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Development and Validation of a Disability Severity Index for Charcot-Marie-Tooth Disease (CMT) - INC 6604

ABSTRACT: Development and Validation of a Disability Severity Index for Charcot-Marie-Tooth Disease (CMT) - INC 6604

PROVIDER: PRJNA374388 | ENA |

REPOSITORIES: ENA

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Transcriptional dysregulation by a nucleus-localized aminoacyl-tRNA synthetase is associated with Charcot-Marie-Tooth neuropathy

Project description:Charcot-Marie-Tooth disease (CMT) is a length-dependent peripheral neuropathy. The aminoacyl-tRNA synthetases constitute the largest protein family implicated in CMT. Aminoacyl-tRNA synthetases are predominantly cytoplasmic, but are also present in the nucleus. Here we show that a nuclear function of tyrosyl-tRNA synthetase (TyrRS) is implicated in a Drosophila model of CMT. CMT-causing mutations in TyrRS induce unique conformational changes, which confer capacity for aberrant interactions with transcriptional regulators in the nucleus, leading to transcription factor E2F1 hyperactivation. Using neuronal tissues, we reveal a broad transcriptional regulation network associated with wild-type TyrRS expression, which is disturbed when a CMT-mutant is expressed. Pharmacological inhibition of TyrRS nuclear entry with embelin reduces, whereas genetic nuclear exclusion of mutant TyrRS prevents hallmark phenotypes of CMT in the Drosophila model. These data highlight that this translation factor may contribute to transcriptional regulation in neurons, and suggest a therapeutic target for CMT.

2019-10-01 | GSE125311 | GEO

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Genetics of CMT - Modifiers of CMT1A, New Causes of CMT - INC 6602

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Histidine supplementation can escalate or rescue HARS deficiency in a Charcot Marie Tooth Disease model

Project description:Aminoacyl-tRNA synthetases (ARSs) are essential enzymes responsible for charging amino acids onto cognate tRNAs during protein synthesis¬. In histidyl-tRNA synthetase (HARS), autosomal dominant mutations in the HARS catalytic domain are associated with Charcot Marie Tooth Disease Type 2W (CMT2W), while anticodon-binding domain mutations cause Usher Syndrome Type IIIB (USH3B). We use yeast as a model system to study disease-causing HARS mutations (V133F, V155G, Y330C, S356N) associated with CMT2W, and Y454S, associated with USH3B. All human HARS variants complemented genomic deletion of the yeast ortholog HTS1 at high expression levels. CMT2W associated mutations, but not Y454S, result in reduced growth. HARS V155G and S356N cause accumulation of insoluble proteins and mistranslation in yeast, and the growth defect of these mutants was rescued by histidine addition to the growth media, restoring the soluble proteome. V133F and Y330C, on the other hand, lead to decreased HARS abundance. Histidine supplementation further reduced viability in yeast expressing V133F and Y330C, and lead to insoluble protein accumulation, indicating histidine toxicity associated with these mutants. Because histidine is in clinical trials as treatment for USH3B, our data will inform future treatment options for these as well as CMT patients, where histidine supplementation may either have a toxic or compensating effect dependingon the nature of the causative HARS variant.

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Development of CMTPeds Scale for Children with CMT - INC 6603

Project description:Development of CMTPeds Scale for Children with CMT - INC 6603

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Project description:Development of CMTPeds Scale for Children with CMT - INC 6603

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Project description:We have generated CRISPR edited versions of hESC line MShef11 to produce MFN2 R94Q/+ and MFN2 R94Q/R94Q lines as a model for Charcot Marie Tooth Disease (CMT) 2A. This were differentiated to limb innervating motor neurons, the predominantly affected cell time in CMT2A and RNA was examined to investigate differences in cell lines.

2022-07-28 | E-MTAB-10831 | biostudies-arrayexpress

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