Key result
LMNA Q517X variant reduces peak Na+ current ~63% via Nav1.5 downregulation, which colchicine rescues.
Why the study?
The pathogenic mechanisms of the LMNA nonsense variant Q517X, identified in patients with severe arrhythmogenic cardiomyopathy and sudden death, were not established.
Effect estimate: 63% reduction
p-value: p=<0.001
The LMNA Q517X variant causes hyper-polymerization of tubulin and downregulation of Nav1.5, leading to abnormal electrical properties in cardiomyocytes that can be rescued by colchicine.
LMNA Q517X sodium current reduction may be colchicine-responsive in models; hypothesis-generating for microtubule inhibition in lamin cardiomyopathies.
In this work, we studied an lmna nonsense mutation encoding for the C-terminally truncated Lamin A/C (LMNA) variant Q517X, which was described in patients affected by a severe arrhythmogenic cardiomyopathy with history of sudden death. We found that LMNA Q517X stably expressed in HL-1 cardiomyocytes abnormally aggregates at the nuclear envelope and within the nucleoplasm. Whole-cell patch clamp experiments showed that LMNA Q517X-expressing cardiomyocytes generated action potentials with reduced amplitude, overshoot, upstroke velocity and diastolic potential compared with LMNA WT-expressing cardiomyocytes. Moreover, the unique features of these cardiomyocytes were 1) hyper-polymerized tubulin network, 2) upregulated acetylated α-tubulin, and 3) cell surface Nav1.5 downregulation. These findings pointed the light on the role of tubulin and Nav1.5 channel in the abnormal electrical properties of LMNA Q517X-expressing cardiomyocytes. When expressed in HEK293 with Nav1.5 and its β1 subunit, LMNA Q517X reduced the peak Na + current (I Na ) up to 63% with a shift toward positive potentials in the activation curve of the channel. Of note, both AP properties in cardiomyocytes and Nav1.5 kinetics in HEK293 cells were rescued in LMNA Q517X-expressing cells upon treatment with colchicine, an FDA-approved inhibitor of tubulin assembly. In conclusion, LMNA Q517X expression is associated with hyper-polymerization and hyper-acetylation of tubulin network with concomitant downregulation of Nav1.5 cell expression and activity, thus revealing 1) new mechanisms by which LMNA may regulate channels at the cell surface in cardiomyocytes and 2) new pathomechanisms and therapeutic targets in cardiac laminopathies.
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Zio et al. (2022) studied Arrhythmogenic cardiomyopathy (n=3). Colchicine (in vitro) vs. Untreated cells was evaluated on Peak Na+ current (INa) (63% reduction, p=<0.001). Expression of the pathogenic LMNA Q517X variant reduced peak Na+ current by up to 63% and downregulated cell surface Nav1.5, which was rescued by treatment with the microtubule inhibitor colchicine.
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