A deregulated stress response underlies distinct INF2 associated disease profiles
A deregulated stress response underlies distinct INF2 associated disease profiles
Abstract Monogenic diseases provide favorable opportunities to elucidate the molecular mechanisms 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. Here we systematically characterize a large panel (>50) of autosomal dominant mutants of the actin regulator inverted formin 2 (INF2) that have been reported to cause the podocytic kidney disease focal segmental glomerulosclerosis (FSGS) and the neurological disorder Charcot Marie-Tooth disease (CMT). We found that INF2 mutations lead to deregulated activation of the formin and a constitutive stress response in cultured cells, primary patient cells and Drosophila nephrocytes. Using quantitative live-cell imaging we were able to identify distinct subsets of INF2 variants that exhibit varying degrees of activation. Furthermore, we could clearly distinguish between INF2 mutations that were linked exclusively to FSGS from those that caused a combination of FSGS and CMT. Our results indicate that cellular profiling of disease-associated mutations can contribute substantially to sequence-based phenotype predictions.
Krahn M.P.、Bayraktar S.、Karli K.、Janning A.、Struk T.、Halbritter J.、Michgehl U.、Schuberth C.E.、Wedlich-S?ldner R.、Nehrig J.、Menis E.、Pavenst?dt H.P.
Medical Cell Biology, Medical Clinic D, University Hospital M¨1nsterInstitute of Cell Dynamics and Imaging, University of M¨1nster||Internal Medicine D, University Hospital M¨1nsterMedical Cell Biology, Medical Clinic D, University Hospital M¨1nsterInstitute of Cell Dynamics and Imaging, University of M¨1nsterInternal Medicine D, University Hospital M¨1nsterDivision of Nephrology, University of LeipzigInternal Medicine D, University Hospital M¨1nsterInstitute of Cell Dynamics and Imaging, University of M¨1nsterInstitute of Cell Dynamics and Imaging, University of M¨1nsterInstitute of Cell Dynamics and Imaging, University of M¨1nsterInstitute of Cell Dynamics and Imaging, University of M¨1nsterInternal Medicine D, University Hospital M¨1nster
基础医学分子生物学遗传学
Krahn M.P.,Bayraktar S.,Karli K.,Janning A.,Struk T.,Halbritter J.,Michgehl U.,Schuberth C.E.,Wedlich-S?ldner R.,Nehrig J.,Menis E.,Pavenst?dt H.P..A deregulated stress response underlies distinct INF2 associated disease profiles[EB/OL].(2025-03-28)[2025-04-28].https://www.biorxiv.org/content/10.1101/838086.点此复制
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