scholarly journals A deregulated stress response underlies distinct INF2 associated disease profiles

2019 ◽  
Author(s):  
S. Bayraktar ◽  
J. Nehrig ◽  
E. Menis ◽  
K. Karli ◽  
A. Janning ◽  
...  
Keyword(s):  
Stress Response ◽  
Molecular Mechanisms ◽  
Cultured Cells ◽  
Medical Diagnostics ◽  
Charcot Marie Tooth Disease ◽  
Monogenic Diseases ◽  
Large Panel ◽  
Genetic And Environmental Factors ◽  
Dominant Mutants ◽  
Tooth Disease

AbstractMonogenic 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.

scholarly journals A Deregulated Stress Response Underlies Distinct INF2-Associated Disease Profiles

2020 ◽  
Vol 31 (6) ◽  
pp. 1296-1313 ◽  
Author(s):  
Samet Bayraktar ◽  
Julian Nehrig ◽  
Ekaterina Menis ◽  
Kevser Karli ◽  
Annette Janning ◽  
...  
Keyword(s):  
Stress Response ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Cultured Cells ◽  
Calcium Influx ◽  
Medical Diagnostics ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Monogenic Diseases ◽  
Tooth Disease

BackgroundMonogenic 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. 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.MethodsWe 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.ResultsWe 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.ConclusionsOur 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 to contribute substantially to sequence-based phenotype predictions.

scholarly journals Neural and Molecular Features on Charcot-Marie-Tooth Disease Plasticity and Therapy

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Paula Juárez ◽  
Francesc Palau
Keyword(s):  
Schwann Cell ◽  
Cell Biology ◽  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Sensory Nerves ◽  
Peripheral Neuropathies ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Molecular Features ◽  
Tooth Disease

In the peripheral nervous system disorders plasticity is related to changes on the axon and Schwann cell biology, and the synaptic formations and connections, which could be also a focus for therapeutic research. Charcot-Marie-Tooth disease (CMT) represents a large group of inherited peripheral neuropathies that involve mainly both motor and sensory nerves and induce muscular atrophy and weakness. Genetic analysis has identified several pathways and molecular mechanisms involving myelin structure and proper nerve myelination, transcriptional regulation, protein turnover, vesicle trafficking, axonal transport and mitochondrial dynamics. These pathogenic mechanisms affect the continuous signaling and dialogue between the Schwann cell and the axon, having as final result the loss of myelin and nerve maintenance; however, some late onset axonal CMT neuropathies are a consequence of Schwann cell specific changes not affecting myelin. Comprehension of molecular pathways involved in Schwann cell-axonal interactions is likely not only to increase the understanding of nerve biology but also to identify the molecular targets and cell pathways to design novel therapeutic approaches for inherited neuropathies but also for most common peripheral neuropathies. These approaches should improve the plasticity of the synaptic connections at the neuromuscular junction and regenerate cell viability based on improving myelin and axon interaction.

scholarly journals Identification of Candidate Genes Associated with Charcot-Marie-Tooth Disease by Network and Pathway Analysis

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Min Zhong ◽  
Qing Luo ◽  
Ting Ye ◽  
XiDan Zhu ◽  
Xiu Chen ◽  
...  
Keyword(s):  
Nervous System ◽  
Candidate Genes ◽  
Peripheral Nervous System ◽  
Molecular Mechanisms ◽  
Clinical Genetic ◽  
Systematic Analysis ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Functional Features ◽  
Tooth Disease

Charcot-Marie-Tooth Disease (CMT) is the most common clinical genetic disease of the peripheral nervous system. Although many studies have focused on elucidating the pathogenesis of CMT, few focuses on achieving a systematic analysis of biology to decode the underlying pathological molecular mechanisms and the mechanism of its disease remains to be elucidated. So our study may provide further useful insights into the molecular mechanisms of CMT based on a systematic bioinformatics analysis. In the current study, by reviewing the literatures deposited in PUBMED, we identified 100 genes genetically related to CMT. Then, the functional features of the CMT-related genes were examined by R software and KOBAS, and the selected biological process crosstalk was visualized with the software Cytoscape. Moreover, CMT specific molecular network analysis was conducted by the Molecular Complex Detection (MCODE) Algorithm. The biological function enrichment analysis suggested that myelin sheath, axon, peripheral nervous system, mitochondrial function, various metabolic processes, and autophagy played important roles in CMT development. Aminoacyl-tRNA biosynthesis, metabolic pathways, and vasopressin-regulated water reabsorption were significantly enriched in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway network, suggesting that these pathways may play key roles in CMT occurrence and development. According to the crosstalk, the biological processes could be roughly divided into a correlative module and two separate modules. MCODE clusters showed that in top 3 clusters, 13 of CMT-related genes were included in the network and 30 candidate genes were discovered which might be potentially related to CMT. The study may help to update the new understanding of the pathogenesis of CMT and expand the potential genes of CMT for further exploration.

scholarly journals Endosomal Targeting of the Phosphoinositide 3-Phosphatase MTMR2 Is Regulated by an N-terminal Phosphorylation Site

2011 ◽  
Vol 286 (18) ◽  
pp. 15841-15853 ◽  
Author(s):  
Norah E. Franklin ◽  
Gregory S. Taylor ◽  
Panayiotis O. Vacratsis
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Molecular Mechanisms ◽  
Tyrosine Phosphatase ◽  
Phosphorylation Site ◽  
Large Protein ◽  
Charcot Marie Tooth Disease ◽  
Lipid Phosphatases ◽  
Sensor Protein ◽  
Endosome Maturation ◽  
Tooth Disease

MTMR2 is a member of the myotubularin family of inositol lipid phosphatases, a large protein-tyrosine phosphatase subgroup that is conserved from yeast to humans. Furthermore, the peripheral neuromuscular disease Charcot-Marie Tooth disease type 4B has been attributed to mutations in the mtmr2 gene. Because the molecular mechanisms regulating MTMR2 have been poorly defined, we investigated whether reversible phosphorylation might regulate MTMR2 function. We used mass spectrometry-based methods to identify a high stoichiometry phosphorylation site on serine 58 of MTMR2. Phosphorylation at Ser58, or a phosphomimetic S58E mutation, markedly decreased MTMR2 localization to endocytic vesicular structures. In contrast, a phosphorylation-deficient MTMR2 mutant (S58A) displayed constitutive localization to early endocytic structures. This localization pattern was accompanied by displacement of a PI(3)P-specific sensor protein and an increase in signal transduction pathways. Thus, MTMR2 phosphorylation is likely to be a critical mechanism by which MTMR2 access to its lipid substrate(s) is temporally and spatially regulated, thereby contributing to the control of downstream endosome maturation events.

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