دورية أكاديمية
DAAM2 variants cause nephrotic syndrome via actin dysregulation.
| العنوان: | DAAM2 variants cause nephrotic syndrome via actin dysregulation. |
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| المؤلفون: | Schneider, R., Deutsch, K., Hoeprich, G.J., Marquez, J., Hermle, T., Braun, D.A., Seltzsam, S., Kitzler, T.M., Mao, Y., Buerger, F., Majmundar, A.J., Onuchic-Whitford, A.C., Kolvenbach, C.M., Schierbaum, L., Schneider, S., Halawi, A.A., Nakayama, M., Mann, N., Connaughton, D.M., Klämbt, V., Wagner, M., Riedhammer, K.M., Renders, L., Katsura, Y., Thumkeo, D., Soliman, N.A., Mane, S., Lifton, R.P., Shril, S., Khokha, M.K., Hoefele, J., Goode, B.L., Hildebrandt, F. |
| المصدر: | Am. J. Hum. Genet. 107, 1113-1128 (2020) |
| بيانات النشر: | Cell Press |
| سنة النشر: | 2020 |
| المجموعة: | PuSH - Publikationsserver des Helmholtz Zentrums München |
| مصطلحات موضوعية: | Actin Cytoskeleton, Daam2, Formins, Monogenic Kidney Diseases, Podocytopathy, Steroid-resistant Nephrotic Syndrome |
| الوصف: | The discovery of >60 monogenic causes of nephrotic syndrome (NS) has revealed a central role for the actin regulators RhoA/Rac1/Cdc42 and their effectors, including the formin INF2. By whole-exome sequencing (WES), we here discovered bi-allelic variants in the formin DAAM2 in four unrelated families with steroid-resistant NS. We show that DAAM2 localizes to the cytoplasm in podocytes and in kidney sections. Further, the variants impair DAAM2-dependent actin remodeling processes: wild-type DAAM2 cDNA, but not cDNA representing missense variants found in individuals with NS, rescued reduced podocyte migration rate (PMR) and restored reduced filopodia formation in shRNA-induced DAAM2-knockdown podocytes. Filopodia restoration was also induced by the formin-activating molecule IMM-01. DAAM2 also co-localizes and co-immunoprecipitates with INF2, which is intriguing since variants in both formins cause NS. Using invitro bulk and TIRF microscopy assays, we find that DAAM2 variants alter actin assembly activities of the formin. In a Xenopus daam2-CRISPR knockout model, we demonstrate actin dysregulation invivo and glomerular maldevelopment that is rescued by WT-DAAM2 mRNA. We conclude that DAAM2 variants are a likely cause of monogenic human SRNS due to actin dysregulation in podocytes. Further, we provide evidence that DAAM2-associated SRNS may be amenable to treatment using actin regulating compounds. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 0002-9297 1537-6605 |
| العلاقة: | info:eu-repo/semantics/altIdentifier/wos/WOS:000596042000007; info:eu-repo/semantics/altIdentifier/isbn/0002-9297; info:eu-repo/semantics/altIdentifier/pissn/0002-9297; info:eu-repo/semanti; https://push-zb.helmholtz-muenchen.de/frontdoor.php?source_opus=60786Test; urn:isbn:0002-9297; urn:issn:0002-9297; urn:issn:1537-6605 |
| DOI: | 10.1016/j.ajhg.2020.11.008 |
| الإتاحة: | https://doi.org/10.1016/j.ajhg.2020.11.008Test https://push-zb.helmholtz-muenchen.de/frontdoor.php?source_opus=60786Test |
| حقوق: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.5018FA2B |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 00029297 15376605 |
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| DOI: | 10.1016/j.ajhg.2020.11.008 |