A glycine substitution in the collagenous domain of Col4a3 in mice recapitulates late onset Alport syndrome

Odiatis, Christoforos; Savva, Isavella; Pieri, Myrtani; Ioannou, Pavlos; Petrou, Petros; Papagregoriou, Gregory; Antoniadou, Kyriaki I.; Makrides, Neoklis; Stefanou, Charalambos; Ljubanović, Danica Galešić; Νικολάου, Γεώργιος; Borza, Dorin-Bogdan; Stylianou, Kostas; Groß, Oliver; Deltas, Constantinos

doi:10.1016/j.mbplus.2020.100053

Cited by 5 publications

(13 citation statements)

References 80 publications

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“…A knock-in mouse model and the a345 hexamer as a focal point in glomerular basement membrane function Several mouse models of Alport syndrome have been studied over the last 25 years. These include knockout mice for Col4a3, Col4a4, and Co14a5 [10][11][12][13][14], harboring variants that eliminate the a345 scaffold from the GBM function, as well as two models that incorporate defective scaffolds [15,16]. However, the phenotypes in the latter mouse models were attributed to reduced amounts or proteolytic cleavage of a345.…”

Section: Breakthroughs In the Pathobiology Of The Collagen IV A345 Sc...mentioning

confidence: 99%

Prospective collagen IVα345 therapies for Alport syndrome

Boudko

Pokidysheva

Hudson

2022

Current Opinion in Nephrology &Amp; Hypertension

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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 recently for development of therapies that target different stages of production and assembly of the collagen IVα345 scaffold in the GBM. These approaches are based on (1) recent advances in technologies allowing to decipher pathogenic mechanisms that underlie scaffold assembly and dysfunction, (2) development of DNA editing tools for gene therapy, (3) RNA splicing interference, and (4) control of mRNA translation.SummaryThere is a growing confidence that these approaches will ultimately provide cure for Alport patients. The development of therapy will be accelerated by studies that provide a deeper understanding of mechanisms that underlie folding, assembly, and function of the collagen IVα345 scaffold.

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Section: Breakthroughs In the Pathobiology Of The Collagen IV A345 Sc...mentioning

confidence: 99%

Prospective collagen IVα345 therapies for Alport syndrome

Boudko

Pokidysheva

Hudson

2022

Current Opinion in Nephrology &Amp; Hypertension

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“…The compound heterozygous mouse was generated by crossing the knockin mouse with the previously established knockout mouse, Col4a3 tm1Dec/J . Here we present in detail only the phenotype of the homozygous knockin ( Col4a3 p.G1332E ) [ 22 , 23 ]. The compound heterozygous mouse has a similar phenotype, while the heterozygous presents TBMN with a reduced life span [ 22 ].…”

Section: Mouse Models For Alport Syndromementioning

confidence: 99%

“…Here we present in detail only the phenotype of the homozygous knockin ( Col4a3 p.G1332E ) [ 22 , 23 ]. The compound heterozygous mouse has a similar phenotype, while the heterozygous presents TBMN with a reduced life span [ 22 ].…”

Section: Mouse Models For Alport Syndromementioning

confidence: 99%

“…All three missense models ( Col4a3 p.G1332E ) are also characterized by an extended lifespan with mean survival time in homozygosity of 15.1 months (n = 31), in heterozygosity of 17.9 months and in compound heterozygosity of 16.07 months while wild-type mice in this study lived on average for 22.7 months (n = 23) in a mixed 129X1/SvJ—C57BL/6J background (initially in C57BL/6J, then backcrossed in 129X1/SvJ for five generations) [ 22 ]. The same mutation on the C57BL/6J background has not been studied in detail, but apparently, it does not significantly affect the mouse lifespan (Deltas C et al, unpublished results).…”

Section: Comparison Of Lifespanmentioning

confidence: 99%

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A Comparative Presentation of Mouse Models That Recapitulate Most Features of Alport Syndrome

Nikolaou

Deltas

2022

Genes

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Alport syndrome is a hereditary kidney disease caused by mutations in the three genes encoding for collagen IV: COL4A3, COL4A4, and COL4A5. Several mouse models have been created for the study of this disease with variable phenotypic outcomes. This review is an up-to-date presentation of the current mouse models existing in the literature with a detailed comparison of the phenotypic features characterizing each model. Although in humans it is primarily a glomerulopathy, data suggest that in some mouse models, the initial symptoms appear in the tubule-interstitial region rather than the glomerulus. Additionally, in some other models, the severity of disease in the tubule-interstitial region is affected by the genetic background. In conclusion, the phenotypic spectrum of each model appears to be affected by the model’s genetic background, the position of the genetic alteration within the gene, and the type of the genetic alteration. Despite these disparities, mouse models recapitulate with relatively high fidelity several features of the human disease, which makes them useful for studies aimed at better understanding cellular pathomechanisms and for finding new treatments.

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“…The prevalence of classic AS is estimated to be around 1:5000–10,000 live births, and it is considered a rare disease [ 32 ]. These data could change if the information is synthesized, and we begin to classify based on the genetic cause.…”

Section: Introductionmentioning

confidence: 99%

Molecular Basis, Diagnostic Challenges and Therapeutic Approaches of Alport Syndrome: A Primer for Clinicians

Martínez-Pulleiro

García-Murias

Fidalgo-Díaz

et al. 2021

IJMS

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Alport syndrome is a genetic and hereditary disease, caused by mutations in the type IV collagen genes COL4A3, COL4A4 and COL4A5, that affects the glomerular basement membrane of the kidney. It is a rare disease with an underestimated prevalence. Genetic analysis of population cohorts has revealed that it is the second most common inherited kidney disease after polycystic kidney disease. Renal involvement is the main manifestation, although it may have associated extrarenal manifestations such as hearing loss or ocular problems. The degree of expression of the disease changes according to the gene affected and other factors, known or yet to be known. The pathophysiology is not yet fully understood, although some receptors, pathways or molecules are known to be linked to the disease. There is also no specific treatment for Alport syndrome; the most commonly used are renin–angiotensin–aldosterone system inhibitors. In recent years, diagnosis has come a long way, thanks to advances in DNA sequencing technologies such as next-generation sequencing (NGS). Further research at the genetic and molecular levels in the future will complete the partial vision of the pathophysiological mechanism that we have, and will allow us to better understand what is happening and how to solve it.

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A glycine substitution in the collagenous domain of Col4a3 in mice recapitulates late onset Alport syndrome

Cited by 5 publications

References 80 publications

Prospective collagen IVα345 therapies for Alport syndrome

Prospective collagen IVα345 therapies for Alport syndrome

A Comparative Presentation of Mouse Models That Recapitulate Most Features of Alport Syndrome

Molecular Basis, Diagnostic Challenges and Therapeutic Approaches of Alport Syndrome: A Primer for Clinicians

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