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Patient mutations linked to arrhythmogenic cardiomyopathy enhance calpain-mediated desmoplakin degradation
Ronald Ng, … , Maegen A. Ackermann, Stuart G. Campbell
Ronald Ng, … , Maegen A. Ackermann, Stuart G. Campbell
Published June 13, 2019
Citation Information: JCI Insight. 2019;4(14):e128643. https://doi.org/10.1172/jci.insight.128643.
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Research Article Cardiology Genetics

Patient mutations linked to arrhythmogenic cardiomyopathy enhance calpain-mediated desmoplakin degradation

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Abstract

Arrhythmogenic cardiomyopathy (ACM) is an inherited disorder with variable genetic etiologies. Here, we focused on understanding the precise molecular pathology of a single clinical variant in DSP, the gene encoding desmoplakin. We initially identified a potentially novel missense desmoplakin variant (p.R451G) in a patient diagnosed with biventricular ACM. An extensive single-family ACM cohort was assembled, revealing a pattern of coinheritance for R451G desmoplakin and the ACM phenotype. An in vitro model system using patient-derived induced pluripotent stem cell lines showed depressed levels of desmoplakin in the absence of abnormal electrical propagation. Molecular dynamics simulations of desmoplakin R451G revealed no overt structural changes, but a significant loss of intramolecular interactions surrounding a putative calpain target site was observed. Protein degradation assays of recombinant desmoplakin R451G confirmed increased calpain vulnerability. In silico screening identified a subset of 3 additional ACM-linked desmoplakin missense mutations with apparent enhanced calpain susceptibility, predictions that were confirmed experimentally. Similar to R451G, these mutations are found in families with biventricular ACM. We conclude that augmented calpain-mediated degradation of desmoplakin represents a shared pathological mechanism for select ACM-linked missense variants. This approach for identifying variants with shared molecular pathologies may represent a powerful new strategy for understanding and treating inherited cardiomyopathies.

Authors

Ronald Ng, Heather Manring, Nikolaos Papoutsidakis, Taylor Albertelli, Nicole Tsai, Claudia J. See, Xia Li, Jinkyu Park, Tyler L. Stevens, Prameela J. Bobbili, Muhammad Riaz, Yongming Ren, Christopher E. Stoddard, Paul M.L. Janssen, T. Jared Bunch, Stephen P. Hall, Ying-Chun Lo, Daniel L. Jacoby, Yibing Qyang, Nathan Wright, Maegen A. Ackermann, Stuart G. Campbell

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Figure 2

Significant loss of desmoplakin and connexin-43 at the intercalated discs in an R451G-positive patient with clinical ACM diagnosis.

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Significant loss of desmoplakin and connexin-43 at the intercalated disc...
(A) Representative immunofluorescence images from a donor control (OSU 652849) and patient III-26, who carried DSP R451G and was clinically diagnosed with ACM. Left ventricular tissue was stained with antibodies for desmoplakin (left), connexin-43 (middle), or plakoglobin (right). Tissues were costained with an antibody for N-cadherin (green), identifying intercalated discs. Scale bar: 40 μm. (B) Mander’s colocalization analysis of selected protein overlap with N-cadherin at intercalated disks. Individual III-26 had significantly lower amounts of desmoplakin (n = 42 control and n = 49 patient) and connexin-43 (n = 50 control and n = 60 patient) at intercalated discs as compared with donor controls. There was no significant loss of plakoglobin at the intercalated disk (n = 40 control and n = 37 patient). *P < 0.0001 using 2-tailed unpaired t test with Bonferroni correction. Error bars represent SEM.

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