Key result
The DSP R451G missense mutation is strongly linked to biventricular arrhythmogenic cardiomyopathy (LOD score 7.65) and promotes disease by increasing the vulnerability of desmoplakin to calpain-mediated degradation.
Why the study?
Arrhythmogenic cardiomyopathy is an inherited disorder with variable genetic etiologies, and the precise molecular pathology of a clinical DSP variant needed to be understood.
Population
A patient with biventricular ACM and an extensive single-family ACM cohort
Design
Translational study with clinical genetics, in vitro patient-derived iPSC models, and in silico simulations
Authors
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May refine genetic counseling in ACM; leaves open calpain inhibition as a therapeutic strategy pending validation.
Effect estimate: LOD score 7.65
Augmented calpain-mediated degradation of desmoplakin represents a shared pathological mechanism for select ACM-linked missense variants, offering a potential new therapeutic target for inherited cardiomyopathies.
Ng et al. (2019) studied Arrhythmogenic cardiomyopathy (ACM) (n=116). DSP R451G mutation vs. Wild-type DSP (mutation-negative family members) was evaluated on Coinheritance of the ACM phenotype and the p.R451G mutation (genetic linkage) (LOD score 7.65). The DSP R451G missense mutation is strongly linked to biventricular arrhythmogenic cardiomyopathy (LOD score 7.65) and promotes disease by increasing the vulnerability of desmoplakin to calpain-mediated degradation.
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