C3 is pleased to share that a research grant has been awarded to Drs. Ana Töpf, Jordi Diaz-Manera, and Volker Straub at the John Walton Muscular Dystrophy Research Centre at Newcastle University. This project, titled “Understanding the variable expression of dominant calpainopathies,” explores the molecular basis for LGMDD4, also known as dominant calpainopathy.
The Challenges to Reach a Genetic Diagnosis
Mutations in CAPN3 can lead to either recessively inherited calpainopathy (LGMD2A/R1) or dominantly inherited calpainopathy (LGMDD4):
- Recessive Calpainopathy (LGMD2A/R1): For years, this was thought to be the only form. A patient must inherit two copies of the CAPN3 gene, each carrying pathogenic variants – one from each parent – to develop the disease.
- Dominant Calpainopathy (LGMDD4): Recent research has identified a dominant form where a patient only needs one pathogenic variant to be affected.
However, questions remain over which variants can cause LGMDD4. This is further complicated by the observation that some individuals with a single LGMDD4-associated variant do not have any symptoms of calpainopathy.
An Internationally Coordinated Effort
This ambitious project requires a variety of expertise and a sufficient number of case studies. The project is being coordinated and carried out by the Newcastle University team, in collaboration with worldwide clinical colleagues involved in the diagnosis and management of individuals living with calpainopathy. Experts from Spain, Germany, Poland, and Belgium will join Newcastle to collect information from published literature, patient registries, and genomic datasets to characterize individuals carrying dominant CAPN3 variants.
A Path to Understanding
Individuals who carry dominant CAPN3 variants fall into three categories:
- Single dominant CAPN3 variant and experiencing calpainopathy symptoms
- Single dominant CAPN3 variant but without symptoms
- Dominant CAPN3 variant in combination with a second pathogenic CAPN3 variant
Participants in the study will undergo a clinical evaluation and lower limb MRI evaluation to fully characterize the effects of carrying the dominant variant.
Additionally, the group will apply a multi-omics approach, including techniques such as transcriptomics, proteomics, and epigenomics, to look for a possible underlying genetic mechanism to explain why dominant CAPN3 variants do not always lead to symptoms.
“The recent discovery that calpainopathy can be inherited in a dominant manner has raised many questions about how symptoms present in these patients, as well as why some individuals carry a dominant variant but do not have symptoms. The results of this study will deepen our understanding of dominant cases and may improve diagnostics. Further, a better understanding of the genetic mechanisms could lead to the identification of new therapeutic targets,” says Jennifer Levy, Scientific Director, Coalition to Cure Calpain 3
“This project will help clarify which clinical, imaging, and genetic findings truly define dominant calpainopathy, and why some people with CAPN3 variants develop symptoms while others do not. By doing so, we hope to make the diagnostic pathway clearer and more accurate for patients and families affected by suspected calpainopathy,” notes Dr. Ana Töpf, Senior Research Associate John Walton Muscular Dystrophy Research Centre