The Toxic Effect of L115f Desmin Mutant in Cardiac Conduction System

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details


The recent exponential increase in human genetic studies due to the advances of next generation sequencing has generated unprecedented numbers of new gene variants. Determining which of these are causative of human disease is a major challenge. Recently, we used trio-based whole-exome sequencing to study a Chinese family with multiple family members affected by cardiac conduction disease (CCD), and identified a heterozygous missense mutation (c.343C>T, p.Leu115Phe) in the desmin (DES) gene as the most likely candidate causal mutation for the development of CCD in this family. Though, we have proved its pathogenicity in desmin protein aggregation by expressing the mutation both in a cellular model and a CRISPR/CAS9 knock-in (KI) mouse model. Whether the desL114F KI mice recapitulate the human CCD phenotype and the pathogenic mechanism underlying the association between the DES mutations and CCD remains unclear. In this project, we will investigate whether the desL114F KI mice recapitulate the phenotype of human CCD or desminopathy by cardiac phenotyping including clinical, electrophysiological, molecular, immunohistochemistry and electronic microscopy analysis. We will explore the molecular mechanism underlying the association between the desL114F and CCD by determining whether desL114F can cause further changes in the subcellular localization and turnover of direct desmin-binding partners, subsequent cell apoptosis in the cardiac conduction system, the loss of desmin-dependent gene regulatory function or the deregulation of expression and function of ion channels and conduction genes. We expect this project will help understand the underlying mechanism of desminopathy-related cardiac remodeling and arrhythmogenesis.

Project IDs

Project ID:PC10907-0932
External Project ID:MOST109-2314-B182-055
Effective start/end date01/08/2031/07/21


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