Arrhythmogenic right ventricular cardiomyopathy in Boxer dogs is associated with calstabin2 deficiency.
OBJECTIVE
To examine the presence and effect of calstabin2-deficiency in Boxer dogs with arrhythmogenic right ventricular cardiomyopathy (ARVC).


METHODS
Thirteen Boxer dogs with ARVC.


METHODS
Tissue samples were collected for histopathology, oligonucleotide microarray, PCR, immunoelectrophoresis, ryanodine channel immunoprecipitation and single-channel recordings, and calstabin2 DNA sequencing.


RESULTS
In cardiomyopathic Boxer dogs, myocardial calstabin2 mRNA and protein were significantly decreased as compared to healthy control dogs (calstabin2 protein normalized to tetrameric cardiac ryanodine receptor (RyR2) complex: affected, 0.51+/-0.04; control, 3.81+/-0.22; P<0.0001). Calstabin2 deficiency in diseased dog hearts was associated with a significantly increased open probability of single RyR2 channels indicating intracellular Ca(2+) leak. PCR-based sequencing of the promoter, exonic and splice site regions of the canine calstabin2 gene did not identify any causative mutations.


CONCLUSIONS
Calstabin2 deficiency is a potential mechanism of Ca(2+) leak-induced ventricular arrhythmias and heart disease in Boxer dogs with ARVC.
Oyama
Mark A
MA
University of Pennsylvania, Philadelphia, PA, USA, USA. maoyama@vet.upenn.edu
Reiken
Steve
S
Lehnart
Stephan E
SE
Chittur
Sridar V
SV
Meurs
Kathryn M
KM
Stern
Joshua
J
Marks
Andrew R
AR
D000818:Animals; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000662:veterinary*; D001483:Base Sequence; D015153:Blotting, Western / Q000662:veterinary; D001947:Breeding; D002118:Calcium / Q000378:metabolism*; D016022:Case-Control Studies; D004283:Dog Diseases / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D004285:Dogs; D005260:Female; D008297:Male; D046228:Microarray Analysis / Q000662:veterinary; D016133:Polymerase Chain Reaction / Q000662:veterinary; D012333:RNA, Messenger / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins / Q000172:deficiency* / Q000235:genetics
D012333:RNA, Messenger; D019837:Ryanodine Receptor Calcium Release Channel; D022021:Tacrolimus Binding Proteins; D002118:Calcium