New research grant aims to improve genetic diagnoses in individuals with CAPN3 mutations

Coalition to Cure Calpain 3 (C3) is pleased to announce a research grant has been awarded to Dr. Svetlana Gorokhova, working together with Dr. Marc Bartoli in the Translational Neuromyology Team, Marseille Medical Genetics Institute at Aix Marseille University. The project,“A diagnostic functional test to rule out dominant forms of calpainopathy,” will develop a tool to help identify the inheritance patterns of CAPN3 variants.

Calpainopathy is a form of limb-girdle muscular dystrophy (LGMD) caused by variants in the CAPN3 gene that encodes the protein calpain 3. Most people with calpainopathy have LGMD2A/R1, which is inherited in a recessive pattern. This means that individuals must have two copies of the abnormal gene for LGMD2A/R1, one inherited from the mother and one from the father, to develop. Several recent reports show that less commonly, calpainopathy is inherited in a dominant manner. This is called LGMD1I/D4 and only needs a single copy of the abnormal gene for individuals to develop muscular dystrophy. You can read more about calpainopathy inheritance here.

Since calpainopathy can be inherited in both recessive and dominant ways, it can be challenging to diagnose an individual with limb-girdle weakness who has only one CAPN3 variant identified: should one continue searching for a second variant or conclude that this patient has the dominant form of the disease? Dr. Gorokhova and her colleagues aim to develop a diagnostic functional assay that could answer if a single variant can cause the dominant form of calpainopathy. This test could help individuals with only one CAPN3 variant get a genetic diagnosis much faster, allowing more efficient disease management and possibly facilitating inclusion in future clinical trials.

C3 Scientific Director Dr. Jennifer Levy says, “Many individuals with LGMD2A/R1 symptoms have had only a single CAPN3 variant identified. I am hopeful that Dr. Gorokhova’s assay will help them to receive a confirmed genetic diagnosis and expect the results will shorten the diagnostic odyssey of future calpainopathy patients.”

Dr. Gorokhova shares, “Our team is working at the interface of basic science and clinical diagnostics. We have a long-standing interest in studying the mysterious and still little understood calpain 3 protein, especially due to its role in muscle disease. On the clinical side, we described the first missense variants associated with LGMD1I/D4. While trying to uncover the molecular mechanism of calpain 3 dominant function, we came across a very surprising observation – all calpain 3 molecules carrying the genetic variants identified in LGMD1I/D4 patients behaved in a similar way. Alexandra Salvi, the PhD student working on this project (and now post-doc at UCSF), with the help of engineer Sebastian Courrier, tested many variants in the CAPN3 gene, establishing the base for the new functional assay that will be extremely helpful in diagnosing CAPN3-related muscle disease. This is yet another example of how basic science research can have direct benefit for patient care!”

It is critical that individuals with LGMD get a genetic confirmation of their diagnosis. CLICK HERE to learn more about genetic testing and access a link to a list of resources, including programs that are available at no cost.