Characterization of pathological pathways activated in muscles of patients with congenital myopathies with disturbed Ca2+ homeostasis
Prof. Susan Treves, University of Basel
Abstract (Lay summary see below)
Congenital myopathies constitute a genetically and phenotypically broad spectrum of disorders clinically characterized by muscle weakness and atrophy, joint contractures, spinal deformities and variable cardiorespiratory involvement.
Historically, these disorders have been defined by their most predominant histopathological features namely, Central Core Disease, Multi-minicore Disease, Nemaline Myopathy, Centronuclear disease and Congenital Fibre Type Disproportion. Their severe complications require patients to receive continual medical attention, resulting in a substantial individual, familial and social disease burden. Each congenital myopathy can be caused by mutations in more than one gene and mutations in the same gene can cause different pathological phenotypes. In the past decade advances in genomics have revealed that many patients carry mutations in genes encoding proteins directly involved in Ca2+ homeostasis; nevertheless it has also become apparent that many patients harbour mutations in genes encoding for proteins not directly involved in Ca2+ regulation such as SEPN1, MTM1 and KBTBD13. More detailed investigations into the latter group of patients have nevertheless revealed that muscles from such patients show profound alterations of calcium regulation and that these may be the cause of the profound muscle weakness. Such findings highlight the fact that the link between the primary effect(s) of the mutation(s) and the secondary changes in Ca2+ homeostasis is still missing.
The overall aim of this project is to identify such a link. We hypothesise that common pathophysiological pathways are activated in muscles of patients with different congenital myopathies who share as a common feature disturbed Ca2+ homeostasis. In such patients muscle function is severely disturbed not only because of a direct effect of the mutations on protein function, but also because the presence of mutations leads to the activation of secondary pathogenic events which result in the transcriptional down-regulation of muscle specific genes involved in excitation-contraction coupling. The identification of a common molecular pathway downstream from the primary mutation is critical in order to develop therapeutical strategies aimed at improving muscle function and thus the quality of life of these patients
Lay summary
Caratterizzazione dei meccanismi patologici attivati nei muscoli di pazienti affetti da miopatie congenite caratterizzate da alterazioni dell’omeostasi del Ca2+ intracellulare.
Le miopatie congenite comprendono un ampio spettro di malattie fenotipicamente e genotipicamente diverse, caratterizzate da debolezza muscolare, atrofia, contratture articolari, scoliosi con la presenza o l’assenza di coinvolgimento cardiorespiratorio. Storicamente queste malattie sono state definite dalle loro caratteristiche istopatologiche come ad esempio, la malattia Central Core, la malattia Multi-minicore, la miopatia Nemaline, la malattia Centronuclear etc. Ogni malattia congenita può essere causata da mutazioni in più geni e mutazioni all’interno dello stesso gene possono causare malattie fenotipicamente e patologicamente diverse. Negli ultimi anni avanzamenti nelle metodiche di sequenziamento del DNA hanno dimostrato che molti pazienti affetti da malattie congenite muscolari hanno mutazioni nei geni codificanti proteine coinvolte nell’omeostasi del calcio. Tuttavia si è anche scoperto che una parte dei pazienti è portatore di mutazioni in geni codificanti proteine non direttamente coinvolte nell’omeostasi del calcio come ad esempio SEPN1, MTM1 e KBTBD13. Ricerche più approfondite hanno pero dimostrato che i muscoli di questi ultimi pazienti mostrano comunque cambiamenti nella regolazione del Ca2+ intracellulare e che questi cambiamenti nell’omeostasi del calcio potrebbero essere la causa della debolezza muscolare. Questi risultati evidenziano anche il fatto che manca ancora un nesso tra l’effetto primario della mutazione e i cambiamenti secondari nell’omeostasi del Ca2+.
Lo scopo principale di questo progetto è di identificare questo nesso. La nostra ipotesi di base è che meccanismi patologici comuni sono attivati nei muscoli di pazienti affetti d miopatie congenite che hanno come caratteristica un’alterazione dell’omeostasi intracellulare del Ca2+. In questi pazienti la funzionalità muscolare è disturbata non solo perché le mutazioni hanno un effetto sulla funzionalità proteica, ma anche perché la presenza di mutazioni causa l’attivazione di eventi patologici secondari, che portano alla diminuita espressione di geni muscolo-specifici che sono coinvolti nell’eccitazione-contrazione. L’identificazione di questi pathways molecolari a valle della mutazione primaria, è fondamentale al fine di sviluppare terapia farmacologiche mirate a migliorare la funzionalità muscolare e dunque la qualità della vita di questi pazienti.
Projekte
- Neue Forschungsprojekte ab 2024
- Die Bedeutung und die Erfolge der Forschung
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