| Yazarlar |
Samet Bayraktar
University of Münster, Germany |
|
Julian Nehrig
University of Münster, Germany |
|
Ekaterina Menis
University of Münster, Germany |
Dr. Öğr. Üyesi Kevser KARLI
Kastamonu Üniversitesi, Türkiye |
|
Annette Janning
University of Münster, Germany |
|
Thaddäus Struk
Universitätsklinikum Münster, Germany |
|
Jan Halbritter
Universität Leipzig, Germany |
|
Ulf Michgehl
Universitätsklinikum Münster, Germany |
|
Michael P. Krahn
Universitätsklinikum Münster, Germany |
|
Christian E. Schuberth
University of Münster, Germany |
|
Hermann Pavenstädt
Universitätsklinikum Münster, Germany |
|
Roland Wedlich-Söldner
University of Münster, Germany |
| Özet |
| Background: Monogenic diseases provide favorable opportunities to elucidate the molecularmechanisms of disease progression and improve medical diagnostics. However, the complex interplay between genetic and environmental factors in disease etiologies makes it difficult to discern the mechanistic links between different alleles of a single locus and their associated pathophysiologies. Inverted formin 2 (INF2), an actin regulator, mediates a stress response-calcium mediated actin reset, or CaAR-that reorganizes the actin cytoskeleton of mammalian cells in response to calcium influx. It has been linked to the podocytic kidney disease focal segemental glomerulosclerosis (FSGS), as well as to cases of the neurologic disorder Charcot-Marie-Tooth disease that are accompanied by nephropathy, mostly FSGS. Methods: We used a combination of quantitative live cell imaging and validation in primary patient cells and Drosophila nephrocytes to systematically characterize a large panel of.50 autosomal dominant INF2 mutants that have been reported to cause either FSGS alone or with Charcot-Marie-Tooth disease. Results: We found that INF2 mutations lead to deregulated activation of formin and a constitutive stress response in cultured cells, primary patient cells, and Drosophila nephrocytes. We were able to clearly distinguish between INF2 mutations that were linked exclusively to FSGS from those that caused a combination of FSGS and Charcot-Marie-Tooth disease. Furthermore, we were able to identify distinct subsets of INF2 variants that exhibit varying degrees of activation. Conclusions: Our results suggest that CaAR can be used as a sensitive assay for INF2 function and for robust evaluation of diseased-linked variants of formin. More broadly, these findings indicate that cellular profiling of disease-associated mutations has potential tocontribute substantially to sequence-based phenotype predictions. |
| Anahtar Kelimeler |
| Makale Türü | Özgün Makale |
| Makale Alt Türü | SCOPUS dergilerinde yayımlanan tam makale |
| Dergi Adı | Journal of the American Society of Nephrology |
| Dergi ISSN | 1046-6673 |
| Makale Dili | İngilizce |
| Basım Tarihi | 06-2020 |
| Cilt No | 31 |
| Sayı | 6 |
| Sayfalar | 1296 / 1313 |
| Doi Numarası | 10.1681/ASN.2019111174 |
| Atıf Sayıları | |
| SCOPUS | 23 |
