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Homa Tajsharghi research group

Understanding the pathogenesis of a new group of muscle diseases

The sarcomere is the functional unit of both cardiac and skeletal muscle contraction. Mutations in sarcomeric proteins are known to cause increasing number of different cardiac and skeletal muscle diseases. Dysfunctional mutations in sarcomeric proteins are the important causes of the hypertrophic cardiomyopathies (HCM) and skeletal myopathies. The range of clinical and morphological manifestations in patients with sarcomeric myopathies is wide. Variability in clinical manifestations in patients with HCM ranges from benign course with minimal symptoms to progressive disease and development of heart failure and sudden death. The skeletal myopathies vary in severity from paralysis at birth to mild conditions compatible with normal life span.

 Fig 1. A&B Electron microscopy and schematic illustrations of the sarcomere, the basic contractile unit of muscle, which is a highly ordered structure, composed of the thin and thick filaments (Fig 1A&B). Myosin is the principal protein component of the sarcomeric thick filament. The thin filament is composed of three components in striated muscle, actin, tropomyosin and troponin with the three subunits (troponin I, troponin C and troponin T).

 We have identified and characterized new human muscle diseases caused by mutations in genes encoding sarcomeric proteins. Although many disease genes have been identified and our studies have led to identification of new muscle diseases, the insights in
their pathogenesis and the pathophysiology of the diseases remains obscure. Therefore, the development of genetically engineered models to be able to verify mutations as being pathogenic and to study functional and structural consequences of such mutations is the valuable goal.

We develop disease models for sarcomeric myopathies in Drosophila and use transfected human muscle cells to verify mutations as being pathogenic and to study functional and structural consequences of
such mutations. The research project also integrates molecular, physiological and protein-structure technologies to investigate functional properties of the proteins and to clarify important questions on the

Fig 2. Newly hatched Drosophila larvae that express different  sarcomeric proteins as GFPfusions. Images are of whole larvae (convential microscopy at left and confocal at right) and show the body wall musculature.

molecular mechanisms leading to the phenotypes of the sarcomeric myopathies. Harnessing and integrating genetically engineered models and molecular and physiological technologies would be powerful tools to determine how different mutations affect the structure, stability, and function of protein constituents of sarcomeric filaments. Results from these studies would further our understanding of the mechanism of pathogenesis for each of these diseases. Emerging insights from models of diseases should provide powerful leads for the identification of potential therapies to prevent disease progress.

Group members

Homa Tajsharghi
PhD, Principal investigator, Associate professor/Docent

Saba Abdul-Hussein
MS, PhD student

Malgorzata Pokrzywa
PhD, Post doc

Kate Bramley-Moore
PhD, Post doc

Mehrnaz Ghobadpour
MSc, Lab technician

Sidansvarig: Dan Baeckström|Sidan uppdaterades: 2012-08-28

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