Ion Channel Dysfunctions in Dilated Cardiomyopathy in Limb-Girdle Muscular Dystrophy.

Abstract

BACKGROUND:

Limb-Girdle muscular dystrophies (LGMD) are a heritable group of genetically determined disorders with a primary involvement of the pelvic or shoulder girdle musculature with partially cardiac manifestation, such as dilated cardiomyopathy (DCM) and life-threatening tachyarrhythmia. We report here that human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes from a patient with LGMD2I and DCM associated with recurrent ventricular tachycardia displayed ion channel dysfunction and abnormality of calcium homeostasis.

METHODS:

Dermal fibroblasts obtained from a patient with LGMD2I harboring a fukutin-related protein gene mutation (826C>A; Leu276Ile) and 3 healthy donors were reprogrammed to hiPSCs. The hiPSCs were differentiated into cardiomyocytes and used for biological and electrophysiological studies.

RESULTS:

Compared with hiPSC cardiomyocytes from the healthy donors, the hiPSC cardiomyocytes from the patient exhibited abnormal action potentials characterized by reduced amplitude and upstroke velocity. The peak and late Na channel currents (INa) as well as the peak L-type calcium channel currents were significantly reduced. The expression of SCN5A and CACNA1C was reduced in DCM cardiomyocytes, consistent with reduction of INa and L-type calcium channel currents. In addition, the rapidly activating delayed rectifier potassium current (IKr) was reduced, whereas the transient outward current (Ito) and slowly activating delayed rectifier potassium current (IKs) were similar in DCM and control cardiomyocytes. Finally, a significant reduction of systolic and diastolic intracellular Ca2+ concentrations was detected in DCM cardiomyocytes.

CONCLUSIONS:

This study demonstrates that patient-specific hiPSC cardiomyocytes can recapitulate some phenotypic properties of LGMD2I with DCM and provide a platform for studies on the cardiac events in LGMD.

• Authors: Ibrahim El-Battrawy, Zhihan Zhao, Huan Lan, Xin Li, Gökhan Yücel, Siegfried Lang, Katherine Sattler, Jan-Dierk Schünemann, Wolfram-Hubertus Zimmermann, Lukas Cyganek, Jochen Utikal, Thomas Wieland, Karen Bieback, Ralf Bauer, Antonius Ratte, Regina Pribe-Wolferts, Kleopatra Rapti, Daniel Nowak, Janina Wittig, Dierk Thomas, Patrick Most, Hugo A Katus, Ursula Ravens, Constanze Schmidt, Martin Borggrefe, Xiao-Bo Zhou, Oliver J Müller, Ibrahim Akin
• Journal: Circulation. Genomic and precision medicine (Circ Genom Precis Med) Vol. 11 Issue 3 Pg. e001893 (03 2018) ISSN: 2574-8300 [Electronic] United States
• PMID: 29545480 (Publication Type: Case Reports, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 American Heart Association, Inc.

Chemical References

• CACNA1C protein, human
• Calcium Channels, L-Type
• NAV1.5 Voltage-Gated Sodium Channel
• Proteins
• SCN5A protein, human
• FKRP protein, human
• Pentosyltransferases

Topics

• Action Potentials
• Calcium Channels, L-Type (genetics, metabolism)
• Cardiomyopathy, Dilated (complications, diagnosis, genetics)
• Fibroblasts (cytology, metabolism)
• Humans
• Induced Pluripotent Stem Cells (cytology)
• Male
• Microscopy, Fluorescence
• Middle Aged
• Muscular Dystrophies, Limb-Girdle (complications, diagnosis, genetics)
• Myocytes, Cardiac (cytology, metabolism)
• NAV1.5 Voltage-Gated Sodium Channel (genetics)
• Patch-Clamp Techniques
• Pentosyltransferases
• Phenotype
• Polymorphism, Single Nucleotide
• Proteins (genetics)