STAC3 disorder: gene therapy and malignant hyperthermia – STAC3

Wider research context: The adaptor protein STAC3 is essential for skeletal muscle excitation-contraction coupling and establishes two distinct interactions with the voltage sensor of EC coupling CaV1.1. A missense mutation in STAC3, W284S, disrupts one of the interactions with CaV1.1 and causes STAC3 disorder (OMIM # 255995). This rare recessively inherited congenital myopathy, for which no cure or treatment is available, is characterized by severe muscle weakness and susceptibility to malignant hyperthermia (MHS).
Hypotheses and objectives: Because affected patients carry two copies of mutated STAC3, whereas in heterozygous individuals the presence of one functional copy prevents the manifestation of symptoms, we hypothesize that introducing a functional copy of STAC3 to complement the genetic mutation associated with this disorder will alleviate the associated symptoms. Furthermore, we hypothesize that investigating the molecular mechanisms leading to MHS in STAC3 disorder will improve our understanding of not only the pathophysiology of MHS, but also of normal STAC3 function.
Approach: First, we will attempt gene therapy in two STAC3 disorder mouse models, an already available Stac3 cKO and a novel Stac3W280S cKI, with different STAC3 constructs. Secondly, we will investigate the molecular basis of MHS in Stac3W280S cKI fibers and reconstituted double Stac3/CaV1.1 KO myotubes.
Originality and innovation: STAC3 disorder is a debilitating disease for which no cure or treatment is available. Establishing a STAC3 disorder mouse model will allow validation of gene therapy in vivo, a first important step towards clinical trial. Additionally, investigating the molecular determinants of how STAC3 disorder causes MHS will further elucidate both the genetic and molecular factors contributing to malignant hyperthermia and STAC3 function in skeletal muscle excitation-contraction coupling. Finally, combining our expertise in both cell culture (Austria) and in vivo models (France) will allow us to bridge the gap between cellular mechanisms and whole organism responses, providing a more comprehensive perspective on the STAC3 disorder and MHS pathophysiology.
Primary researchers involved: Austria. The proposed work will be carried out by the applicant (M. Campiglio), a postdoc and a technical assistant. France: The proposed work will be carried out by the applicants (J. Laporte and J. Böhm), a postdoc and a part-time (50%) technical assistant.