin Exp Nephrol, 2008. 12(5): p. 317-25.

12.           Inagi, R., Endoplasmic reticulum stress as a progression factor for kidney injury. Curr Opin Pharmacol, 2010. 10(2): p. 156-65.

13.           Inagi, R., Endoplasmic reticulum stress in the kidney as a novel mediator of kidney injury. Nephron Exp Nephrol, 2009. 112(1): p. e1-9.

14.           Dickhout, J.G. and J.C. Krepinsky, Endoplasmic reticulum stress and renal disease. Antioxid Redox Signal, 2009. 11(9): p. 2341-52.


[ Modified: Thursday, 1 January 1970, 1:00 AM ]