A Missense Mutation in DCST2 Causes the Strongman Syndrome

Talita C. Conte1, Martine Tétreault1, Marie-Josée Dicaire1, Rebecca Robertson1, Sylvie Provost2, Najwa Al-Bustani1, Marie-Pierre Dubé2, Véronique Bolduc1, Myriam Srour1,3, Erin K. O’Ferrall4, Jean-Pierre Bouchard5, Gina Ravenscroft6, Russell Hepple7, Tanja Taivassalo7,8, Nigel Laing6,9, Phillipa Lamont9, Jean Mathieu10, Bernard Brais1,10

1. Neurogenetics of motion laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada; 2. Montreal Heart Institute Research Center, Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, 5000 Belanger Street and Université de Montréal, Faculty of Medicine, 2900 chemin de la tour, Montreal, Canada; 3. Montreal Children Hospital-MUHC, McGill University, Montreal, Quebec H3H 1P3, Canada; 4. Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B, Canada; 5. Department of Neurological Sciences, Hôpital de l'Enfant-Jésus, Quebec City, Quebec G1J 1Z4, Canada; 6. Western Australian Institute for Medical Research and the Centre for Medical Research, University of Western Australia, Nedlands, Western Australia 6009, Australia; 7. Department of Kinesiology Centre for Translational Biology, McGill University Health Center, Montreal, Quebec H4A 3J1, Canada; 8. Respiratory and Epidemiology Clinical Research, Unit, Montreal Chest Institute—McGill University, Health Center, Montreal, Quebec H3A 2B4, Canada; 9. Department of Anatomical Pathology, Royal Perth Hospital, Perth, Western Australia 6000, Australia; 10. Cliniques des maladies neuromusculaires, CSSS de Jonquière, Jonquière, Quebec G7H 7K9, Canada

Since old times the human history reveals iconic characters that were popular due to their incredible strength. Muscle mass and strength are variable traits in humans, but little is known about key molecular players influencing these conditions. Loss of function mutations in myostatin are described to cause muscle hypertrophy with increased strength in mammals, however only a single pediatric case has been reported in humans to date. In this study, we describe a new disorder that we call the Strongman Syndrome (SM) in which affected individuals experience incapacitating myalgia, large well-defined muscles, muscle fatigability on repeated contractions, and a personal history of above average strength. Combining linkage analysis and exome sequencing of a large dominant French-Canadian family, we identified a single segregating missense variant predicted to be damaging in DCST2, a gene of unknown function. Transfected DCST2 localizes to the ER, but DCST2 carrying SM mutation is mislocalized. DCST2 is expressed in skeletal muscle and immunofluorescent labeling of the muscle of control individuals showed that DCST2 is in close proximity to SERCA and STIM1. In a patient with SM mutation, DCST2 has the same localization as in the muscle of controls, but it also forms DCST2-enriched punctate structures that are also positive for SERCA. DCST2 BioID analysis revealed that DCST2 might interact with CCDC47 (also known as Calumin), STIM1, and several components of the Endoplasmic Reticulum Complex subunit (EMC); all proteins with important roles in Ca2+ homeostasis in the cell. Preliminary data obtained from calcium assays using myoblasts of a SM patient showed that Store-Operated Calcium Entry (SOCE) might be affected in these cells. We hypothesize that mutated DCST2 in SM cases will modify Ca2+ homeostasis in muscle leading to prolonged intracellular Ca2+ availability and/or store depletion, causing longer contractions in patients which leads first to the muscle hypertrophy, herculean strength, cramps and fatigability and with time to an incapacitating myalgia. The uncovering of DCST2 function is of such importance that it will contribute to a better understanding of pathways important for muscle mass, strength and myalgia, and it may lead to novel targets for the development of new strategies to treat muscle pain, fatigue and weakness in SM, in other neuromuscular diseases and in conditions in which muscle atrophy is present, such as aging.