Arrhythmogenic right ventricular cardiomyopathy plakophilin-2 mutations disrupt desmosome assembly and stability.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by life-threatening ventricular arrhythmias and fibrofatty replacement of the cardiac tissue. Desmosomes are prominent cell-cell junctions found in a variety of tissues that resist mechanical stress, including the heart, and recruit the intermediate filament cytoskeleton to sites of cell-cell contact. Mutations in several desmosomal components including plakophilin-2 have been identified in ARVC patients; however, the molecular interactions disrupted by plakophilin-2 mutations are currently unknown. To understand the pathological basis of ARVC, the authors analyzed desmosome assembly and stability in epithelial cell lines expressing mutants of plakophilin-2 found in ARVC patients. Mutant plakophilin-2 proteins were unable to disrupt established desmosomes when expressed in an E-cadherin-expressing epithelial cell model; however, they were unable to initiate de novo assembly of desmosomes in an N-cadherin-expressing epithelial cell model. These studies expand our understanding of desmosome assembly and dynamics.
Hall
Chad
C
Department of Oral Biology, University of Nebraska Medical Center College of Dentistry, Lincoln, Nebraska 68583, USA.
Li
Shumin
S
Li
Hong
H
Creason
Valeta
V
Wahl
James K
JK
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics*; D045744:Cell Line, Tumor; D051180:Desmoplakins / Q000378:metabolism; D003896:Desmosomes / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D051191:Plakophilins / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion
D051180:Desmoplakins; C495337:PKP2 protein, human; D051191:Plakophilins; D011993:Recombinant Fusion Proteins