C3 is excited to share that a research grant has been awarded to Dr. Svetlana Gorokhova and Dr. Marc Bartoli, Translational Neuromyology Team, Marseille Medical Genetics Institute at Aix Marseille University. The project, “Optimizing the functional assay to identify novel CAPN3 variants responsible for the dominant form of calpainopathy,” will develop a tool to help identify the inheritance patterns of CAPN3 variants.
Genetic diagnosis of calpainopathy can be challenging
Calpainopathy is a muscle disease caused by pathogenic variants (i.e. mutations) in the CAPN3 gene. Initially, this disorder was considered to be exclusively recessive – two pathogenic CAPN3 variants (one inherited from patient’s mother and one from patient’s father) had to be identified in order to establish the genetic diagnosis of LGMD2A/R1. More recently, a dominant form of calpainopathy has been described (LGMDD4). Patients affected by LGMDD4 carry only one pathogenic CAPN3 variant. You can read more about calpainopathy inheritance here. The existence of both dominant and recessive forms of calpainopathy makes the genetic diagnosis highly challenging. If only one CAPN3 variant is identified by a genetic test, should one continue searching for the second variant or conclude that this patient has a dominant form of disease? Do certain variants cause only recessive or only dominant forms?
A new assay to analyze CAPN3 variants
Dr. Gorokhova’s early data suggest that there are two types of pathogenic CAPN3 variants – those that are only observed in recessive cases (“AR-only variants”) and those that are detected in both dominant and recessive cases (“AD/AR variants”). With the support of a C3 research grant, her lab recently developed an assay that can distinguish these two types of CAPN3 variants, thus making genetic diagnosis much easier. However, due to the unstable nature of the calpain-3 protein, the assay cannot be directly implemented in the diagnostic hospital setting. The current project implements several significant improvements to the original assay that will make it much more robust and easier to interpret. The research team will also use a novel sophisticated data mining approach to identify new variants that could potentially cause LGMDD4, and will then use the optimized assay to analyze these variants. The proposed optimization of the assay and the discovery of new pathogenic AD/AR variants will help calpainopathy patients get a genetic diagnosis much faster, thus allowing more efficient management of their clinical care. Moreover, a systematic analysis of all AD/AR variants will also provide insights into the molecular mechanism of dominance in calpainopathy, which is key to advancing the design of new therapies.
Many individuals within the calpainopathy community have had only a single CAPN3 variant identified. I am hopeful that Dr. Gorokhova’s work will help them to receive a confirmed genetic diagnosis and expect the results will shorten the diagnostic odyssey of future patients. - Jennifer Levy, C3 Scientific DirectorThis project gives us the opportunity to better understand how different CAPN3 variants behave. By refining our assay and expanding the catalog of variants associated with dominant disease, we hope to reduce uncertainty for patients and provide a definitive diagnosis faster. - Dr. Gorokhova